Agonists of parathyroid hormone 1 and incretin receptors

Abstract

Disclosed are compounds that are parathyroid hormone receptor 1 agonists, and methods useful for preventing or treating osteoporosis, fracture, osteomalacia, arthritis, thrombocytopenia, hypoparathyroidism, hyperphosphatemia or tumoral calcinosis. Also disclosed are agonists of GLP-1R, GCGR, and / or GIPR, and methods of treating various therapeutic indications by administering an effective amount of an agonist of GLP-1R, GCGR, and / or GIPR.

Description

[0001] GPX-02525

[0002] AGONISTS OF PARATHYROID HORMONE 1 AND INCRETIN RECEPTORS CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U. S. Provisional Patent Application Nos. 63 / 907,676, filed October 29, 2025; 63 / 793,948, filed April 24, 2025; 63 / 752,522, filed January 31, 2025; and 63 / 721,146, filed November 15, 2024.

[0003] BACKGROUND

[0004] Regulation of calcium concentration is important to normal function of the gastrointestinal tract, skeletal system, nervous system, muscular nervous system and cardiovascular system. Parathyroid hormone (PTH) synthesis and release is primarily controlled by serum calcium levels.

[0005] Osteoporosis is characterized by bone loss resulting in an increased incidence of fracture. This condition, which is most prevalent in the spine and hip, affects 1 in 3 postmenopausal women, a lesser but significant number of aging men, and is also caused by other conditions including hypogonadism and prolonged glucocorticoid use. Current therapies to treat osteoporosis, such as bisphosphonates, hormone replacement therapy, SERMs and calcitonin, serve to arrest further bone loss by inhibiting bone resorption.

[0006] Although these treatments may slow or even prevent continued bone loss, new bone formation leading to increased bone mass and strength does not occur. Consequently, there is still a need for a therapeutic agent capable of stimulating bone formation. Such a therapeutic agent would be beneficial both to patients who are at risk of developing osteoporosis or who present with established osteoporosis.

[0007] Parathyroid hormone (PTH) is a significant regulator of calcium homeostasis and acts, in part, by mobilizing calcium from the skeleton through increased bone resorption.

[0008] Additionally, pulsatile administration of PTH can stimulate new bone formation, both in laboratory animals and in humans. Thus, there is evidence to suggest that targeting the receptor for PTH with a small molecule agonist mimicking the actions of PTH, would be a suitable approach for generating an anabolic response in bone. PTH elicits its effects by binding and activating a class B, G protein-coupled receptor of the 7 transmembrane superfamily, designated PTH1R. PTH1R activates multiple signaling pathways, but predominantly the adenylyl cyclase / cyclic AMP and the phospholipase C / calcium mobilization pathways.

[0009] - 1 - FH13161920.1 GPX-02525

[0010] The glucagon-like peptide- 1 receptor (GLP-1R) is a receptor protein found on beta cells of the pancreas and on neurons of the brain. It is involved in the control of blood sugar level by enhancing insulin secretion. Glucagon-like peptide- 1 (GLP-1) is a hormone consisting of 30 amino acids. It is released by intestinal L cells when nutrients are consumed. GLP- 1 has multiple effects, including enhancing insulin secretion from pancreatic beta cells in response to glucose, increasing insulin expression, preventing beta-cell apoptosis, promoting the formation of new beta cells, reducing glucagon secretion, slowing down stomach emptying, promoting satiety, and improving glucose disposal in peripheral tissues. GLP-1R is also expressed in the brain, where it is involved in the control of appetite.

[0011] Furthermore, mice that over express GLP-1R display improved memory and learning.

[0012] Due to these diverse effects, there has been significant interest in developing long-lasting agonists of the GLP-1 receptor (GLP-1R) for the treatment of type 2 diabetes and other conditions. Indeed, glucagon-like peptide- 1 receptor agonists gained approval as drugs to treat diabetes and obesity starting in the 2000s.

[0013] The gastric inhibitory polypeptide receptor (GIPR), also known as the glucosedependent insulinotropic polypeptide receptor, is a protein that in humans is encoded by the GIPR gene. GIPR is a member of the class B family of G protein coupled receptors. GIPR is found on beta-cells in the pancreas where it serves as the receptor for the hormone Gastric inhibitory polypeptide (GIP). Gastric inhibitory polypeptide, also called glucose-dependent insulinotropic polypeptide, is a 42-amino acid polypeptide synthesized by K cells of the duodenum and small intestine. It was originally identified as an activity in gut extracts that inhibited gastric acid secretion and gastrin release but subsequently was demonstrated to stimulate insulin release potently in the presence of elevated glucose. The insulinotropic effect on pancreatic islet beta-cells was then recognized to be the principal physiologic action of GIP. Together with glucagon-like peptide- 1, GIP is largely responsible for the secretion of insulin after eating. It is involved in several other facets of the anabolic response.

[0014] The glucagon receptor (GCGR) is a 62 kDa protein that is activated by glucagon and is a member of the class B G-protein coupled family of receptors, coupled to G alpha i, Gs and to a lesser extent G alpha q. Stimulation of the receptor results in the activation of adenylate cyclase and phospholipase C and in increased levels of the secondary messengers intracellular cAMP and calcium. Through interaction with GCGR, glucagon has been shown to increase hepatic glucose output in hypoglycemic state, reduce body weight and appetite, stimulate insulin secretion under certain circumstances and as a key hormone that modulates

[0015] - 2 - FH13161920.1 GPX-02525

[0016] postprandial amino acid metabolism. In humans, the glucagon receptor is encoded by the GCGR gene.

[0017] Inactivating mutation of glucagon receptor in humans causes resistance to glucagon and is associated with pancreatic alpha cell hyperplasia, nesidioblastosis, hyperglucagonemia, and pancreatic neuroendocrine tumors, also known as Mahvash disease. Glucagon receptors are mainly expressed in liver and kidney with lesser amounts found in heart, adipose tissue, spleen, thymus, adrenal glands, pancreas, cerebral cortex, and gastrointestinal tract.

[0018] Accordingly, there is a need in the art to provide small molecule therapeutics that treat or prevent hypoparathyroidism, osteoporosis and related conditions. In particular, there is a need for providing compounds that act as PTH1R agonists.

[0019] Additionally, there is a need in the art to provide small molecule modulators of the GLP-1R, GIPR, and / or GCGR in order to provide treatments for conditions such as diabetes, obesity, liver disease, and heart disease. More particularly, there is a need for GLP-1R / GIPR / GCGR triagonists to treat these conditions, which should be more efficacious compared to currently available GLP-1 agonists.

[0020] SUMMARY

[0021] In certain aspects, provided herein are compounds according to Formula (XXII):

[0022] R4aR5a

[0023] R4b-N N-R5b

[0024] R n i i °

[0025] ° R1

[0026] 2'N~4

[0027]

[0028] R2O (XXII);

[0029] or pharmaceutically acceptable salts thereof;

[0030] wherein:

[0031] R1is hydrogen or (Ci-Ce)alkyl;

[0032] R2is hydrogen or (Ci-Ce)alkyl optionally substituted with one or more substituents selected from hydroxy, (Ci-Ce)alkoxy, halo, cyano, (C3-C8)cycloalkyl and 4- to 7-membered heterocycloalkyl; wherein (C3-Cs)cycloalkyl, 4- to 7-membered heterocycloalkyl are each optionally substituted with one or more substituents selected from halo, (Ci-C6)alkyl,

[0033] - 3 - FH13161920.1 GPX-02525

[0034] hydroxy, (Ci-Ce)alkoxy, (Ci-C6)alkoxy(Ci-C6)alkyl, (Ci-Ce)haloalkyl, (Ci-C6)haloalkoxy, cyano, and N(RC)2;

[0035] R3is (Ci-Ce)alkyl optionally substituted with halo, (C3-Cs)cycloalkyl or phenyl, each of which is optionally substituted with one or more substituents selected from halo, (Ci-Ce)haloalkyl and (Ci-Ce)alkyl;

[0036] R4aand R4bare independently hydrogen, phenyl, N(Rd)2, CON(Rd)2, ORe, (Ci-Ce)alkyl, or (C3-Cs)cycloalkyl; wherein the (Ci-Ce)alkyl is optionally substituted with one or more instances of halo, hydroxy, heterocycloalkyl, phenyl, N(Rd)2, or CON(Rd)2; and R5aand R5bare independently hydrogen, phenyl, N(Rd)2, CON(Rd)2, ORe, or (Ci-Ce)alkyl, wherein the (Ci-Ce)alkyl is optionally substituted with one or more instances of halo, hydroxy, heterocycloalkyl, phenyl, N(Rd)2, or CON(Rd)2; wherein at least one of R4a, R4b, R5a, and R5bis phenyl, N(Rd)2, CON(Rd)2, ORe, or (Ci-C6)alkyl; wherein the (Ci-C6)alkyl is substituted with one or more instances of alkoxy, phenyl, N(Rd)2, or CON(Rd)2;

[0037] Rcis independently for each occurrence hydrogen or (Ci-Ce)alkyl; or two occurrences of Rctaken together with the nitrogen to which they are attached form a 4- to 7-membered heterocycloalkyl;

[0038] Rdis independently for each occurrence hydrogen or (Ci-Ce)alkyl; or two occurrences of Rdtaken together with the nitrogen to which they are attached form a 4- to 7-membered heterocycloalkyl; and

[0039] Reis hydrogen or (Ci-C6)alkyl.

[0040] In certain aspects, provided herein are compounds according to Formula (I):

[0041] R4aR5a

[0042]

[0043] or pharmaceutically acceptable salts thereof;

[0044] wherein:

[0045] R1is hydrogen or (Ci-Ce)alkyl;

[0046] - 4 - FH13161920.1 GPX-02525

[0047] R2is hydrogen or (Ci-Ce)alkyl optionally substituted with one or more substituents selected from hydroxy, (Ci-Ce)alkoxy, halo, cyano, (C3-Cs)cycloalkyl and 4- to 7-membered heterocycloalkyl; wherein (C3-Cs)cycloalkyl, 4- to 7-membered heterocycloalkyl are each optionally substituted with one or more substituents selected from halo, (Ci-Ce)alkyl, hydroxy, (Ci-Ce)alkoxy, (Ci-C6)alkoxy(Ci-C6)alkyl, (Ci-C6)haloalkyl, (Ci-C6)haloalkoxy, cyano, and N(RC)2;

[0048] R3is (Ci-Ce)alkyl optionally substituted with halo, (C3-Cs)cycloalkyl or phenyl, each of which is optionally substituted with one or more substituents selected from halo, (Ci-Ce)haloalkyl and (Ci-Ce)alkyl;

[0049] R4aand R4bare independently hydrogen, phenyl, N(Rd)2, CON(Rd)2, ORe, or (Ci-Ce)alkyl; wherein the (Ci-Ce)alkyl is optionally substituted with one or more instances of halo, hydroxy, heterocycloalkyl, phenyl, N(Rd)2, or CON(Rd)2; and

[0050] R5aand R5bare independently hydrogen, phenyl, N(Rd)2, CON(Rd)2, ORe, or (Ci-Ce)alkyl, wherein the (Ci-Ce)alkyl is optionally substituted with one or more instances of halo, hydroxy, heterocycloalkyl, phenyl, N(Rd)2, or CON(Rd)2; wherein at least one of R4a, R4b, R5a, and R5bis phenyl, N(Rd)2, CON(Rd)2, ORe, or (Ci-C6)alkyl; wherein the (Ci-C6)alkyl is substituted with one or more instances of alkoxy, phenyl, N(Rd)2, or CON(Rd)2;

[0051] Rcis independently for each occurrence hydrogen or (Ci-Ce)alkyl; or two occurrences of Rctaken together with the nitrogen to which they are attached form a 4- to 7-membered heterocycloalkyl;

[0052] Rdis independently for each occurrence hydrogen or (Ci-Ce)alkyl; or two occurrences of Rdtaken together with the nitrogen to which they are attached form a 4- to 7-membered heterocycloalkyl; and

[0053] Reis hydrogen or (Ci-C6)alkyl.

[0054] In certain aspects, provided herein are compounds having the structure of Formula

[0055] R4aR5a

[0056] R4b-I

[0057] >2

[0058]

[0059] or pharmaceutically acceptable salts thereof, wherein:

[0060] - 5 - FH13161920.1 GPX-02525

[0061] R1and R2taken together with the carbon atom to which they are attached form a heterocyclic ring having the structure:

[0062] , R

[0063] ia

[0064] N.

[0065]

[0066] Rais (Ci-Ce)alkyl optionally substituted with 4- to 7-membered heterocycloalkyl;

[0067]

[0068] (b) R 0; wherein:

[0069] Rbis (Ci-Ce)alkyl substituted with:

[0070] (i) 4- to 7-membered heterocycloalkyl and fluoro; or

[0071] (ii) (C3-Cs)cycloalkyl optionally substituted with one or more of (Ci- Cs) alkyl and cyano; and

[0072] Rcis hydrogen or (Ci-Ce)alkyl; or

[0073] (

[0074]

[0075] c) 0; wherein:

[0076] Reis hydrogen, (Ci-Ce)alkyl optionally substituted with 4- to 7-membered heterocycloalkyl; and

[0077] Rfis hydrogen or (Ci-Ce)alkyl;

[0078] R3is (Ci-Ce)alkyl optionally substituted with (C3-Cs)cycloalkyl or phenyl, each of which is optionally substituted with one or more substituents selected from halo, (Ci-Ce)haloalkyl, and (Ci-Ce)alkyl;

[0079] R4aand R4bare independently hydrogen, phenyl, N(Rd)2, C0N(Rd)2, ORg, or (Ci-Ce)alkyl, wherein the (Ci-Ce)alkyl is optionally substituted with one or more instances of halo, hydroxy, heterocycloalkyl, phenyl, N(Rd)2, or C0N(Rd)2;

[0080] R5aand R5bare independently hydrogen, phenyl, N(Rd)2, C0N(Rd)2, ORg, or (Ci-Ce)alkyl, wherein the (Ci-Ce)alkyl is optionally substituted with one or more instances of halo, hydroxy, heterocycloalkyl, phenyl, N(Rd)2, or C0N(Rd)2;

[0081] - 6 - FH13161920.1 GPX-02525

[0082] Rdis independently for each occurrence hydrogen or (Ci-Ce)alkyl, or two occurrences of Rdtaken together with the nitrogen to which they are attached form a 4- to 7-membered heterocycloalkyl; and

[0083] Rgis hydrogen or (Ci-C6)alkyl.

[0084] In certain aspects, provided herein are compounds according to Formula (III):

[0085] R4aR5a

[0086]

[0087] (III),

[0088] or pharmaceutically acceptable salts thereof;

[0089] wherein:

[0090] R1is hydrogen or (Ci-Ce)alkyl;

[0091] R2is hydrogen or (Ci-Ce)alkyl optionally substituted with one or more substituents selected from hydroxy, (Ci-Ce)alkoxy, halo, cyano, (C3-Cs)cycloalkyl and 4- to 7-membered heterocycloalkyl; wherein (C3-Cs)cycloalkyl, 4- to 7-membered heterocyclo alkyl are each optionally substituted with one or more substituents selected from halo, (Ci-Ce)alkyl, hydroxy, (Ci-Ce)alkoxy, (Ci-C6)alkoxy(Ci-C6)alkyl, halo, (Ci-C6)haloalkyl, (Ci-C6)haloalkoxy, cyano, and N(RC)2;

[0092] R3is (Ci-Ce)alkyl substituted with one or more substituents selected from halo and (C3-Cs)cycloalkyl, wherein (C3-Cs)cycloalkyl is substituted with one or more substituents selected from halo, halo(Ci-C6)alkyl and (Ci-Ce)alkyl;

[0093] R4aand R4bare independently hydrogen, phenyl, N(Rd)2, CON(Rd)2, ORe, or (Ci-Ce)alkyl, wherein the (Ci-Ce)alkyl is optionally substituted with one or more instances of halo, hydroxy, heterocycloalkyl, phenyl, N(Rd)2, or CON(Rd)2; and

[0094] R5aand R5bare independently hydrogen, phenyl, N(Rd)2, CON(Rd)2, ORe, or (Ci-Ce)alkyl, wherein the (Ci-Ce)alkyl is optionally substituted with one or more instances of halo, hydroxy, heterocycloalkyl, phenyl, N(Rd)2, or CON(Rd)2;

[0095] FH13161920.1 GPX-02525

[0096] Rcis independently for each occurrence hydrogen or (Ci-Ce)alkyl; or two occurrences of Rctaken together with the nitrogen to which they are attached form a 4- to 7-membered heterocycloalkyl;

[0097] Rdis independently for each occurrence hydrogen or (Ci-Ce)alkyl; or two occurrences of Rdtaken together with the nitrogen to which they are attached form a 4- to 7-membered heterocycloalkyl; and

[0098] Reis hydrogen or (Ci-C6)alkyl.

[0099] In certain aspects, provided herein are compounds having the structure of Formula (XXIII):

[0100]

[0101] or pharmaceutically acceptable salts thereof, wherein:

[0102] Rais hydrogen, ORe, SRe, (Ci-Ce)alkyl, (C3-Cs)cycloalkyl, (C3-Cs)cycloalkyl(Ci-Ce)alkyl, (Ce-Cio)aryl, (C6-Cio)aryl(Ci-C6)alkyl, 4- to 7-membered heterocycloalkyl, 4- to 7-membered heterocycloalkyl(Ci-C6)alkyl, 5- to 10-membered heteroaryl, or 5- to 10-membered heteroaryl(Ci-C6)alkyl; wherein (Ci-Ce)alkyl, (C3-Cs)cycloalkyl, (C3-C8)cycloalkyl(Ci-C6)alkyl, (Ce-Cio)aryl, (C6-Cio)aryl(Ci-C6)alkyl, 4- to 7-membered heterocycloalkyl, 4- to 7-membered heterocycloalkyl(Ci-C6)alkyl, 5- to 10-membered heteroaryl, or 5- to 10-membered heteroaryl(Ci-C6)alkyl are optionally substituted with one or more substituents selected from halo, hydroxy, (Ci-Ce)alkyl, (Ci-C6)hydroxyalkyl, (Ci-C6)haloalkyl, (Ci-Ce)alkoxy, (Ci-C6)cycloalkoxy, (Ci-C6)haloalkoxy, cyano, N(Rf)2, and SO2N(Rf)2;

[0103] R1and R2taken together with the carbon atom to which they are attached form:

[0104]

[0105] - 8 - FH13161920.1 GPX-02525

[0106]

[0107] Rbis:

[0108] i) hydrogen;

[0109] ii) (Ci-Ce)alkyl optionally substituted with one or more substituents selected from hydroxy, (Ci-Ce)alkoxy, halo, cyano, N(Rf)2, (C3-Cs)cycloalkyl, 4- to 10-membered heterocycloalkyl, and 5- to 10-membered heteroaryl; wherein (C3-Cs)cycloalkyl, 4- to 10-membered heterocycloalkyl, and 5- to 10-membered heteroaryl are each optionally substituted with one or more substituents selected from halo, (Ci-Ce)alkyl, (C3-Cs)cycloalkyl, hydroxy, (Ci-Ce)alkoxy, (Ci-Ce)hydroxy alkyl, (Ci-C6)alkoxy(Ci-C6)alkyl, (Ci-C6)haloalkyl, (Ci-C6)haloalkoxy, C(0)N(Rf)2, CO2Rf, CH2CO2Rf, 5- to 10-membered heteroaryl, cyano, oxo, =NRf, N(Rf)SO2Rf, SO2Rf, CH2N(Rf)C(O)N(Rf)2, N(Rf)C(0)Rf, and N(Rf)2;

[0110] iii) (C3-Cs)cycloalkyl optionally substituted with one or more substituents selected from (Ci-Ce)alkyl, halo, and hydroxy;

[0111] iv) 4- to 7-membered heterocyclo alkyl optionally substituted with one or more substituents selected from (Ci-Ce)alkyl, halo, and hydroxy; or

[0112] v) (C2-Ce)alkynyl optionally substituted with one or more substituents selected from (Ci-Ce)alkyl, halo, and hydroxy;

[0113] Rcis hydrogen or (Ci-Ce)alkyl;

[0114] Rdis hydrogen, (Ci-Ce)alkyl, or hydroxy, and ~ represents a single bond or a double bond; wherein: i) — represents a double bond when Rdis hydrogen or (Ci-Ce)alkyl; or ii) — represents a single bond when Rdis hydroxy;

[0115] Reis hydrogen or (Ci-Ce)alkyl;

[0116] Rfis independently for each occurrence hydrogen or (Ci-Ce)alkyl, wherein (Ci-Ce)alkyl is optionally substituted with phenyl, or two occurrences of Rftaken together with the nitrogen to which they are attached form a 4- to 7- membered heterocycloalkyl; and R3is:

[0117] i) (Ci-Ce)alkyl optionally substituted with one or more substituents selected from halo, pentafluoro thio, (C3-Cs)cycloalkyl, 4- to 10-membered heterocycloalkyl, and 5- to 10-membered heteroaryl; wherein (C3-Cs)cycloalkyl is optionally substituted with one or more substituents selected from halo, (Ci-C6)haloalkyl, (C2-Ce)alkynyl, (Ci-Ce)alkyl, (Ci-Ce)hydroxyalkyl, and (Ci-C6)alkoxy(Ci-C6)alkyl; or

[0118] - 9 - FH13161920.1 GPX-02525

[0119] ii) (C3-Cs)cycloalkyl optionally substituted with one or more substituents selected from halo, hydroxy, and (Ci-C6)alkyl.

[0120] In certain aspects, provided herein are compounds having the structure of Formula (IV):

[0121]

[0122] or pharmaceutically acceptable salts thereof, wherein:

[0123] Rais hydrogen, ORe, SRe, (Ci-Ce)alkyl, (C3-Cs)cycloalkyl, (C3-Cs)cycloalkyl(Ci-Ce)alkyl, (Ce-Cio)aryl, or (C6-Cio)aryl(Ci-C6)alkyl, wherein (Ci-Ce)alkyl, (C3-Cs)cycloalkyl, (C3-C8)cycloalkyl(Ci-C6)alkyl, (Ce-Cio)aryl, or (C6-Cio)aryl(Ci-C6)alkyl, are optionally substituted with one or more substituents selected from halo, hydroxy, (Ci-Ce)alkoxy, (Ci-Ce)haloalkoxy and cyano;

[0124] R1and R2taken together with the carbon atom to which they are attached form:

[0125]

[0126] Rbis hydrogen or (Ci-Ce)alkyl optionally substituted with one or more substituents selected from hydroxy, (Ci-Ce)alkoxy, halo, cyano, (C3-Cs)cycloalkyl and 4- to 7-membered heterocycloalkyl; wherein (C3-Cs)cycloalkyl, and 4- to 7-membered heterocycloalkyl are each optionally substituted with one or more substituents selected from halo, (Ci-Ce)alkyl, hydroxy, (Ci-Ce)alkoxy, (Ci-Ce)hydroxy alkyl, (Ci-C6)alkoxy(Ci-C6)alkyl, (Ci-C6)haloalkyl,

[0127] - 10 - FH13161920.1 GPX-02525

[0128] (Ci-C6)haloalkoxy, C02Rf, 5- to 10-membered heteroaryl, cyano, N(Rf)S02Rf, SO2Rf, N(Rf)C(O)Rf, and N(Rf)2;

[0129] Rcis hydrogen or (Ci-Ce)alkyl;

[0130] Rdis hydrogen, (Ci-Ce)alkyl, or hydroxy, and ~ represents a single bond or a double bond; wherein: i) — represents a double bond when Rdis hydrogen or (Ci-Ce)alkyl; or ii) — represents a single bond when Rdis hydroxy;

[0131] Reis hydrogen or (Ci-Ce)alkyl;

[0132] Rfis independently for each occurrence hydrogen or (Ci-Ce)alkyl, wherein (Ci-Ce)alkyl is optionally substituted with phenyl, or two occurrences of Rftaken together with the nitrogen to which they are attached form a 4- to 7- membered heterocycloalkyl; and R3is (Ci-Ce)alkyl optionally substituted with one or more substituents selected from halo, pentafluoro thio, (C3-Cs)cycloalkyl, and 4- to 10-membered heterocycloalkyl; wherein (C3-Cs)cycloalkyl is optionally substituted with one or more substituents selected from halo, (Ci-C6)haloalkyl, and (Ci-C6)alkyl.

[0133] In certain aspects, provided herein are compounds having the structure of Formula (IVb-i):

[0134] N

[0135]

[0136] or pharmaceutically acceptable salts thereof, wherein:

[0137] Rais cyclopropyl substituted with one or more instances of fluoro;

[0138] Rbis methyl substituted with (C3-Cs)cycloalkyl, wherein (C3-Cs)cycloalkyl is further substituted with hydroxy;

[0139] Rcis methyl; and

[0140] R3is methyl substituted with cyclobutyl, wherein the cyclobutyl is further substituted with one or more fluoro.

[0141] In certain aspects, provided herein are compounds according to Formula (V):

[0142] - 11 - FH13161920.1 GPX-02525

[0143] X

[0144] R

[0145]

[0146] or pharmaceutically acceptable salts thereof, wherein:

[0147] X is N or CRX;

[0148] Y is N(R4)2;

[0149] R1is hydrogen or (Ci-Ce)alkyl optionally substituted with one or more substituents selected from hydroxy, (Ci-Ce)alkoxy, halo, cyano, (C3-Cs)cycloalkyl and 4- to 7-membered heterocycloalkyl; wherein (C3-Cs)cycloalkyl, 4- to 7-membered heterocycloalkyl are each optionally substituted with one or more substituents selected from halo, (Ci-Ce)alkyl, hydroxy, (Ci-Ce)alkoxy, (Ci-C6)alkoxy(Ci-C6)alkyl, (Ci-C6)haloalkyl, (Ci-C6)haloalkoxy, cyano, and N(RC)2;

[0150] Rcis independently for each occurrence hydrogen or (Ci-Ce)alkyl; or two occurrences of Rctaken together with the nitrogen to which they are attached form a 4- to 7- membered heterocycloalkyl;

[0151] R2is hydrogen or (Ci-Ce)alkyl;

[0152] R3is (Ci-C6)haloalkyl or (Ci-Ce)alkyl substituted with (C3-Cs)cycloalkyl, wherein (C3-Cs)cycloalkyl is optionally substituted with one or more substituents selected from halo, (Ci-Ce)alkyl, and (Ci-C6)haloalkyl

[0153] R4is independently for each occurrence hydrogen or (Ci-Ce)alkyl; or two occurrences of R4taken together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycloalkyl; and

[0154] Rxis hydrogen or (Ci-C6)alkyl.

[0155] In certain aspects, provided herein are compounds of Formula (XXIV):

[0156]

[0157] R2(XXIV);

[0158] or pharmaceutically acceptable salts thereof, wherein:

[0159] - 12 - FH13161920.1 GPX-02525

[0160] R1and R2taken together with the carbon atom to which they are attached form:

[0161] R\,0

[0162]

[0163] Rais hydrogen or (Ci-Ce)alkyl optionally substituted with one or more substituents selected from hydroxy, (Ci-Ce)alkoxy, (Ci-C6)haloalkoxy, C(0)N(Rc)2, halo, cyano, (C3-Cs)cycloalkyl and 4- to 7-membered heterocycloalkyl; wherein (C3-Cs)cycloalkyl, 4- to 7-membered heterocycloalkyl are each optionally substituted with one or more substituents selected from halo, (Ci-Ce)alkyl, hydroxy, (Ci-Ce)hydroxy alkyl, CChR0, SChR0, SO2N(CO)RC, C(0)N(RC)2, =NH, C(0)N0H, (Ci-C6)alkoxy, (Ci-C6)alkoxy(Ci-C6)alkyl, (Ci-C6)haloalkyl, (Ci-C6)haloalkoxy, cyano, and N(RC)2;

[0164] Rbis hydrogen or (Ci-Ce)alkyl;

[0165] Rcis independently for each occurrence hydrogen or (Ci-Ce)alkyl; or two occurrences of Rctaken together with the nitrogen to which they are attached form a 4- to 7- membered heterocycloalkyl;

[0166] R3is (Ci-Ce)alkyl optionally substituted with one or more substituents selected from halo and (C3-Cs)cycloalkyl, wherein (C3-Cs)cycloalkyl is optionally substituted with one or more substituents selected from (Ci-Ce)alkyl, (Ci-C6)haloalkyl, and halo;

[0167] R4is independently for each occurrence hydrogen, (Ci-Ce)alkyl, or two occurrences of R4taken together with the nitrogen atom to which they are attached forms a 4- to 7-membered heterocycloalkyl;

[0168] X1is CH or N;

[0169] X2is CR5or N; provided that at least one of X1is X2is N;

[0170] R5is hydrogen, hydroxy, (Ci-Ce)alkyl, (Ci-C6)haloalkyl, (Ci-C6)haloalkoxy, (Ci-Ce)hydroxyalkyl, (Ci-C6)alkoxy(Ci-C6)alkyl, (C3-Cs)cycloalkyl, CN, CO2R6, (Ci-C6)haloalkoxy(Ci-C6)alkyl, C(O)N(R7)2, or halo;

[0171] R6is hydrogen or (Ci-Ce)alkyl;

[0172] R7is independently for each occurrence selected from hydrogen and (Ci-Ce)alkyl,

[0173] - 13 - FH13161920.1 GPX-02525

[0174] provided the compound is not:

[0175]

[0176] In certain aspects, provided herein are compounds of Formula (VI):

[0177]

[0178] r2(VI);

[0179] or pharmaceutically acceptable salts thereof, wherein:

[0180] R1and R2taken together with the carbon atom to which they are attached form:

[0181] (a) O; or

[0182]

[0183] Rais hydrogen or (Ci-Ce)alkyl optionally substituted with one or more substituents selected from hydroxy, (Ci-Ce)alkoxy, (Ci-C6)haloalkoxy, C(O)N(RC)2, halo, cyano, (C3-Cs)cycloalkyl and 4- to 7-membered heterocycloalkyl; wherein (C3-Cs)cycloalkyl, 4- to 7-membered heterocycloalkyl are each optionally substituted with one or more substituents selected from halo, (Ci-C6)alkyl, hydroxy, CO2RC, SO2RC, SO2N(CO)RC, C(O)N(RC)2, C(O)NOH, (Ci-Ce)alkoxy, (Ci-C6)alkoxy(Ci-C6)alkyl, (Ci-C6)haloalkyl, (Ci-C6)haloalkoxy, cyano, and N(RC)2;

[0184] Rbis hydrogen or (Ci-Ce)alkyl;

[0185] Rcis independently for each occurrence hydrogen or (Ci-Ce)alkyl; or two occurrences of Rctaken together with the nitrogen to which they are attached form a 4- to 7-membered heterocycloalkyl;

[0186] - 14 - FH13161920.1 GPX-02525

[0187] R3is (Ci-Ce)alkyl optionally substituted with one or more substituents selected from halo and (C3-Cs)cycloalkyl, wherein (C3-C8)cycloalkyl is optionally substituted with one or more substituents selected from (Ci-Ce)alkyl, (Ci-C6)haloalkyl, and halo;

[0188] R4is independently for each occurrence hydrogen, (Ci-Ce)alkyl, or two occurrences of R4taken together with the nitrogen atom to which they are attached forms a 4- to 7-membered heterocycloalkyl;

[0189] X1is CH or N;

[0190] X2is CR5or N; provided that at least one of X1is X2is N;

[0191] R5is hydrogen, hydroxy, (Ci-Ce)alkyl, (Ci-C6)haloalkyl, (Cl-C6)haloalkoxy, (Ci-Ce)hydroxyalkyl, (Ci-C6)alkoxy(Ci-C6)alkyl, (C3-Cs)cycloalkyl, CN, CO2R6, (Ci-C6)haloalkoxy(Ci-C6)alkyl, C(O)N(R7)2, or halo;

[0192] R6is hydrogen or (Ci-Ce)alkyl;

[0193] R7is independently for each occurrence selected from hydrogen and (Ci-Ce)alkyl,

[0194] provided the compound is not:

[0195]

[0196] In certain aspects, provided herein are compounds of Formula (VII):

[0197] 3 yD4

[0198] R

[0199] / 6

[0200] N

[0201] >=

[0202] N

[0203]

[0204] R7(VII);

[0205] or pharmaceutically acceptable salts thereof, wherein:

[0206] R1is (Ci-Ce)alkyl optionally substituted with halo or (C3-Cs)cycloalkyl, wherein (C3-Cs)cycloalkyl is optionally substituted with one or more substituents selected from halo and (Ci-C6)alkyl;

[0207] X is N or CR2;

[0208] R2is hydrogen, halo, N(Ra)2, or (Ci-Ce)alkyl;

[0209] - 15 - FH13161920.1 GPX-02525

[0210] R3is hydrogen, N(Ra)2, (Ci-Ce)alkoxy, (C3-Cs)cycloalkyl, or (Ci-Ce)alkyl, wherein (C3-C8)cycloalkyl and (Ci-Ce)alkyl are each optionally substituted with one or more halo;

[0211] R4is hydrogen, (Ci-Ce)alkyl or N(Ra)2;

[0212] Rais independently for each occurrence hydrogen or (Ci-Ce)alkyl, or two occurrences of Rataken together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycloalkyl;

[0213] R6is hydrogen or (Ci-Ce)alkyl optionally substituted with one or more substituents selected from hydroxy, (Ci-Ce)alkoxy, halo, cyano, (C3-Cs)cycloalkyl and 4- to 7-membered heterocycloalkyl; wherein (C3-Cs)cycloalkyl, 4- to 7-membered heterocycloalkyl are each optionally substituted with one or more substituents selected from halo, (Ci-Ce)alkyl, hydroxy, (Ci-Ce)alkoxy, (Ci-C6)alkoxy(Ci-C6)alkyl, (Ci-C6)haloalkyl, (Ci-C6)haloalkoxy, cyano, and N(RC)2;

[0214] Rcis independently for each occurrence hydrogen or (Ci-Ce)alkyl; or two occurrences of Rctaken together with the nitrogen to which they are attached form a 4- to 7- membered heterocycloalkyl; and

[0215] R7is hydrogen or (Ci-C6)alkyl.

[0216] In certain aspects, provided herein are compounds according to Formula (VIII):

[0217]

[0218] or pharmaceutically acceptable salts thereof, wherein:

[0219] X and Y are defined such that:

[0220] a) X is hydrogen and Y is halo;

[0221] b) X is N(R4)2and Y is hydrogen; or

[0222] c) X is halo and Y is N(R4)2;

[0223] R1is hydrogen or (Ci-Ce)alkyl optionally substituted with one or more substituents selected from hydroxy, (Ci-Ce)alkoxy, halo, cyano, (C3-Cs)cycloalkyl and 4- to 7-membered heterocycloalkyl; wherein (C3-Cs)cycloalkyl, 4- to 7-membered heterocycloalkyl are each optionally substituted with one or more substituents selected from halo, (Ci-Ce)alkyl,

[0224] - 16 - FH13161920.1 GPX-02525

[0225] hydroxy, (Ci-Ce)alkoxy, (Ci-C6)alkoxy(Ci-C6)alkyl, (Ci-Ce)haloalkyl, (Ci-C6)haloalkoxy, cyano, and N(RC)2;

[0226] Rcis independently for each occurrence hydrogen or (Ci-Ce)alkyl; or two occurrences of Rctaken together with the nitrogen to which they are attached form a 4- to 7- membered heterocycloalkyl;

[0227] R2is hydrogen or (Ci-Ce)alkyl;

[0228] R3is (Ci-Ce)alkyl optionally substituted with halo or (C3-Cs)cycloalkyl, wherein (C3-Cs)cycloalkyl is optionally substituted with one or more substituents selected from halo, (Ci-Ce)alkyl, and (Ci-C6)haloalkyl; and

[0229] R4is independently for each occurrence hydrogen or (Ci-Ce)alkyl; or two occurrences of R4taken together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycloalkyl.

[0230] In certain aspects, provided herein are compounds having the structure of Formula (IX):

[0231]

[0232] or pharmaceutically acceptable salts thereof, wherein:

[0233] R1is (Ci-Ce)alkyl optionally substituted with halo or (C3-Cs)cycloalkyl, wherein (C3-Cs)cycloalkyl is optionally substituted with one or more substituents selected from halo, (Ci-Ce)alkyl, and (Ci-C6)haloalkyl; and

[0234] R2is hydrogen or (Ci-Ce)alkyl;

[0235] R3is hydrogen or (Ci-Ce)alkyl optionally substituted with one or more substituents selected from hydroxy, (Ci-Ce)alkoxy, halo, cyano, (C3-Cs)cycloalkyl and 4- to 7-membered heterocycloalkyl; wherein (C3-Cs)cycloalkyl, 4- to 7-membered heterocycloalkyl are each optionally substituted with one or more substituents selected from halo, (Ci-Ce)alkyl, hydroxy, (Ci-Ce)alkoxy, (Ci-C6)alkoxy(Ci-C6)alkyl, (Ci-C6)haloalkyl, (Ci-C6)haloalkoxy, cyano, and N(RC)2; and

[0236] - 17 - FH13161920.1 GPX-02525

[0237] Rcis independently for each occurrence hydrogen or (Ci-Ce)alkyl; or two occurrences of Rctaken together with the nitrogen to which they are attached form a 4- to 7- membered heterocycloalkyl.

[0238] In certain aspects, provided herein are compounds of Formula (Xi) or (Xii):

[0239]

[0240] or pharmaceutically acceptable salts thereof, wherein:

[0241] R1is hydrogen or (Ci-Ce)alkyl optionally substituted with one or more halo or (C3-Cs)cycloalkyl, wherein (C3-Cs)cycloalkyl is optionally substituted with one or more substituents selected from halo, (Ci-Ce)alkyl, and (Ci-C6)haloalkyl;

[0242] R2is hydrogen or (Ci-Ce)alkyl;

[0243] R3is hydrogen or (Ci-Ce)alkyl;

[0244] R4is hydrogen or (Ci-Ce)alkyl optionally substituted with one or more substituents selected from hydroxy, (Ci-Ce)alkoxy, halo, cyano, (C3-Cs)cycloalkyl and 4- to 7-membered heterocycloalkyl; wherein (C3-Cs)cycloalkyl, 4- to 7-membered heterocycloalkyl are each optionally substituted with one or more substituents selected from halo, (Ci-Ce)alkyl, hydroxy, (Ci-Ce)alkoxy, (Ci-C6)alkoxy(Ci-C6)alkyl, (Ci-C6)haloalkyl, (Ci-C6)haloalkoxy, cyano, and N(RC)2; and

[0245] Rcis independently for each occurrence hydrogen or (Ci-Ce)alkyl; or two occurrences of Rctaken together with the nitrogen to which they are attached form a 4- to 7- membered heterocycloalkyl.

[0246] In certain aspects, provided herein are compounds according to Formula (XI):

[0247]

[0248] - 18 - FH13161920.1 GPX-02525

[0249] or pharmaceutically acceptable salts thereof, wherein:

[0250] X is N or CRX;

[0251] Y is N(R4)2;

[0252] R1is hydrogen or (Ci-Ce)alkyl optionally substituted with one or more substituents selected from hydroxy, (Ci-Ce)alkoxy, halo, cyano, (C3-Cs)cycloalkyl and 4- to 7-membered heterocycloalkyl; wherein (C3-Cs)cycloalkyl, 4- to 7-membered heterocycloalkyl are each optionally substituted with one or more substituents selected from halo, (Ci-Ce)alkyl, hydroxy, (Ci-Ce)alkoxy, (Ci-C6)alkoxy(Ci-C6)alkyl, (Ci-C6)haloalkyl, (Ci-C6)haloalkoxy, cyano, and N(RC)2;

[0253] Rcis independently for each occurrence hydrogen or (Ci-Ce)alkyl; or two occurrences of Rctaken together with the nitrogen to which they are attached form a 4- to 7- membered heterocycloalkyl;

[0254] R2is hydrogen or (Ci-Ce)alkyl;

[0255] R3is (Ci-C6)haloalkyl or (Ci-Ce)alkyl substituted with (C3-Cs)cycloalkyl, wherein (C3-Cs)cycloalkyl is optionally substituted with one or more substituents selected from halo, (Ci-Ce)alkyl, and (Ci-C6)haloalkyl

[0256] R4is independently for each occurrence hydrogen or (Ci-Ce)alkyl; or two occurrences of R4taken together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycloalkyl; and

[0257] Rxis hydrogen or (Ci-C6)alkyl.

[0258] In certain aspects, provided herein are compounds according to Formula (XII):

[0259] N

[0260] R3fl

[0261] O

[0262] ^HR1a

[0263] M-Rlb

[0264]

[0265] or pharmaceutically acceptable salts thereof, wherein:

[0266] X is N or CRX;

[0267] Y is N(R4)2;

[0268] - 19 - FH13161920.1 GPX-02525

[0269] Rlaand Rlbare each independently hydrogen or (Ci-Ce)alkyl, or Rlaand Rlbtaken together with the carbon atom to which they are attached form a 4- to 7-membered heterocycloalkyl or (C3-C8)cycloalkyl.

[0270] R2is hydrogen or (Ci-Ce)alkyl;

[0271] R3is (Ci-C6)haloalkyl or (Ci-Ce)alkyl substituted with (C3-Cs)cycloalkyl, wherein (C3-Cs)cycloalkyl is optionally substituted with one or more substituents selected from halo, (Ci-Ce)alkyl, and (Ci-C6)haloalkyl;

[0272] R4is independently for each occurrence hydrogen or (Ci-Ce)alkyl; or two occurrences of R4taken together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycloalkyl; and

[0273] Rxis hydrogen or (Ci-C6)alkyl.

[0274] In certain aspects, provided herein are compounds according to Formula (XIII)

[0275] N N(R4)2

[0276] ii

[0277] N

[0278] 1

[0279]

[0280] R2(XIII);

[0281] or pharmaceutically acceptable salts thereof, wherein:

[0282] R1and R2taken together with the carbon atom to which they are attached form:

[0283] (a) O; or

[0284]

[0285] Rais hydrogen or (Ci-Ce)alkyl optionally substituted with one or more substituents selected from hydroxy, (Ci-Ce)alkoxy, (Ci-C6)haloalkoxy, halo, cyano, (C3-Cs)cycloalkyl and 4- to 7-membered heterocycloalkyl; wherein (C3-Cs)cycloalkyl, 4- to 7-membered heterocycloalkyl are each optionally substituted with one or more substituents selected from

[0286] - 20 - FH13161920.1 GPX-02525

[0287] halo, (Ci-C6)alkyl, hydroxy, CO2RC, SO2RC, (Ci-C6)alkoxy, (Ci-C6)alkoxy(Ci-C6)alkyl, (Ci-Ce)haloalkyl, (Ci-C6)haloalkoxy, cyano, and N(RC)2;

[0288] Rbis hydrogen or (Ci-Ce)alkyl;

[0289] Rcis independently for each occurrence hydrogen or (Ci-Ce)alkyl; or two occurrences of Rctaken together with the nitrogen to which they are attached form a 4- to 7- membered heterocycloalkyl;

[0290] R3is (Ci-Ce)alkyl optionally substituted with one or more substituents selected from halo and (C3-Cs)cycloalkyl, wherein (C3-Cs)cycloalkyl is optionally substituted with one or more substituents selected from (Ci-Ce) alkyl and halo;

[0291] R4is independently for each occurrence hydrogen, (Ci-Ce)alkyl, or two occurrences of R4taken together with the nitrogen atom to which they are attached forms a 4- to 7-membered heterocycloalkyl; and

[0292] R5is hydrogen, (Ci-Ce)alkyl, (Ci-C6)haloalkyl, (Ci-C6)hydroxyalkyl, (Ci-Ce)alkoxyalkyl, (C3-Cs)cycloalkyl, (Ci-Ce)alkoxy alkyl, or (Ci-C6)haloalkoxy(Ci-C6)alkyl.

[0293] In certain aspects, provided herein are compounds having the structure of Formula (XIV):

[0294] RaNH2

[0295] R3(CH2)n

[0296]

[0297] 0(XIV),

[0298] or pharmaceutically acceptable salts thereof, wherein:

[0299] Rais hydrogen (Ci-Ce)alkyl, (C3-Cs)cycloalkyl, (C3-C8)cycloalkyl(Ci-C6)alkyl, wherein (Ci-Ce)alkyl, (C3-Cs)cycloalkyl, (C3-C8)cycloalkyl(Ci-C6)alkyl are optionally substituted with one or more substituents selected from halo, hydroxy, (Ci-Ce)alkoxy, (Ci-C6)haloalkoxy and cyano;

[0300] R1and R2taken together with the carbon atom to which they are attached form:

[0301]

[0302] - 21 - FH13161920.1 GPX-02525

[0303] Rbis hydrogen or (Ci-Ce)alkyl optionally substituted with one or more substituents selected from hydroxy, (Ci-Ce)alkoxy, halo, cyano, (C3-Cs)cycloalkyl and 4- to 7-membered heterocycloalkyl; wherein (C3-Cs)cycloalkyl, and 4- to 7-membered heterocycloalkyl are each optionally substituted with one or more substituents selected from halo, (Ci-Ce)alkyl, hydroxy, (Ci-Ce)alkoxy, (Ci-Ce)hydroxy alkyl (Ci-C6)alkoxy(Ci-C6)alkyl, (Ci-C6)haloalkyl, (Ci-C6)haloalkoxy, CO2Rf, 5- to 10-membered heteroaryl, cyano, N(Rf)SO2Rf, SO2Rf, NRf(CO)Rf, and N(Rf)2;

[0304] Rcis hydrogen or (Ci-Ce)alkyl;

[0305] Rfis independently for each occurrence hydrogen or (Ci-Ce)alkyl, wherein (Ci-Ce)alkyl is optionally substituted with phenyl, or two occurrences of Rftaken together with the nitrogen to which they are attached form a 4- to 7- membered heterocycloalkyl;

[0306] R3is (Ci-Ce)alkyl optionally substituted with one or more substituents selected from halo, pentafluoro thio, (C3-Cs)cycloalkyl, and 4- to 10-membered heterocycloalkyl wherein (C3-Cs)cycloalkyl is optionally substituted with one or more substituents selected from halo, (Ci-C6)haloalkyl. and (Ci-Ce)alkyl; and

[0307] n is an integer from 1 to 6.

[0308] In certain aspects, provided herein are compounds of Formula (XXV), (XXVI), (XXVII), (XXVIII) (XXIX), (XXX), or (XXXI):

[0309]

[0310] - 22 - FH13161920.1 GPX-02525

[0311]

[0312] or pharmaceutically acceptable salts thereof, wherein:

[0313] R1and R2taken together with the carbon atom to which they are attached form:

[0314] R\,. O

[0315] ;N' ^

[0316] < YN^

[0317] (a) ORb

[0318] ; or

[0319]

[0320] Rais hydrogen or (Ci-Ce)alkyl optionally substituted with one or more substituents selected from hydroxy, (Ci-Ce)alkoxy, (Ci-C6)haloalkoxy, halo, cyano, (C3-Cs)cycloalkyl, and 4- to 7-membered heterocycloalkyl; wherein (C3-Cs)cycloalkyl and 4- to 7-membered heterocycloalkyl are each optionally substituted with one or more substituents selected from

[0321] - 23 - FH13161920.1 GPX-02525

[0322] halo, (Ci-C6)alkyl, hydroxy, CO2RC, SO2RC, (Ci-C6)alkoxy, (Ci-C6)alkoxy(Ci-C6)alkyl, (Ci-Ce)haloalkyl, (Ci-C6)haloalkoxy, cyano, and N(RC)2;

[0323] Rbis hydrogen or (Ci-Ce)alkyl;

[0324] Rcis independently for each occurrence hydrogen or (Ci-Ce)alkyl; or two occurrences of Rctaken together with the nitrogen to which they are attached form a 4- to 7- membered heterocycloalkyl;

[0325] R3is (Ci-Ce)alkyl optionally substituted with one or more substituents selected from halo and (C3-Cs)cycloalkyl, wherein (C3-Cs)cycloalkyl is optionally substituted with one or more substituents selected from (Ci-Ce)alkyl and halo;

[0326] R4is independently for each occurrence hydrogen, (Ci-Ce)alkyl, or two occurrences of R4taken together with the nitrogen atom to which they are attached forms a 4- to 7-membered heterocycloalkyl;

[0327] R5is hydrogen, (Ci-Ce)alkyl, (Ci-C6)haloalkyl, (Ci-C6)hydroxyalkyl, (Ci-Ce)alkoxyalkyl, (C3-Cs)cycloalkyl, (C3-C8)cycloalkyl(Ci-C6)alkyl, CN, CO2R6, (Ci-Ce)alkoxyalkyl, (Ci-C6)haloalkoxy(Ci-C6)alkyl, C(O)N(R7)2, or halo; wherein (C3-C8)cycloalkyl(Ci-C6)alkyl is optionally substituted with hydroxy;

[0328] R6is hydrogen or (Ci-Ce)alkyl;

[0329] R7is independently for each occurrence selected from hydrogen and (Ci-Ce)alkyl; and X is CH or N.

[0330] In certain aspects, provided herein are compounds of Formula (XV), (XVI), (XVII), (XVIII) (XIX), (XX), or (XXI):

[0331]

[0332] - 24 - FH13161920.1 GPX-02525

[0333]

[0334] or pharmaceutically acceptable salts thereof, wherein:

[0335] R1and R2taken together with the carbon atom to which they are attached form:

[0336] R\,. O

[0337] ;N' ^

[0338] < YN^

[0339] (a) ORb

[0340] ; or

[0341]

[0342] Rais hydrogen or (Ci-Ce)alkyl optionally substituted with one or more substituents selected from hydroxy, (Ci-Ce)alkoxy, (Ci-C6)haloalkoxy, halo, cyano, (C3-Cs)cycloalkyl and 4- to 7-membered heterocycloalkyl; wherein (C3-Cs)cycloalkyl, 4- to 7-membered heterocycloalkyl are each optionally substituted with one or more substituents selected from

[0343] - 25 - FH13161920.1 GPX-02525

[0344] halo, (Ci-C6)alkyl, hydroxy, CO2RC, SO2RC, (Ci-C6)alkoxy, (Ci-C6)alkoxy(Ci-C6)alkyl, (Ci-Ce)haloalkyl, (Ci-C6)haloalkoxy, cyano, and N(RC)2;

[0345] Rbis hydrogen or (Ci-Ce)alkyl;

[0346] Rcis independently for each occurrence hydrogen or (Ci-Ce)alkyl; or two occurrences of Rctaken together with the nitrogen to which they are attached form a 4- to 7- membered heterocycloalkyl;

[0347] R3is (Ci-Ce)alkyl optionally substituted with one or more substituents selected from halo and (Cs-Csjcycloalkyl, wherein (Cs-Csjcycloalkyl is optionally substituted with one or more substituents selected from (Ci-Ce)alkyl and halo;

[0348] R4is independently for each occurrence hydrogen, (Ci-Ce)alkyl, or two occurrences of R4taken together with the nitrogen atom to which they are attached forms a 4- to 7-membered heterocycloalkyl;

[0349] R5is hydrogen, (Ci-Ce)alkyl, (Ci-C6)haloalkyl, (Ci-Cejhydroxyalkyl, (Ci-Cejalkoxyalkyl, (C3-Cs)cycloalkyl, CN, CO2R6, (Ci-Ce)alkoxyalkyl, (Ci-C6)haloalkoxy(Ci-C6)alkyl, C(O)N(R7)2, or halo;

[0350] R6is hydrogen or (Ci-Ce)alkyl;

[0351] R7is independently for each occurrence selected from hydrogen, (Ci-Ce)alkyl; and X is CH or N.

[0352] In certain aspects, provided herein are pharmaceutical compositions, comprising a compound of the disclosure; and at least one pharmaceutically acceptable excipient.

[0353] In certain aspects, provided herein are methods for treating or preventing osteoporosis, fracture, osteomalacia, arthritis, thrombocytopenia, hypoparathyroidism, hyperphosphatemia or tumoral calcinosis, comprising administering to a subject in need thereof a therapeutically amount of a compound of the disclosure, or a pharmaceutically acceptable salt thereof.

[0354] In certain aspects, provided herein are methods of:

[0355] a) reducing of HbA1c;

[0356] b) treating or preventing type 2 diabetes, hyperglycemia, impaired glucose tolerance, or non-insulin dependent diabetes, and / or obesity;

[0357] c) reducing body weight and / or food intake, and / or inducing satiety; and / or d) treating or preventing Alzheimer's disease, nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), and / or cardiovascular diseases;

[0358] - 26 - FH13161920.1 GPX-02525

[0359] comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the disclosure, or a pharmaceutically acceptable salt thereof.

[0360] Other features, objects, and advantages of the invention will be apparent from the detailed description, and from the claims.

[0361] BRIEF DESCRIPTION OF THE FIGURES

[0362] Figure 1 tabulates exemplary compounds of the invention, and their characterization data and PTH1R activity.

[0363] DETAILED DESCRIPTION

[0364] Definitions

[0365] For convenience, before further description of the present invention, certain terms employed in the specification, examples and appended claims are collected here. These definitions should be read in light of the remainder of the disclosure and as understood by a person of skill in the art.

[0366] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.

[0367] In order for the present invention to be more readily understood, certain terms and phrases are defined below and throughout the specification.

[0368] The articles “a” and “an” are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element.

[0369] The phrase “and / or,” as used herein in the specification and in the claims, should be understood to mean “either or both” of the elements so conjoined, i.e., elements that are conjunctively present in some cases and disjunctively present in other cases. Multiple elements listed with “and / or” should be construed in the same fashion, i.e., “one or more” of the elements so conjoined. Other elements may optionally be present other than the elements specifically identified by the “and / or” clause, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, a reference to “A and / or B”, when

[0370] - 27 - FH13161920.1 GPX-02525

[0371] used in conjunction with open-ended language such as “comprising” can refer, in one embodiment, to A only (optionally including elements other than B); in another embodiment, to B only (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements); etc.

[0372] As used herein in the specification and in the claims, “or” should be understood to have the same meaning as “and / or” as defined above. For example, when separating items in a list, “or” or “and / or” shall be interpreted as being inclusive, i.e., the inclusion of at least one, but also including more than one, of a number or list of elements, and, optionally, additional unlisted items. Only terms clearly indicated to the contrary, such as “only one of’ or “exactly one of,” or, when used in the claims, “consisting of,” will refer to the inclusion of exactly one element of a number or list of elements. In general, the term “or” as used herein shall only be interpreted as indicating exclusive alternatives (i.e., “one or the other but not both”) when preceded by terms of exclusivity, such as “either,” “one of,” “only one of,” or “exactly one of.” “Consisting essentially of,” when used in the claims, shall have its ordinary meaning as used in the field of patent law.

[0373] As used herein in the specification and in the claims, the phrase “at least one,” in reference to a list of one or more elements, should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed within the list of elements and not excluding any combinations of elements in the list of elements. This definition also allows that elements may optionally be present other than the elements specifically identified within the list of elements to which the phrase “at least one” refers, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, “at least one of A and B” (or, equivalently, “at least one of A or B,” or, equivalently “at least one of A and / or B”) can refer, in one embodiment, to at least one, optionally including more than one, A, with no B present (and optionally including elements other than B); in another embodiment, to at least one, optionally including more than one, B, with no A present (and optionally including elements other than A); in yet another embodiment, to at least one, optionally including more than one, A, and at least one, optionally including more than one, B (and optionally including other elements); etc.

[0374] It should also be understood that, unless clearly indicated to the contrary, in any methods claimed herein that include more than one step or act, the order of the steps or acts of the method is not necessarily limited to the order in which the steps or acts of the method are recited.

[0375] - 28 - FH13161920.1 GPX-02525

[0376] In the claims, as well as in the specification above, all transitional phrases such as “comprising,” “including,” “carrying,” “having,” “containing,” “involving,” “holding,” “composed of,” and the like are to be understood to be open-ended, i.e., to mean including but not limited to. Only the transitional phrases “consisting of’ and “consisting essentially of’ shall be closed or semi-closed transitional phrases, respectively, as set forth in the United States Patent Office Manual of Patent Examining Procedures, Section 2111.03.

[0377] Certain compounds contained in compositions of the present invention may exist in particular geometric or stereoisomeric forms. In addition, polymers of the present invention may also be optically active. The present invention contemplates all such compounds, including cis- and trans-isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention. Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention.

[0378] “Geometric isomer" means isomers that differ in the orientation of substituent atoms in relationship to a carbon-carbon double bond, to a cycloalkyl ring, or to a bridged bicyclic system. Atoms (other than H) on each side of a carbon- carbon double bond may be in an E (substituents are on opposite sides of the carbon- carbon double bond) or Z (substituents are oriented on the same side) configuration. " R," " S," " S*," " R*," " E," " Z," "cis," and "trans," indicate configurations relative to the core molecule. Certain of the disclosed compounds may exist in “atropisomeric” forms or as “atropisomers.” Atropisomers are stereoisomers resulting from hindered rotation about single bonds where the steric strain barrier to rotation is high enough to allow for the isolation of the conformers. The compounds of the invention may be prepared as individual isomers by either isomer- specific synthesis or resolved from a mixture of isomers. Conventional resolution techniques include forming the salt of a free base of each isomer of an isomeric pair using an optically active acid (followed by fractional crystallization and regeneration of the free base), forming the salt of the acid form of each isomer of an isomeric pair using an optically active amine (followed by fractional crystallization and regeneration of the free acid), forming an ester or amide of each of the isomers of an isomeric pair using an optically pure acid, amine or alcohol (followed by chromatographic separation and removal of the chiral auxiliary), or resolving an isomeric mixture of either a starting material or a final product using various well known chromatographic methods.

[0379] If, for instance, a particular enantiomer of compound of the present invention is desired, it may be prepared by asymmetric synthesis, or by derivation with a chiral auxiliary,

[0380] - 29 - FH13161920.1 GPX-02525

[0381] where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers. Alternatively, where the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, diastereomeric salts are formed with an appropriate optically active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means well known in the art, and subsequent recovery of the pure enantiomers.

[0382] Percent purity by mole fraction is the ratio of the moles of the enantiomer (or diastereomer) or over the moles of the enantiomer (or diastereomer) plus the moles of its optical isomer. When the stereochemistry of a disclosed compound is named or depicted by structure, the named or depicted stereoisomer is at least about 60%, about 70%, about 80%, about 90%, about 99% or about 99.9% by mole fraction pure relative to the other stereoisomers. When a single enantiomer is named or depicted by structure, the depicted or named enantiomer is at least about 60%, about 70%, about 80%, about 90%, about 99% or about 99.9% by mole fraction pure. When a single diastereomer is named or depicted by structure, the depicted or named diastereomer is at least about 60%, about 70%, about 80%, about 90%, about 99% or about 99.9% by mole fraction pure.

[0383] When a disclosed compound is named or depicted by structure without indicating the stereochemistry, and the compound has at least one chiral center, it is to be understood that the name or structure encompasses either enantiomer of the compound free from the corresponding optical isomer, a racemic mixture of the compound or mixtures enriched in one enantiomer relative to its corresponding optical isomer. When a disclosed compound is named or depicted by structure without indicating the stereochemistry and has two or more chiral centers, it is to be understood that the name or structure encompasses a diastereomer free of other diastereomers, a number of diastereomers free from other diastereomeric pairs, mixtures of diastereomers, mixtures of diastereomeric pairs, mixtures of diastereomers in which one diastereomer is enriched relative to the other diastereomer(s) or mixtures of diastereomers in which one or more diastereomer is enriched relative to the other diastereomers. The invention embraces all of these forms.

[0384] Structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds produced by the replacement of a hydrogen with deuterium or tritium, or of a carbon with a13C- or deenriched carbon are within the scope of this invention.

[0385] The term “prodrug” as used herein encompasses compounds that, under physiological conditions, are converted into therapeutically active agents. A common method for making a - 30 - FH13161920.1 GPX-02525

[0386] prodrug is to include selected moieties that are hydrolyzed under physiological conditions to reveal the desired molecule. In other embodiments, the prodrug is converted by an enzymatic activity of the host animal.

[0387] The phrase “pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject chemical from one organ or portion of the body, to another organ or portion of the body. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation, not injurious to the patient, and substantially non-pyrogenic. Some examples of materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as com starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer’s solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations. In certain embodiments, pharmaceutical compositions of the present invention are non-pyrogenic, i.e., do not induce significant temperature elevations when administered to a patient.

[0388] The term “pharmaceutically acceptable salts” refers to the relatively non-toxic, inorganic and organic acid addition salts of the compound(s). These salts can be prepared in situ during the final isolation and purification of the compound(s), or by separately reacting a purified compound(s) in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts, and the like. (See, for example, Berge et al. (1977) “Pharmaceutical Salts”, J. Pharm. Sci. 66:1-19.) In other cases, the compounds useful in the methods of the present invention may contain one or more acidic functional groups and, thus, are capable of forming

[0389] - 31 - FH13161920.1 GPX-02525

[0390] pharmaceutically acceptable salts with pharmaceutically acceptable bases. The term “pharmaceutically acceptable salts” in these instances refers to the relatively non-toxic inorganic and organic base addition salts of a compound(s). These salts can likewise be prepared in situ during the final isolation and purification of the compound(s), or by separately reacting the purified compound(s) in its free acid form with a suitable base, such as the hydroxide, carbonate, or bicarbonate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, or tertiary amine. Representative alkali or alkaline earth salts include the lithium, sodium, potassium, calcium, magnesium, and aluminum salts, and the like. Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like (see, for example, Berge et al., supra).

[0391] The term “pharmaceutically acceptable cocrystals” refers to solid coformers that do not form formal ionic interactions with the small molecule.

[0392] A “therapeutically effective amount” (or “effective amount”) of a compound with respect to use in treatment, refers to an amount of the compound in a preparation which, when administered as part of a desired dosage regimen (to a mammal, preferably a human) alleviates a symptom, ameliorates a condition, or slows the onset of disease conditions according to clinically acceptable standards for the disorder or condition to be treated or the cosmetic purpose, e.g., at a reasonable benefit / risk ratio applicable to any medical treatment.

[0393] The term “prophylactic or therapeutic” treatment is art-recognized and includes administration to the host of one or more of the subject compositions. If it is administered prior to clinical manifestation of the unwanted condition (e.g., disease or other unwanted state of the host animal) then the treatment is prophylactic, (i.e., it protects the host against developing the unwanted condition), whereas if it is administered after manifestation of the unwanted condition, the treatment is therapeutic, (i.e., it is intended to diminish, ameliorate, or stabilize the existing unwanted condition or side effects thereof).

[0394] The term “patient” or “subject” refers to a mammal in need of a particular treatment. In certain embodiments, a patient is a primate, canine, feline, or equine. In certain embodiments, a patient is a human.

[0395] An aliphatic chain comprises the classes of alkyl, alkenyl and alkynyl defined below. A straight aliphatic chain is limited to unbranched carbon chain moieties. As used herein, the term “aliphatic group” refers to a straight chain, branched-chain, or cyclic aliphatic hydrocarbon group and includes saturated and unsaturated aliphatic groups, such as an alkyl group, an alkenyl group, or an alkynyl group.

[0396] - 32 - FH13161920.1 GPX-02525

[0397] “Alkyl” refers to a fully saturated cyclic or acyclic, branched or unbranched carbon chain moiety having the number of carbon atoms specified, or up to 30 carbon atoms if no specification is made. In preferred embodiments, “alkyl” refers to a fully saturated acyclic branched or unbranched carbon chain moiety. For example, alkyl of 1 to 8 carbon atoms refers to moieties such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl, and those moieties which are positional isomers of these moieties. Alkyl of 10 to 30 carbon atoms includes decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, heneicosyl, docosyl, tricosyl and tetracosyl. In certain embodiments, a straight chain or branched chain alkyl has 30 or fewer carbon atoms in its backbone (e.g., C1-C30 for straight chains, C3-C30 for branched chains), and more preferably 20 or fewer. Alkyl groups may be substituted or unsubstituted.

[0398] As used herein, the term “alkoxy” refers to an alkyl group, appended to the parent molecular moiety through an oxygen atom. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy.

[0399] As used herein, the term “alkoxyalkyl”, refers to an alkyl group substituted by an alkoxy group.

[0400] As used herein, the term “carboxyalkyl”, refers to an alkyl group substituted by a carboxyl group.

[0401] As used herein, the term “cyanoalkyl”, refers to an alkyl group substituted by a cyano group.

[0402] As used herein, the term “heteroalkyl” refers to an alkyl moiety as hereinbefore defined which contain one or more oxygen, sulfur, nitrogen, phosphorus, or silicon atoms in place of carbon atoms.

[0403] As used herein, the term “hydroxy” is a term of art and refers to an -OH group.

[0404] As used herein, the term “oxo” refers to a =0 group.

[0405] As used herein, the term “O-heteroaryl” refers to a heteroaryl attached to the parent molecular moiety via an oxygen atom (-O-).

[0406] As used herein, the term “amino” is a term of art that refers to both unsubstituted and substituted amines, e.g., a moiety that may be represented by the general formulas:

[0407] _ Ra

[0408] / Ra|a+

[0409] - Z - N— Rb

[0410]

[0411] Rb and

[0412] - 33 - FH13161920.1 GPX-02525

[0413] wherein Ra, Rb, and Rceach independently represent a hydrogen, an alkyl, an alkenyl, -(CH2)X-Rd, or Raand Rb, taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure; Rdrepresents an aryl, a heteroaryl, a cycloalkyl, a cycloalkenyl, a heterocyclyl or a polycyclyl; and x is zero or an integer in the range of 1 to 8. In certain preferred embodiments, the term “amino” refers to -NH2.

[0414] As used herein, the term “haloalkyl” refers to an alkyl group as hereinbefore defined substituted with at least one halogen.

[0415] As used herein, the term “haloalkoxy” refers to an alkoxy group as defined herein substituted with at least one halogen atom. For example, haloalkoxy groups include fluoroalkoxy groups, such as trifluoromethoxy, difluoromethoxy, and the like.

[0416] As used herein, the term “haloalkoxyalkyl”, refers to an alkyl group substituted by a haloalkoxy group. An example haloalkoxyalkyl group is trifluoromethoxymethyl.

[0417] As used herein, the term “hydroxy alkyl” refers to an alkyl group as hereinbefore defined substituted with at least one hydroxyl.

[0418] As used herein, the term “alkylene” refers to an alkyl group having the specified number of carbons, for example from 2 to 12 carbon atoms, that contains two points of attachment to the rest of the compound on its longest carbon chain. Non-limiting examples of alkylene groups include methylene -(CH2)-, ethylene -(CH2CH2)-, n-propylene -(CH2CH2CH2)-, isopropylene -(CH2CH(CHs))-, and the like. Alkylene groups can be cyclic or acyclic, branched or unbranched carbon chain moiety, and may be optionally substituted with one or more substituents.

[0419] " Cycloalkyl" means mono- or bicyclic or bridged or spirocyclic or fused, or polycyclic saturated carbocyclic rings, each having from 3 to 12 carbon atoms. Preferred cycloalkyls have from 3-10 carbon atoms in their ring structure, and more preferably have 3-6 carbons in the ring structure. Examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. Bicyclic cycloalkyl ring systems include bridged monocyclic rings and fused bicyclic rings. Bridged monocyclic rings contain a monocyclic cycloalkyl ring where two non-adjacent carbon atoms of the monocyclic ring are linked by an alkylene bridge of between one and three additional carbon atoms (z.e., a bridging group of the form -(CEh)^-, where w is 1, 2, or 3). Representative examples of bicyclic ring systems include, but are not limited to, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo [3.3.1] nonane, and bicyclo[4.2.1]nonane. Fused bicyclic cycloalkyl ring systems contain a monocyclic cycloalkyl ring fused to either a phenyl, a - 34 - FH13161920.1 GPX-02525

[0420] monocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclic heterocycloalkyl, a monocyclic heterocycloalkenyl, or a monocyclic heteroaryl. The bridged or fused bicyclic cycloalkyl is attached to the parent molecular moiety through any carbon atom contained within the monocyclic cycloalkyl ring. In certain embodiments, the fused bicyclic cycloalkyl is a 5 or 6 membered monocyclic cycloalkyl ring fused to either a phenyl ring, a 5 or 6 membered monocyclic cycloalkyl, a 5 or 6 membered monocyclic cycloalkenyl, a 5 or 6 membered monocyclic heterocycloalkyl, a 5 or 6 membered monocyclic heterocycloalkenyl, or a 5 or 6 membered monocyclic heteroaryl, wherein the fused bicyclic cycloalkyl is optionally substituted. Examples of spirocyclic ring systems include, but are not limited to, spiro[3.3]heptane and spiro[2.2]pentane. Cycloalkyl groups may be substituted or unsubstituted.

[0421] As used herein, the term “(cycloalkyl)alkyl” refers to an alkyl group substituted with one or more cycloalkyl groups. An example cyclo alkylalkyl group is cyclohexylmethyl.

[0422] “1,2-Disubstituted cyclohexyl” as used herein refers to a cyclohexane ring that contains points of attachment at the 1 and 2 positions of the cyclohexane ring to the rest of the compound. Similarly, “1,2-disubstituted cyclopentyl” as used herein refers to a cyclopentane ring that contains points of attachment at the 1 and 2 positions of the cyclopentane ring to the rest of the compound. 1,2-Disubstituted cyclohexyl and 1,2-disubstituted cyclopentyl can also be referred to as 1,2-cyclohexylene and 1,2-cyclopentylene, respectively.

[0423] As used herein, the term “halocycloalkyl” refers to a cycloalkyl group as hereinbefore defined substituted with at least one halogen.

[0424] " Cycloheteroalkyl" refers to a cycloalkyl moiety as hereinbefore defined which contain one or more oxygen, sulfur, nitrogen, phosphorus, or silicon atoms in place of carbon atoms. Preferred cycloheteroalkyls have from 4-8 carbon atoms and heteroatoms in their ring structure, and more preferably have 4-6 carbons and heteroatoms in the ring structure.

[0425] Cycloheteroalkyl groups may be substituted or unsubstituted.

[0426] Unless the number of carbons is otherwise specified, “lower alkyl,” as used herein, means an alkyl group, as defined above, but having from one to ten carbons, more preferably from one to six carbon atoms in its backbone structure such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. Likewise, “lower alkenyl” and “lower alkynyl” have similar chain lengths. Throughout the application, preferred alkyl groups are lower alkyls. In certain embodiments, a substituent designated herein as alkyl is a lower alkyl.

[0427] - 35 - FH13161920.1 GPX-02525

[0428] “Alkenyl” refers to any cyclic or acyclic, branched or unbranched unsaturated carbon chain moiety having the number of carbon atoms specified, or up to 26 carbon atoms if no limitation on the number of carbon atoms is specified; and having one or more double bonds in the moiety. Alkenyl of 6 to 26 carbon atoms is exemplified by hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodenyl, tridecenyl, tetradecenyl, pentadecenyl, hexadecenyl, heptadecenyl, octadecenyl, nonadecenyl, eicosenyl, heneicosoenyl, docosenyl, tricosenyl, and tetracosenyl, in their various isomeric forms, where the unsaturated bond(s) can be located anywhere in the moiety and can have either the (Z) or the (E) configuration about the double bond(s).

[0429] “Alkynyl” refers to hydrocarbyl moieties of the scope of alkenyl, but having one or more triple bonds in the moiety.

[0430] The term “aryl” as used herein includes 3- to 12-membered substituted or unsubstituted single-ring aromatic groups in which each atom of the ring is carbon (i.e., carbocyclic aryl) or where one or more atoms are heteroatoms (i.e., heteroaryl). Preferably, aryl groups include 5-to 12-membered rings, more preferably 6- to 10-membered rings The term “aryl” also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is aromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and / or heterocyclyls. Carboycyclic aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, and the like. In preferred embodiments, aryl groups are carbocyclic aryl groups.

[0431] Heteroaryl groups include substituted or unsubstituted aromatic 3- to 12-membered ring structures, more preferably 5- to 12-membered rings, more preferably 5- to 10-membered rings, whose ring structures include one to four heteroatoms. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine, pyrimidine, indazole, quinoline, benzofuran, and the like. In preferred embodiments, “heteroaryl” refers to a monocyclic, bicyclic, or polycyclic aromatic group having 3 to 12 total atoms including one or more heteroatoms such as nitrogen, oxygen, or sulfur in the ring structure. Exemplary heteroaryl groups include azaindolyl, benzo(b)thienyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, benzoxadiazolyl, furanyl, imidazolyl, imidazopyridinyl, indolyl, indolinyl, indazolyl, isoindolinyl, isoxazolyl, isothiazolyl, isoquinolinyl, oxadiazolyl, oxazolyl, purinyl, pyranyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrrolyl, pyrrolo[2,3-d]pyrimidinyl, pyrazolo[3,4-d]pyrimidinyl, quinolinyl, quinazolinyl, triazolyl, thiazolyl, thiophenyl, tetrahydroindolyl, tetrazolyl, thiadiazolyl, thienyl, thiomorpholinyl, triazolyl or tropanyl, and - 36 - FH13161920.1 GPX-02525

[0432] the like. The “heteroaryl” may be substituted at one or more ring positions with one or more substituents such as halogen, azide, alkyl, arylalkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamide, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, fluoroalkyl (such as trifluromethyl), cyano, or the like. The term “heteroaryl” also includes polycyclic ring systems having two or more cyclic rings in which two or more atoms are common to two adjoining rings (the rings are "fused rings") wherein at least one of the rings is an aromatic group having one or more heteroatoms in the ring structure, e.g., the other cyclic rings may be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and / or heterocyclyls. Such heteroaryl groups may be connected to the rest of the molecule through either the aromatic group having one or more heteroatoms in the ring structure or the other cyclic group. For example, heteroaryl includes indole, which comprises a benzene ring and a pyrrole ring that are fused together. An indole substituent may be attached to a parent structure through either the benzene ring or through the pyrrole ring of the indole. Aryl and heteroaryl can be monocyclic, bicyclic, or polycyclic.

[0433] The term “halo”, “halide”, or “halogen” as used herein means halogen and includes, for example, and without being limited thereto, fluoro, chloro, bromo, iodo and the like, in both radioactive and non-radioactive forms. In a preferred embodiment, halo is selected from the group consisting of fluoro, chloro and bromo.

[0434] The terms “heterocyclyl” or “heterocyclic group” or “heterocycloalkyl” refer to 3- to 12-membered ring structures, more preferably 5- to 12-membered rings, more preferably 5- to 10-membered rings, whose ring structures include one to four heteroatoms. Heterocycles and heterocycloalkyls can be monocyclic, bicyclic, spirocyclic, or polycyclic. Heterocycles and heterocycloalkyls can be completely saturated or can contain one or more units of unsaturation. In preferred embodiments, the degree of unsaturation in a heterocycle or heterocyclo alkyl does not result in an aromatic ring system. Heterocycles and heterocycloalkyls have 3 to 12 atoms including at least one heteroatom, such as nitrogen, oxygen, or sulfur. In certain embodiments, heterocycles and heterocycloalkyls include those substituted with oxo (=0) groups, such as lactones and lactams. Heterocyclyl groups include, for example, thiophene, thianthrene, furan, pyran, isobenzofuran, chromene, xanthene, phenoxathiin, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, pyrimidine, phenanthroline, phenazine, phenarsazine, phenothiazine, furazan, phenoxazine, pyrrolidine,

[0435] - 37 - FH13161920.1 GPX-02525

[0436] oxolane, thiolane, oxazole, piperidine, piperazine, morpholine, lactones, lactams such as azetidinones and pyrrolidinones, sultams, sultones, and the like. Heterocycloalkyl groups can be fully saturated or partially saturated. Heterocycloalkyl groups include, for example, bicyclic ring systems having either or both constituent rings saturated (e.g., 2,3-dihydroindole, 4, 5,6,7 -tetrahydro-benzofuran, decahydroquinoline, and the like) or partially saturated (e.g., octahydroquinoline and the like). For purposes of exemplification, which should not be construed as limiting the scope of this invention, the following are examples of heterocyclic and heterocycloalkyl rings: aziridinyl, azirinyl, oxiranyl, thiiranyl, thiirenyl, dioxiranyl, diazirinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, azetyl, oxetanyl, oxetyl, thietanyl, thietyl, diazetidinyl, dioxetanyl, dithietanyl, dioxalanyl, azepines, azetidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, oxopiperidinyl, oxopyrrolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, quinuclidinyl, thiomorpholinyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1-dioxido thiomorpholinyl (thiomorpholine sulfone), thiopyranyl, trithianyl, and 2-azobicyclo[3.1.0]hexane.

[0437] The heterocyclic ring can be substituted at one or more positions with such substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphate, phosphonate, phosphinate, carbonyl, carboxyl, silyl, sulfamoyl, sulfinyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, -CF3, -CN, and the like.

[0438] As used herein, the term “(heterocycloalkyl)alkyl” refers to an alkyl group substituted with one or more heterocycloalkyl (i.e., heterocyclyl) groups.

[0439] The term “substituted” refers to moieties having substituents replacing a hydrogen on one or more carbons of the backbone. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds.

[0440] - 38 - FH13161920.1 GPX-02525

[0441] The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this invention, the heteroatoms such as nitrogen may have hydrogen substituents and / or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. Substituents can include any substituents described herein, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxy, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamide, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety. In preferred embodiments, the substituents on substituted alkyls are selected from Ci-6 alkyl, C3-6 cycloalkyl, halogen, carbonyl, cyano, or hydroxyl. In more preferred embodiments, the substituents on substituted alkyls are selected from fluoro, carbonyl, cyano, or hydroxyl. It will be understood by those skilled in the art that substituents can themselves be substituted, if appropriate. Unless specifically stated as “un substituted,” references to chemical moieties herein are understood to include substituted variants. For example, reference to an “aryl” group or moiety implicitly includes both substituted and unsubstituted variants.

[0442] As used herein, the definition of each expression, e.g., alkyl, m, n, etc., when it occurs more than once in any structure, is intended to be independent of its definition elsewhere in the same structure.

[0443] As used herein, “small molecules” refers to small organic or inorganic molecules of molecular weight below about 3,000 Daltons. In general, small molecules useful for the invention have a molecular weight of less than 3,000 Daltons (Da). The small molecules can be, e.g., from at least about 100 Da to about 3,000 Da (e.g., between about 100 to about 3,000 Da, about 100 to about 2500 Da, about 100 to about 2,000 Da, about 100 to about 1,750 Da, about 100 to about 1,500 Da, about 100 to about 1,250 Da, about 100 to about 1,000 Da, about 100 to about 750 Da, about 100 to about 500 Da, about 200 to about 1500, about 500 to about 1000, about 300 to about 1000 Da, or about 100 to about 250 Da).

[0444] In some embodiments, a “small molecule” refers to an organic, inorganic, or organometallic compound typically having a molecular weight of less than about 1000. In some embodiments, a small molecule is an organic compound, with a size on the order of 1 nm. In some embodiments, small molecule drugs of the invention encompass oligopeptides and other biomolecules having a molecular weight of less than about 1000.

[0445] - 39 - FH13161920.1 GPX-02525

[0446] An “effective amount” is an amount sufficient to effect beneficial or desired results. For example, a therapeutic amount is one that achieves the desired therapeutic effect. This amount can be the same or different from a prophylactically effective amount, which is an amount necessary to prevent onset of disease or disease symptoms. An effective amount can be administered in one or more administrations, applications or dosages. A therapeutically effective amount of a composition depends on the composition selected. The compositions can be administered from one or more times per day to one or more times per week; including once every other day. The skilled artisan will appreciate that certain factors may influence the dosage and timing required to effectively treat a subject, including but not limited to the severity of the disease or disorder, previous treatments, the general health and / or age of the subject, and other diseases present. Moreover, treatment of a subject with a therapeutically effective amount of the compositions described herein can include a single treatment or a series of treatments.

[0447] The terms “decrease,” “reduce,” “reduced”, “reduction”, “decrease,” and “inhibit” are all used herein generally to mean a decrease by a statistically significant amount relative to a reference. However, for avoidance of doubt, “reduce,” “reduction” or “decrease” or “inhibit” typically means a decrease by at least 10% as compared to a reference level and can include, for example, a decrease by at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, up to and including, for example, the complete absence of the given entity or parameter as compared to the reference level, or any decrease between 10-99% as compared to the absence of a given treatment.

[0448] The terms “increased”, “increase” or “enhance” or “activate” are all used herein to generally mean an increase by a statically significant amount; for the avoidance of any doubt, the terms “increased”, “increase” or “enhance” or “activate” means an increase of at least 10% as compared to a reference level, for example an increase of at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90% or up to and including a

[0449] 100% increase or any increase between 10-100% as compared to a reference level, or at least about a 2-fold, or at least about a 3-fold, or at least about a 4-fold, or at least about a 5-fold or at least about a 10-fold increase, or any increase between 2-fold and 10-fold or

[0450] greater as compared to a reference level.

[0451] - 40 - FH13161920.1 GPX-02525

[0452] As used herein, the term “modulate” includes up-regulation and down-regulation, e.g., enhancing or inhibiting a response.

[0453] A “radiopharmaceutical agent,” as defined herein, refers to a pharmaceutical agent which contains at least one radiation-emitting radioisotope. Radiopharmaceutical agents are routinely used in nuclear medicine for the diagnosis and / or therapy of various diseases. The radiolabeled pharmaceutical agent, for example, a radiolabeled antibody, contains a radioisotope (RI) which serves as the radiation source. As contemplated herein, the term “radioisotope” includes metallic and non-metallic radioisotopes. The radioisotope is chosen based on the medical application of the radiolabeled pharmaceutical agents. When the radioisotope is a metallic radioisotope, a chelator is typically employed to bind the metallic radioisotope to the rest of the molecule. When the radioisotope is a non-metallic radioisotope, the non-metallic radioisotope is typically linked directly, or via a linker, to the rest of the molecule.

[0454] For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 67th Ed., 1986-87, inside cover.

[0455] Compounds of the Invention

[0456] In certain aspects, provided herein is a compound according to Formula (XXII):

[0457] R4aR5a

[0458] R4b-N N-R5b

[0459] R n i i °

[0460] ° R1

[0461] 2'N~4

[0462]

[0463] R2O (XXII);

[0464] or a pharmaceutically acceptable salt thereof;

[0465] wherein:

[0466] R1is hydrogen or (Ci-Ce)alkyl;

[0467] R2is hydrogen or (Ci-Ce)alkyl optionally substituted with one or more substituents selected from hydroxy, (Ci-Ce)alkoxy, halo, cyano, (C3-Cs)cycloalkyl and 4- to 7-membered heterocycloalkyl; wherein (C3-Cs)cycloalkyl, 4- to 7-membered heterocycloalkyl are each optionally substituted with one or more substituents selected from halo, (Ci-Ce)alkyl,

[0468] - 41 - FH13161920.1 GPX-02525

[0469] hydroxy, (Ci-Ce)alkoxy, (Ci-C6)alkoxy(Ci-C6)alkyl, (Ci-Ce)haloalkyl, (Ci-C6)haloalkoxy, cyano, and N(RC)2;

[0470] R3is (Ci-Ce)alkyl optionally substituted with halo, (C3-Cs)cycloalkyl or phenyl, each of which is optionally substituted with one or more substituents selected from halo, (Ci-Ce)haloalkyl and (Ci-Ce)alkyl;

[0471] R4aand R4bare independently hydrogen, phenyl, N(Rd)2, CON(Rd)2, ORe, (Ci-Ce)alkyl, or (C3-Cs)cycloalkyl; wherein the (Ci-Ce)alkyl is optionally substituted with one or more instances of halo, hydroxy, heterocycloalkyl, phenyl, N(Rd)2, or CON(Rd)2; and R5aand R5bare independently hydrogen, phenyl, N(Rd)2, CON(Rd)2, ORe, or (Ci-Ce)alkyl, wherein the (Ci-Ce)alkyl is optionally substituted with one or more instances of halo, hydroxy, heterocycloalkyl, phenyl, N(Rd)2, or CON(Rd)2; wherein at least one of R4a, R4b, R5a, and R5bis phenyl, N(Rd)2, CON(Rd)2, ORe, or (Ci-C6)alkyl; wherein the (Ci-C6)alkyl is substituted with one or more instances of alkoxy, phenyl, N(Rd)2, or CON(Rd)2;

[0472] Rcis independently for each occurrence hydrogen or (Ci-Ce)alkyl; or two occurrences of Rctaken together with the nitrogen to which they are attached form a 4- to 7-membered heterocycloalkyl;

[0473] Rdis independently for each occurrence hydrogen or (Ci-Ce)alkyl; or two occurrences of Rdtaken together with the nitrogen to which they are attached form a 4- to 7-membered heterocycloalkyl; and

[0474] Reis hydrogen or (Ci-C6)alkyl.

[0475] In certain aspects, provided herein is a compound according to Formula (I):

[0476] R4aR5a

[0477]

[0478] or a pharmaceutically acceptable salt thereof;

[0479] wherein:

[0480] R1is hydrogen or (Ci-Ce)alkyl;

[0481] - 42 - FH13161920.1 GPX-02525

[0482] R2is hydrogen or (Ci-Ce)alkyl optionally substituted with one or more substituents selected from hydroxy, (Ci-Ce)alkoxy, halo, cyano, (C3-Cs)cycloalkyl and 4- to 7-membered heterocycloalkyl; wherein (C3-Cs)cycloalkyl, 4- to 7-membered heterocycloalkyl are each optionally substituted with one or more substituents selected from halo, (Ci-Ce)alkyl, hydroxy, (Ci-Ce)alkoxy, (Ci-C6)alkoxy(Ci-C6)alkyl, (Ci-C6)haloalkyl, (Ci-C6)haloalkoxy, cyano, and N(RC)2;

[0483] R3is (Ci-Ce)alkyl optionally substituted with halo, (C3-Cs)cycloalkyl or phenyl, each of which is optionally substituted with one or more substituents selected from halo, (Ci-Ce)haloalkyl and (Ci-Ce)alkyl;

[0484] R4aand R4bare independently hydrogen, phenyl, N(Rd)2, CON(Rd)2, ORe, or (Ci-Ce)alkyl; wherein the (Ci-Ce)alkyl is optionally substituted with one or more instances of halo, hydroxy, heterocycloalkyl, phenyl, N(Rd)2, or CON(Rd)2; and

[0485] R5aand R5bare independently hydrogen, phenyl, N(Rd)2, CON(Rd)2, ORe, or (Ci-Ce)alkyl, wherein the (Ci-Ce)alkyl is optionally substituted with one or more instances of halo, hydroxy, heterocycloalkyl, phenyl, N(Rd)2, or CON(Rd)2; wherein at least one of R4a, R4b, R5a, and R5bis phenyl, N(Rd)2, CON(Rd)2, ORe, or (Ci-C6)alkyl; wherein the (Ci-C6)alkyl is substituted with one or more instances of alkoxy, phenyl, N(Rd)2, or CON(Rd)2;

[0486] Rcis independently for each occurrence hydrogen or (Ci-Ce)alkyl; or two occurrences of Rctaken together with the nitrogen to which they are attached form a 4- to 7-membered heterocycloalkyl;

[0487] Rdis independently for each occurrence hydrogen or (Ci-Ce)alkyl; or two occurrences of Rdtaken together with the nitrogen to which they are attached form a 4- to 7-membered heterocycloalkyl; and

[0488] Reis hydrogen or (Ci-C6)alkyl.

[0489] In certain embodiments, the compound has the structure of Formula (la) or (lb):

[0490]

[0491] - 43 - FH13161920.1 GPX-02525

[0492] or a pharmaceutically acceptable salt thereof.

[0493] In certain embodiments, R1is methyl.

[0494] In certain embodiments, R2is (Ci-Ce)alkyl substituted with 4- to 7- membered heterocycloalkyl.

[0495] In certain embodiments, R2is methyl substituted with 4- to 7- membered heterocycloalkyl.

[0496] In certain embodiments, R2is methyl substituted with 4- to 7- membered heterocycloalkyl and fluoro.

[0497] In certain embodiments, R3is (Ci-Ce)alkyl optionally substituted with (C3-Cs)cycloalkyl.

[0498] In certain embodiments, R3is methyl substituted with (C3-Cs)cycloalkyl.

[0499] In certain embodiments, R3is methyl substituted with cyclopropyl, cyclobutyl, or cyclopentyl.

[0500] In certain embodiments, three of R4a, R4b, R5aand R5bare hydrogen.

[0501] In certain embodiments, one of R4a, R4b, R5aand R5bis (Ci-Ce)alkyl substituted with one or more instances of alkoxy, phenyl, N(Rd)2, or CON(Rd)2.

[0502] In certain embodiments, one of R4a, R4b, R5aand R5bis phenyl.

[0503] In certain embodiments, one of R4a, R4b, R5aand R5bis N(Rd)2, CON(Rd)2, or ORe.

[0504] In certain embodiments, each Rdis hydrogen.

[0505] In certain embodiments, each Rdis methyl.

[0506] In certain embodiments, one Rdis methyl and one Rdis hydrogen.

[0507] In certain embodiments, Reis hydrogen.

[0508] In certain aspects, provided herein is a compound having the structure of Formula (II):

[0509] - 44 - FH13161920.1 GPX-02525

[0510] R4aR5a

[0511] R4b-N N-R5b

[0512] ^R1

[0513]

[0514] R2(II);

[0515] or a pharmaceutically acceptable salt thereof, wherein:

[0516] R1and R2taken together with the carbon atom to which they are attached form a heterocyclic ring having the structure:

[0517] R

[0518] ia

[0519] N.

[0520]

[0521] Rais (Ci-Ce)alkyl optionally substituted with 4- to 7-membered heterocycloalkyl;

[0522]

[0523] (b) R 0; wherein:

[0524] Rbis (Ci-Ce)alkyl substituted with:

[0525] (i) 4- to 7-membered heterocycloalkyl and fluoro; or

[0526] (ii) (C3-Cs)cycloalkyl optionally substituted with one or more of (Ci- Cs) alkyl and cyano; and

[0527] Rcis hydrogen or (Ci-Ce)alkyl; or

[0528] (

[0529]

[0530] c) 0; wherein:

[0531] Reis hydrogen, (Ci-Ce)alkyl optionally substituted with 4- to 7-membered heterocycloalkyl; and

[0532] Rfis hydrogen or (Ci-Ce)alkyl;

[0533] R3is (Ci-Ce)alkyl optionally substituted with (C3-Cs)cycloalkyl or phenyl, each of which is optionally substituted with one or more substituents selected from halo, (Ci-C6)haloalkyl, and (Ci-Ce)alkyl;

[0534] - 45 - FH13161920.1 GPX-02525

[0535] R4aand R4bare independently hydrogen, phenyl, N(Rd)2, C0N(Rd)2, ORg, or (Ci-Ce)alkyl, wherein the (Ci-Ce)alkyl is optionally substituted with one or more instances of halo, hydroxy, heterocycloalkyl, phenyl, N(Rd)2, or CON(Rd)2;

[0536] R5aand R5bare independently hydrogen, phenyl, N(Rd)2, CON(Rd)2, ORg, or (Ci-Ce)alkyl, wherein the (Ci-Ce)alkyl is optionally substituted with one or more instances of halo, hydroxy, heterocycloalkyl, phenyl, N(Rd)2, or CON(Rd)2;

[0537] Rdis independently for each occurrence hydrogen or (Ci-Ce)alkyl, or two occurrences of Rdtaken together with the nitrogen to which they are attached form a 4- to 7-membered heterocycloalkyl; and

[0538] Rgis hydrogen or (Ci-C6)alkyl.

[0539] In certain embodiments, the compound has the structure of formula (Ila) or (lib):

[0540]

[0541] or a pharmaceutically acceptable salt thereof, wherein:

[0542] if the compound is formula (Ila), then R1and R2taken together with the carbon atom to which they are attached form a heterocyclic ring having the structure of (Ila-i), (Ila-ii), or (Ila-iii):

[0543]

[0544] - 46 - FH13161920.1 GPX-02525

[0545] R4aR5a

[0546] R4b-N N-R5b

[0547]

[0548] ReO (Ila-iii); or

[0549] if the compound is Formula (lib), then R1and R2taken together with the carbon atom to which they are attached form a heterocyclic ring having the structure (Ilb-i), (Ilb-ii), or (Ilb-iii):

[0550] R4b-N N-R5b

[0551] N N R

[0552] O (Ilb-i),

[0553] R4b-N N- R5b

[0554] Rb

[0555] I

[0556] _N

[0557] N

[0558] (Ilb-ii), or

[0559] R4aR5a

[0560] R‘

[0561] Re

[0562] N

[0563] N

[0564]

[0565] Rf (Ilb-iii).

[0566] In certain embodiments, R3is (Ci-Ce)alkyl optionally substituted with (C3-Cs)cycloalkyl.

[0567] In certain embodiments, R3is methyl substituted with (C3-Cs)cycloalkyl.

[0568] - 47 - FH13161920.1 GPX-02525

[0569] In certain embodiments, R3is methyl substituted with cyclopropyl, cyclobutyl, or cyclopentyl.

[0570] In certain embodiments, three of R4a, R4b, R5aand R5bare hydrogen.

[0571] In certain embodiments, one of R4a, R4b, R5aand R5bis (Ci-C6)alkyl.

[0572] In certain embodiments, one of R4a, R4b, R5aand R5bis methyl.

[0573] In certain aspects, provided herein is a compound according to Formula (III):

[0574] R4aR5a

[0575]

[0576] (III),

[0577] or a pharmaceutically acceptable salt thereof;

[0578] wherein:

[0579] R1is hydrogen or (Ci-Ce)alkyl;

[0580] R2is hydrogen or (Ci-Ce)alkyl optionally substituted with one or more substituents selected from hydroxy, (Ci-Ce)alkoxy, halo, cyano, (C3-Cs)cycloalkyl and 4- to 7-membered heterocycloalkyl; wherein (C3-Cs)cycloalkyl, 4- to 7-membered heterocyclo alkyl are each optionally substituted with one or more substituents selected from halo, (Ci-Ce)alkyl, hydroxy, (Ci-Ce)alkoxy, (Ci-C6)alkoxy(Ci-C6)alkyl, halo, (Ci-C6)haloalkyl, (Ci-C6)haloalkoxy, cyano, and N(RC)2;

[0581] R3is (Ci-Ce)alkyl substituted with one or more substituents selected from halo and (C3-Cs)cycloalkyl, wherein (C3-Cs)cycloalkyl is substituted with one or more substituents selected from halo, halo(Ci-C6)alkyl and (Ci-Ce)alkyl;

[0582] R4aand R4bare independently hydrogen, phenyl, N(Rd)2, CON(Rd)2, ORe, or (Ci-Ce)alkyl, wherein the (Ci-C6)alkyl is optionally substituted with one or more instances of halo, hydroxy, heterocycloalkyl, phenyl, N(Rd)2, or CON(Rd)2; and

[0583] - 48 - FH13161920.1 GPX-02525

[0584] R5aand R5bare independently hydrogen, phenyl, N(Rd)2, CON(Rd)2, ORe, or (Ci-Ce)alkyl, wherein the (Ci-Ce)alkyl is optionally substituted with one or more instances of halo, hydroxy, heterocycloalkyl, phenyl, N(Rd)2, or CON(Rd)2;

[0585] Rcis independently for each occurrence hydrogen or (Ci-Ce)alkyl; or two occurrences of Rctaken together with the nitrogen to which they are attached form a 4- to 7-membered heterocycloalkyl;

[0586] Rdis independently for each occurrence hydrogen or (Ci-Ce)alkyl; or two occurrences of Rdtaken together with the nitrogen to which they are attached form a 4- to 7-membered heterocycloalkyl; and

[0587] Reis hydrogen or (Ci-C6)alkyl.

[0588] In certain embodiments, the compound has the structure of Formula (Illa) or (Illb):

[0589]

[0590] (Illb),

[0591] or a pharmaceutically acceptable salt thereof.

[0592] In certain embodiments, R3is (Ci-Ce)alkyl substituted with one or more instances of fluoro.

[0593] In certain embodiments, R3is 4,4,4-trifluorobutyl.

[0594] In certain embodiments, R3is (Ci-Ce)alkyl substituted with cyclobutyl, wherein cyclobutyl is substituted with one or more instances of fluoro or (Ci-Ce)fluoroalkyl.

[0595] In certain embodiments, R3is 2,2-difluoromethyl, 3,3-difluoromethyl, or 3-(trifluoromethyl)cyclobutylmethyl.

[0596] In certain embodiments, three of R4a, R4b, R5aand R5bare hydrogen.

[0597] In certain embodiments, one of R4a, R4b, R5aand R5bis (Ci-C6)alkyl.

[0598] - 49 - FH13161920.1 GPX-02525

[0599] In certain embodiments, one of R4a, R4b, R5aand R5bis methyl.

[0600] In certain aspects, provided herein is a compound having the structure of Formula (XXIII):

[0601]

[0602] or a pharmaceutically acceptable salt thereof, wherein:

[0603] Rais hydrogen, ORe, SRe, (Ci-Ce)alkyl, (C3-Cs)cycloalkyl, (C3-Cs)cycloalkyl(Ci-Ce)alkyl, (Ce-Cio)aryl, (C6-Cio)aryl(Ci-C6)alkyl, 4- to 7-membered heterocycloalkyl, 4- to 7-membered heterocycloalkyl(Ci-C6)alkyl, 5- to 10-membered heteroaryl, or 5- to 10-membered heteroaryl(Ci-C6)alkyl; wherein (Ci-Ce)alkyl, (C3-Cs)cycloalkyl, (C3-C8)cycloalkyl(Ci-C6)alkyl, (Ce-Cio)aryl, (C6-Cio)aryl(Ci-C6)alkyl, 4- to 7-membered heterocycloalkyl, 4- to 7-membered heterocycloalkyl(Ci-C6)alkyl, 5- to 10-membered heteroaryl, or 5- to 10-membered heteroaryl(Ci-C6)alkyl are optionally substituted with one or more substituents selected from halo, hydroxy, (Ci-Ce)alkyl, (Ci-C6)hydroxyalkyl, (Ci-C6)haloalkyl, (Ci-Ce)alkoxy, (Ci-C6)cycloalkoxy, (Ci-C6)haloalkoxy, cyano, N(Rf)2, and SO2N(Rf)2;

[0604] R1and R2taken together with the carbon atom to which they are attached form:

[0605]

[0606] Rbis:

[0607] i) hydrogen;

[0608] - 50 - FH13161920.1 GPX-02525

[0609] ii) (Ci-Ce)alkyl optionally substituted with one or more substituents selected from hydroxy, (Ci-Ce)alkoxy, halo, cyano, N(Rf)2, (C3-Cs)cycloalkyl, 4- to 10-membered heterocycloalkyl, and 5- to 10-membered heteroaryl; wherein (C3-Cs)cycloalkyl, 4- to 10-membered heterocycloalkyl, and 5- to 10-membered heteroaryl are each optionally substituted with one or more substituents selected from halo, (Ci-Ce)alkyl, (C3-Cs)cycloalkyl, hydroxy, (Ci-Ce)alkoxy, (Ci-Ce)hydroxy alkyl, (Ci-C6)alkoxy(Ci-C6)alkyl, (Ci-C6)haloalkyl, (Ci-C6)haloalkoxy, C(0)N(Rf)2, CO2Rf, CH2CO2Rf, 5- to 10-membered heteroaryl, cyano, oxo, =NRf, N(Rf)SO2Rf, SO2Rf, CH2N(Rf)C(O)N(Rf)2, N(Rf)C(0)Rf, and N(Rf)2;

[0610] iii) (C3-Cs)cycloalkyl optionally substituted with one or more substituents selected from (Ci-Ce)alkyl, halo, and hydroxy;

[0611] iv) 4- to 7-membered heterocyclo alkyl optionally substituted with one or more substituents selected from (Ci-Ce)alkyl, halo, and hydroxy; or

[0612] v) (C2-Ce)alkynyl optionally substituted with one or more substituents selected from (Ci-Ce)alkyl, halo, and hydroxy;

[0613] Rcis hydrogen or (Ci-Ce)alkyl;

[0614] Rdis hydrogen, (Ci-Ce)alkyl, or hydroxy, and ~ represents a single bond or a double bond; wherein: i) — represents a double bond when Rdis hydrogen or (Ci-Ce)alkyl; or ii) — represents a single bond when Rdis hydroxy;

[0615] Reis hydrogen or (Ci-Ce)alkyl;

[0616] Rfis independently for each occurrence hydrogen or (Ci-Ce)alkyl, wherein (Ci-Ce)alkyl is optionally substituted with phenyl, or two occurrences of Rftaken together with the nitrogen to which they are attached form a 4- to 7- membered heterocycloalkyl; and R3is:

[0617] i) (Ci-Ce)alkyl optionally substituted with one or more substituents selected from halo, pentafluoro thio, (C3-Cs)cycloalkyl, 4- to 10-membered heterocycloalkyl, and 5- to 10-membered heteroaryl; wherein (C3-Cs)cycloalkyl is optionally substituted with one or more substituents selected from halo, (Ci-C6)haloalkyl, (C2-Ce)alkynyl, (Ci-Ce)alkyl, (Ci-Ce)hydroxyalkyl, and (Ci-C6)alkoxy(Ci-C6)alkyl; or

[0618] ii) (C3-Cs)cycloalkyl optionally substituted with one or more substituents selected from halo, hydroxy, and (Ci-C6)alkyl.

[0619] In certain aspects, provided herein is a compound having the structure of Formula (IV):

[0620] - 51 - FH13161920.1 GPX-02525

[0621] RaNH2

[0622] R2

[0623]

[0624] r1(IV),

[0625] or a pharmaceutically acceptable salt thereof, wherein:

[0626] Rais hydrogen, ORe, SRe, (Ci-Ce)alkyl, (C3-Cs)cycloalkyl, (C3-Cs)cycloalkyl(Ci-Ce)alkyl, (Ce-Cio)aryl, or (C6-Cio)aryl(Ci-C6)alkyl, wherein (Ci-Ce)alkyl, (C3-Cs)cycloalkyl, (C3-C8)cycloalkyl(Ci-C6)alkyl, (Ce-Cio)aryl, or (C6-Cio)aryl(Ci-C6)alkyl, are optionally substituted with one or more substituents selected from halo, hydroxy, (Ci-Ce)alkoxy, (Ci-Ce)haloalkoxy and cyano;

[0627] R1and R2taken together with the carbon atom to which they are attached form:

[0628]

[0629] Rbis hydrogen or (Ci-Ce)alkyl optionally substituted with one or more substituents selected from hydroxy, (Ci-Ce)alkoxy, halo, cyano, (C3-Cs)cycloalkyl and 4- to 7-membered heterocycloalkyl; wherein (C3-Cs)cycloalkyl, and 4- to 7-membered heterocycloalkyl are each optionally substituted with one or more substituents selected from halo, (Ci-Ce)alkyl, hydroxy, (Ci-Ce)alkoxy, (Ci-Ce)hydroxy alkyl, (Ci-C6)alkoxy(Ci-C6)alkyl, (Ci-C6)haloalkyl, (Ci-C6)haloalkoxy, CO2Rf, 5- to 10-membered heteroaryl, cyano, N(Rf)SO2Rf, SO2Rf, N(Rf)C(O)Rf, and N(Rf)2;

[0630] Rcis hydrogen or (Ci-Ce)alkyl;

[0631] Rdis hydrogen, (Ci-Ce)alkyl, or hydroxy, and ~ represents a single bond or a double bond; wherein: i) — represents a double bond when Rdis hydrogen or (Ci-Ce)alkyl; or ii) — represents a single bond when Rdis hydroxy;

[0632] - 52 - FH13161920.1 GPX-02525

[0633] Reis hydrogen or (Ci-Ce)alkyl;

[0634] Rfis independently for each occurrence hydrogen or (Ci-Ce)alkyl, wherein (Ci-Ce)alkyl is optionally substituted with phenyl, or two occurrences of Rftaken together with the nitrogen to which they are attached form a 4- to 7- membered heterocycloalkyl; and R3is (Ci-Ce)alkyl optionally substituted with one or more substituents selected from halo, pentafluoro thio, (C3-Cs)cycloalkyl, and 4- to 10-membered heterocycloalkyl; wherein (C3-Cs)cycloalkyl is optionally substituted with one or more substituents selected from halo, (Ci-C6)haloalkyl, and (Ci-C6)alkyl.

[0635] In certain embodiments:

[0636] Rbis hydrogen or (Ci-Ce)alkyl optionally substituted with one or more substituents selected from hydroxy, (Ci-Ce)alkoxy, halo, cyano, (C3-Cs)cycloalkyl and 4- to 7-membered heterocycloalkyl; wherein (C3-Cs)cycloalkyl, and 4- to 7-membered heterocycloalkyl are each optionally substituted with one or more substituents selected from halo, (Ci-Ce)alkyl, hydroxy, (Ci-Ce)alkoxy, (Ci-C6)alkoxy(Ci-C6)alkyl, (Ci-C6)haloalkyl, (Ci-C6)haloalkoxy, cyano, and N(Rf)2.

[0637] In certain embodiments:

[0638] R3is (Ci-Ce)alkyl optionally substituted with one or more substituents selected from halo, pentafluoro thio, and (C3-Cs)cycloalkyl, wherein (C3-Cs)cycloalkyl is optionally substituted with one or more substituents selected from halo, (Ci-C6)haloalkyl. and (Ci-C6)alkyl.

[0639] In certain embodiments, the compound has the structure of any one of Formulae (IVa-i) to (IVc-iv):

[0640]

[0641] (IVa-ii);

[0642] - 53 - FH13161920.1 GPX-02525

[0643] (IVb-ii);

[0644] (IVb-iv); (IVc-i); (IVc-ii);

[0645]

[0646] (IVc-iv);

[0647] - 54- FH13161920.1 GPX-02525

[0648] or a pharmaceutically acceptable salt thereof:

[0649] In certain embodiments, Rais hydrogen.

[0650] In certain embodiments, Rais (Ci-Ce)alkyl optionally substituted with one or more substituents selected from fluoro, hydroxy and cyano.

[0651] In certain embodiments, Rais methyl, ethyl, isopropyl, or n-butyl, each of which is optionally substituted with one or more instances of fluoro.

[0652] In certain embodiments, Rais (C3-Cs)cycloalkyl optionally substituted with one or more instances of fluoro.

[0653] In certain embodiments, Rais cyclopropyl optionally substituted with one or more instances of fluoro.

[0654] In certain preferred embodiments, Rais cyclopropyl substituted with a fluoro.

[0655] In certain embodiments, Rais (C3-C8)cycloalkyl(Ci-C6)alkyl.

[0656] In certain embodiments, Rais phenyl, benzyl, or phenethyl.

[0657] In certain embodiments, Rais hydrogen, hydroxy, thiomethoxy, methyl, ethyl, isopropyl, n-butyl, difluoromethyl, cyclopropyl, cyclobutylmethyl, hydroxymethyl, 2-

[0658]

[0659] p.

[0660] In certain preferred embodiments, Rais

[0661] In certain embodiments, the compound has the structure of any one of Formulae (IVa-i) to (IVa-iv):

[0662] - 55 - FH13161920.1 GPX-02525

[0663]

[0664] In certain embodiments, the compound has the structure of any one of Formulae (IVb-i) to (IVb-iv):

[0665]

[0666] In certain embodiments, the compound has the structure of any one of Formulae (IVc-i) to (IVc-iv):

[0667] - 56 - FH13161920.1 GPX-02525

[0668] (IVc-ii);

[0669]

[0670] (IVc-iv).

[0671] In certain embodiments, Rbis (Ci-Ce)alkyl optionally substituted with one or more substituents selected from hydroxy and fluoro.

[0672] In certain embodiments, Rbis (Ci-Ce)alkyl optionally substituted with (C3-Cs)cycloalkyl, wherein (C3-Cs)cycloalkyl is substituted with one or more substituents selected from fluoro, hydroxy, (Ci-Ce)alkyl, (Ci-Ce)fluoroalkyl, cyano, and N(Rf)2.

[0673] In certain preferred embodiments, Rbis (Ci-Ce)alkyl substituted with (C3-Cs)cycloalkyl, wherein (C3-Cs)cycloalkyl is substituted with hydroxy.

[0674] In certain embodiments, each Rfis hydrogen.

[0675] In certain embodiments, each Rfis methyl.

[0676] In certain embodiments, Rbis (Ci-Ce)alkyl substituted with 4- to 7-membered heterocycloalkyl, wherein 4- to 7-membered heterocycloalkyl is optionally substituted with one or more substituents selected from halo, hydroxy, (Ci-Ce)alkyl, and (Ci-C6)alkoxy.

[0677] In certain embodiments, Rbis:

[0678] - 57 - FH13161920.1 GPX-02525

[0679]

[0680] - 58 - FH13161920.1 GPX-02525

[0681] In certain embodiments, Rcis methyl.

[0682] In certain embodiments, R3is (Ci-Ce)alkyl optionally substituted with one or more fluoro atoms.

[0683] In certain embodiments, R3is (Ci-Ce)alkyl substituted with (C3-Cs)cycloalkyl, wherein (C3-Cs)cycloalkyl is optionally substituted with one or more substituents selected from halo and (Ci-C6)alkyl.

[0684] In certain embodiments, R3is methyl substituted with (C3-Cs)cycloalkyl, wherein (C3-Cs)cycloalkyl is optionally substituted with one or more substituents selected from halo and (Ci-C6)alkyl.

[0685] In certain embodiments, the (C3-Cs)cycloalkyl is cyclopropyl, cyclobutyl, or cyclopentyl, each of which is optionally substituted with one or more instances of a substituent selected from fluoro and (Ci-C6)alkyl.

[0686] In certain embodiments, R3is methyl substituted with cyclobutyl, wherein the cyclobutyl being is substituted with one or more fluoro, and optionally the cyclobutyl is substituted with two fluoro.

[0687] In certain embodiments, R3is:

[0688]

[0689] - 59 - FH13161920.1 GPX-02525

[0690] In certain embodiments, R

[0691]

[0692] 3is F

[0693] In certain aspects, provided herein is a compound having the structure of Formula (IVb-i):

[0694]

[0695] or a pharmaceutically acceptable salt thereof, wherein:

[0696] Rais cyclopropyl substituted with one or more instances of fluoro;

[0697] Rbis methyl substituted with (C3-Cs)cycloalkyl, wherein (C3-Cs)cycloalkyl is further substituted with hydroxy;

[0698] Rcis methyl; and

[0699] R3is methyl substituted with cyclobutyl, wherein the cyclobutyl is further substituted with one or more fluoro.

[0700] In certain embodiments:

[0701]

[0702] In certain embodiments, the compound has the structure of compound no. 257:

[0703] - 60 - FH13161920.1 GPX-02525

[0704]

[0705] (257).

[0706] In certain aspects, provided herein is a compound according to Formula (V):

[0707]

[0708] or a pharmaceutically acceptable salt thereof, wherein:

[0709] X is N or CRX;

[0710] Y is N(R4)2;

[0711] R1is hydrogen or (Ci-Ce)alkyl optionally substituted with one or more substituents selected from hydroxy, (Ci-Ce)alkoxy, halo, cyano, (C3-Cs)cycloalkyl and 4- to 7-membered heterocycloalkyl; wherein (C3-Cs)cycloalkyl, 4- to 7-membered heterocycloalkyl are each optionally substituted with one or more substituents selected from halo, (Ci-Ce)alkyl, hydroxy, (Ci-Ce)alkoxy, (Ci-C6)alkoxy(Ci-C6)alkyl, (Ci-C6)haloalkyl, (Ci-C6)haloalkoxy, cyano, and N(RC)2;

[0712] Rcis independently for each occurrence hydrogen or (Ci-Ce)alkyl; or two occurrences of Rctaken together with the nitrogen to which they are attached form a 4- to 7- membered heterocycloalkyl;

[0713] R2is hydrogen or (Ci-Ce)alkyl;

[0714] R3is (Ci-C6)haloalkyl or (Ci-Ce)alkyl substituted with (C3-Cs)cycloalkyl, wherein (C3-Cs)cycloalkyl is optionally substituted with one or more substituents selected from halo, (Ci-Ce)alkyl, and (Ci-C6)haloalkyl

[0715] - 61 - FH13161920.1 GPX-02525

[0716] R4is independently for each occurrence hydrogen or (Ci-Ce)alkyl; or two occurrences of R4taken together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycloalkyl; and

[0717] Rxis hydrogen or (Ci-C6)alkyl.

[0718] In certain embodiments, the compound has the structure of Formula (Va) or (Vb):

[0719] Y

[0720]

[0721] or a pharmaceutically acceptable salt thereof.

[0722] In certain embodiments, Y is NH2.

[0723] In certain embodiments, R3is CH2CH2CH2CF3, or cyclopentylmethyl.

[0724] In certain embodiments, X is CH.

[0725] In certain embodiments, X is N.

[0726] In certain embodiments, R1is (Ci-Ce)alkyl substituted with 4- to 7-membered heterocycloalkyl.

[0727] In certain embodiments, R1is methyl substituted with 4- to 7-membered heterocycloalkyl.

[0728] In certain embodiments, R2is hydrogen.

[0729] In certain embodiments, R2is (Ci-C6)alkyl.

[0730] In certain embodiments, R2is methyl.

[0731] In certain aspects, provided herein is a compound of Formula (XXIV):

[0732] - 62 - FH13161920.1 GPX-02525

[0733]

[0734] or a pharmaceutically acceptable salt thereof, wherein:

[0735] R1and R2taken together with the carbon atom to which they are attached form:

[0736] R\ / O

[0737]

[0738] Rais hydrogen or (Ci-Ce)alkyl optionally substituted with one or more substituents selected from hydroxy, (Ci-Ce)alkoxy, (Ci-C6)haloalkoxy, C(O)N(RC)2, halo, cyano, (C3-Cs)cycloalkyl and 4- to 7-membered heterocycloalkyl; wherein (C3-Cs)cycloalkyl, 4- to 7-membered heterocycloalkyl are each optionally substituted with one or more substituents selected from halo, (Ci-Ce)alkyl, hydroxy, (Ci-Ce)hydroxy alkyl, CChR0, SChR0, SO2N(CO)RC, C(O)N(RC)2, =NH, C(O)NOH, (Ci-C6)alkoxy, (Ci-C6)alkoxy(Ci-C6)alkyl, (Ci-C6)haloalkyl, (Ci-C6)haloalkoxy, cyano, and N(RC)2;

[0739] Rbis hydrogen or (Ci-Ce)alkyl;

[0740] Rcis independently for each occurrence hydrogen or (Ci-Ce)alkyl; or two occurrences of Rctaken together with the nitrogen to which they are attached form a 4- to 7- membered heterocycloalkyl;

[0741] R3is (Ci-Ce)alkyl optionally substituted with one or more substituents selected from halo and (C3-Cs)cycloalkyl, wherein (C3-Cs)cycloalkyl is optionally substituted with one or more substituents selected from (Ci-Ce)alkyl, (Ci-C6)haloalkyl, and halo;

[0742] R4is independently for each occurrence hydrogen, (Ci-Ce)alkyl, or two occurrences of R4taken together with the nitrogen atom to which they are attached forms a 4- to 7-membered heterocycloalkyl;

[0743] X1is CH or N;

[0744] X2is CR5or N; provided that at least one of X1is X2is N;

[0745] - 63 - FH13161920.1 GPX-02525

[0746] R5is hydrogen, hydroxy, (Ci-Ce)alkyl, (Ci-Ce)haloalkyl, (Ci-C6)haloalkoxy, (Ci-Ce)hydroxyalkyl, (Ci-C6)alkoxy(Ci-C6)alkyl, (C3-Cs)cycloalkyl, CN, CO2R6, (Ci-C6)haloalkoxy(Ci-C6)alkyl, C(O)N(R7)2, or halo;

[0747] R6is hydrogen or (Ci-Ce)alkyl;

[0748] R7is independently for each occurrence selected from hydrogen and (Ci-Ce)alkyl,

[0749] provided the compound is not:

[0750]

[0751] In certain aspects, provided herein is a compound of Formula (VI):

[0752]

[0753] r2(VI);

[0754] or a pharmaceutically acceptable salt thereof, wherein:

[0755] R1and R2taken together with the carbon atom to which they are attached form:

[0756] (a) O; or

[0757]

[0758] Rais hydrogen or (Ci-Ce)alkyl optionally substituted with one or more substituents selected from hydroxy, (Ci-Ce)alkoxy, (Ci-C6)haloalkoxy, C(O)N(RC)2, halo, cyano, (C3-Cs)cycloalkyl and 4- to 7-membered heterocycloalkyl; wherein (C3-Cs)cycloalkyl, 4- to 7-membered heterocycloalkyl are each optionally substituted with one or more substituents selected from halo, (Ci-C6)alkyl, hydroxy, CO2RC, SO2RC, SO2N(CO)RC, C(O)N(RC)2, C(O)NOH, (Ci-Ce)alkoxy, (Ci-C6)alkoxy(Ci-C6)alkyl, (Ci-C6)haloalkyl, (Ci-C6)haloalkoxy, cyano, and N(RC)2;

[0759] - 64 - FH13161920.1 GPX-02525

[0760] Rbis hydrogen or (Ci-Ce)alkyl;

[0761] Rcis independently for each occurrence hydrogen or (Ci-Ce)alkyl; or two occurrences of Rctaken together with the nitrogen to which they are attached form a 4- to 7-membered heterocycloalkyl;

[0762] R3is (Ci-Ce)alkyl optionally substituted with one or more substituents selected from halo and (C3-Cs)cycloalkyl, wherein (C3-Cs)cycloalkyl is optionally substituted with one or more substituents selected from (Ci-Ce)alkyl, (Ci-C6)haloalkyl, and halo;

[0763] R4is independently for each occurrence hydrogen, (Ci-Ce)alkyl, or two occurrences of R4taken together with the nitrogen atom to which they are attached forms a 4- to 7-membered heterocycloalkyl;

[0764] X1is CH or N;

[0765] X2is CR5or N; provided that at least one of X1is X2is N;

[0766] R5is hydrogen, hydroxy, (Ci-Ce)alkyl, (Ci-C6)haloalkyl, (Cl-C6)haloalkoxy, (Ci-Ce)hydroxyalkyl, (Ci-C6)alkoxy(Ci-C6)alkyl, (C3-Cs)cycloalkyl, CN, CO2R6, (Ci-C6)haloalkoxy(Ci-C6)alkyl, C(O)N(R7)2, or halo;

[0767] R6is hydrogen or (Ci-Ce)alkyl;

[0768] R7is independently for each occurrence selected from hydrogen and (Ci-Ce)alkyl, £ 'T

[0769] <...1,. A...i,

[0770] o

[0771] provided the compound is not:

[0772]

[0773] In certain embodiments, the compound is represented by Formula (Via), (VIb), (Vic),

[0774]

[0775] - 65 - FH13161920.1 GPX-02525

[0776]

[0777] (Vic); or

[0778] In certain embodiments, Rais hydrogen or (Ci-Ce)alkyl optionally substituted with one or more substituents selected from hydroxy, (Ci-Ce)alkoxy, halo, cyano, (C3-Cs)cycloalkyl and 4- to 7-membered heterocycloalkyl; wherein (C3-Cs)cycloalkyl, 4- to 7-membered heterocycloalkyl are each optionally substituted with one or more substituents selected from halo, (Ci-Ce)alkyl, hydroxy, (Ci-Ce)alkoxy, (Ci-C6)alkoxy(Ci-C6)alkyl, (Ci-C6)haloalkyl, (Ci-C6)haloalkoxy, cyano, and N(RC)2.

[0779] In certain embodiments, X1is N.

[0780] In certain embodiments, X2is CR5.

[0781] In certain embodiments, R5is cyano, chloro, fluoro, CO2H, (Ci-Ce)alkyl, or (Ci-Ce)fluoroalkyl.

[0782] In certain embodiments, R5is hydrogen.

[0783] In certain embodiments, X2is N.

[0784] In certain embodiments, X1is CH.

[0785] In certain embodiments, R1is (Ci-Ce)alkyl substituted with 4- to 7-membered heterocycloalkyl.

[0786] In certain embodiments, R2is hydrogen or methyl.

[0787] In certain embodiments, R3is methyl substituted with (C3-Cs)cycloalkyl.

[0788] In certain embodiments, R3is -CH2CH2CH2CH3, -CH2CH2CH2CF3, -CH2CH2CF3,

[0789]

[0790] - 66 - FH13161920.1 GPX-02525

[0791] In certain embodiments, each R4is hydrogen.

[0792] In certain aspects, provided herein is a compound of Formula (VII):

[0793]

[0794] or a pharmaceutically acceptable salt thereof, wherein:

[0795] R1is (Ci-Ce)alkyl optionally substituted with halo or (C3-Cs)cycloalkyl, wherein (C3-Cs)cycloalkyl is optionally substituted with one or more substituents selected from halo and (Ci-C6)alkyl;

[0796] X is N or CR2;

[0797] R2is hydrogen, halo, N(Ra)2, or (Ci-Ce)alkyl;

[0798] R3is hydrogen, N(Ra)2, (Ci-Ce)alkoxy, (C3-Cs)cycloalkyl, or (Ci-Ce)alkyl, wherein (C3-Cs)cycloalkyl and (Ci-Ce)alkyl are each optionally substituted with one or more halo;

[0799] R4is hydrogen, (Ci-Ce)alkyl or N(Ra)2;

[0800] Rais independently for each occurrence hydrogen or (Ci-Ce)alkyl, or two occurrences of Rataken together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycloalkyl;

[0801] R6is hydrogen or (Ci-Ce)alkyl optionally substituted with one or more substituents selected from hydroxy, (Ci-Ce)alkoxy, halo, cyano, (C3-Cs)cycloalkyl and 4- to 7-membered heterocycloalkyl; wherein (C3-Cs)cycloalkyl, 4- to 7-membered heterocycloalkyl are each optionally substituted with one or more substituents selected from halo, (Ci-Ce)alkyl, hydroxy, (Ci-Ce)alkoxy, (Ci-C6)alkoxy(Ci-C6)alkyl, (Ci-C6)haloalkyl, (Ci-C6)haloalkoxy, cyano, and N(RC)2;

[0802] Rcis independently for each occurrence hydrogen or (Ci-Ce)alkyl; or two occurrences of Rctaken together with the nitrogen to which they are attached form a 4- to 7- membered heterocycloalkyl; and

[0803] R7is hydrogen or (Ci-C6)alkyl.

[0804] In certain embodiments, the compound has the structure of Formula (Vila) or (Vllb):

[0805] - 67 - FH13161920.1 GPX-02525

[0806]

[0807] pharmaceutically acceptable salt thereof.

[0808] In certain embodiments, R4is hydrogen, (Ci-Ce)alkyl or N(Ra)2;

[0809] In certain embodiments, R1is (Ci-Ce)alkyl substituted with (C3-C8)cycloalkyl.

[0810] In certain embodiments, R6is (Ci-Ce)alkyl optionally substituted with 4- to 7-membered heterocycloalkyl.

[0811] In certain embodiments, R6is methyl substituted with 4- to 7-membered heterocycloalkyl.

[0812] In certain embodiments, R7is methyl.

[0813] In certain embodiments, Xis CN(Ra)2; and R3and R4are each hydrogen.

[0814] In certain embodiments, Xis CR2, R3is N(Ra)2; and R4is hydrogen.

[0815] In certain embodiments, R2is hydrogen, fluoro, or (Ci-C6)alkyl.

[0816] In certain embodiments, X is N; and R3and R4are each N(Ra)2.

[0817] In certain embodiments, each Rais hydrogen.

[0818] In certain aspects, provided herein is a compound according to Formula (VIII):

[0819]

[0820] - 68 - FH13161920.1 GPX-02525

[0821] X and Y are defined such that:

[0822] a) X is hydrogen and Y is halo;

[0823] b) X is N(R4)2and Y is hydrogen; or

[0824] c) X is halo and Y is N(R4)2;

[0825] R1is hydrogen or (Ci-Ce)alkyl optionally substituted with one or more substituents selected from hydroxy, (Ci-Ce)alkoxy, halo, cyano, (C3-Cs)cycloalkyl and 4- to 7-membered heterocycloalkyl; wherein (C3-Cs)cycloalkyl, 4- to 7-membered heterocycloalkyl are each optionally substituted with one or more substituents selected from halo, (Ci-Ce)alkyl, hydroxy, (Ci-Ce)alkoxy, (Ci-C6)alkoxy(Ci-C6)alkyl, (Ci-C6)haloalkyl, (Ci-C6)haloalkoxy, cyano, and N(RC)2;

[0826] Rcis independently for each occurrence hydrogen or (Ci-Ce)alkyl; or two occurrences of Rctaken together with the nitrogen to which they are attached form a 4- to 7- membered heterocycloalkyl;

[0827] R2is hydrogen or (Ci-Ce)alkyl;

[0828] R3is (Ci-Ce)alkyl optionally substituted with halo or (C3-Cs)cycloalkyl, wherein (C3-Cs)cycloalkyl is optionally substituted with one or more substituents selected from halo, (Ci-Ce)alkyl, and (Ci-C6)haloalkyl; and

[0829] R4is independently for each occurrence hydrogen or (Ci-Ce)alkyl; or two occurrences of R4taken together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycloalkyl.

[0830] In certain embodiments, the compound has the structure of Formula (Villa) or (Vlllb)

[0831]

[0832] or a pharmaceutically acceptable salt thereof.

[0833] In certain embodiments, Y is chloro.

[0834] In certain embodiments, X is NH2.

[0835] - 69 - FH13161920.1 GPX-02525

[0836] In certain embodiments, X is hydrogen.

[0837] In certain embodiments, Y is NH2; and X is chloro.

[0838] In certain aspects, provided herein is a compound having the structure of Formula (IX):

[0839]

[0840] or a pharmaceutically acceptable salt thereof, wherein:

[0841] R1is (Ci-Ce)alkyl optionally substituted with halo or (C3-Cs)cycloalkyl, wherein (C3-Cs)cycloalkyl is optionally substituted with one or more substituents selected from halo, (Ci-Ce)alkyl, and (Ci-C6)haloalkyl; and

[0842] R2is hydrogen or (Ci-Ce)alkyl;

[0843] R3is hydrogen or (Ci-Ce)alkyl optionally substituted with one or more substituents selected from hydroxy, (Ci-Ce)alkoxy, halo, cyano, (C3-Cs)cycloalkyl and 4- to 7-membered heterocycloalkyl; wherein (C3-Cs)cycloalkyl, 4- to 7-membered heterocycloalkyl are each optionally substituted with one or more substituents selected from halo, (Ci-Ce)alkyl, hydroxy, (Ci-Ce)alkoxy, (Ci-C6)alkoxy(Ci-C6)alkyl, (Ci-C6)haloalkyl, (Ci-C6)haloalkoxy, cyano, and N(RC)2; and

[0844] Rcis independently for each occurrence hydrogen or (Ci-Ce)alkyl; or two occurrences of Rctaken together with the nitrogen to which they are attached form a 4- to 7- membered heterocycloalkyl.

[0845] In certain embodiments, the compound has the structure of Formula (IXa) or (IXb):

[0846]

[0847] - 70 - FH13161920.1 GPX-02525

[0848] or a pharmaceuically acceptable salt thereof.

[0849] In certain aspects, provided herein is a compound of Formula (Xi) or (Xii):

[0850]

[0851] or a pharmaceutically acceptable salt thereof, wherein:

[0852] R1is hydrogen or (Ci-Ce)alkyl optionally substituted with one or more halo or (C3-Cs)cycloalkyl, wherein (C3-Cs)cycloalkyl is optionally substituted with one or more substituents selected from halo, (Ci-Ce)alkyl, and (Ci-C6)haloalkyl;

[0853] R2is hydrogen or (Ci-Ce)alkyl;

[0854] R3is hydrogen or (Ci-Ce)alkyl;

[0855] R4is hydrogen or (Ci-Ce)alkyl optionally substituted with one or more substituents selected from hydroxy, (Ci-Ce)alkoxy, halo, cyano, (C3-Cs)cycloalkyl and 4- to 7-membered heterocycloalkyl; wherein (C3-Cs)cycloalkyl, 4- to 7-membered heterocycloalkyl are each optionally substituted with one or more substituents selected from halo, (Ci-Ce)alkyl, hydroxy, (Ci-Ce)alkoxy, (Ci-C6)alkoxy(Ci-C6)alkyl, (Ci-C6)haloalkyl, (Ci-C6)haloalkoxy, cyano, and N(RC)2; and

[0856] Rcis independently for each occurrence hydrogen or (Ci-Ce)alkyl; or two occurrences of Rctaken together with the nitrogen to which they are attached form a 4- to 7- membered heterocycloalkyl.

[0857] In certain embodiments, the compound has the structure of Formula (Xi):

[0858] N-R3

[0859]

[0860] R4O (Xi),

[0861] or a pharmaceutically acceptable salt thereof.

[0862] - 71 - FH13161920.1 GPX-02525

[0863] In certain embodiments, the compound has the structure of Formula (Xi-a) (Xi-b), (Xii-a), or (Xii-b):

[0864]

[0865] or a pharmaceutically acceptable salt thereof.

[0866] In certain embodiments, the compound has the structure of Formula (Xi-a) or (Xi-b):

[0867]

[0868] or a pharmaceutically acceptable salt thereof.

[0869] In certain embodiments, R2is methyl.

[0870] In certain embodiments, R2is hydrogen.

[0871] In certain embodiments, R1is methyl substituted with C3-Cs)cycloalkyl.

[0872] In certain embodiments, R3is methyl.

[0873] - 72 - FH13161920.1 GPX-02525

[0874] In certain embodiments, R4is 4- to 7-membered heterocycloalkyl optionally substituted with one or more substituents selected from halo, (Ci-Ce)alkyl, hydroxy, (Ci-Ce)alkoxy, (Ci-C6)alkoxy(Ci-C6)alkyl, (Ci-C6)haloalkyl, (Ci-C6)haloalkoxy, cyano, and N(RC)2.

[0875] In certain aspects, provided herein is a compound according to Formula (XI):

[0876]

[0877] or a pharmaceutically acceptable salt thereof, wherein:

[0878] X is N or CRX;

[0879] Y is N(R4)2;

[0880] R1is hydrogen or (Ci-Ce)alkyl optionally substituted with one or more substituents selected from hydroxy, (Ci-Ce)alkoxy, halo, cyano, (C3-Cs)cycloalkyl and 4- to 7-membered heterocycloalkyl; wherein (C3-Cs)cycloalkyl, 4- to 7-membered heterocycloalkyl are each optionally substituted with one or more substituents selected from halo, (Ci-Ce)alkyl, hydroxy, (Ci-Ce)alkoxy, (Ci-C6)alkoxy(Ci-C6)alkyl, (Ci-C6)haloalkyl, (Ci-C6)haloalkoxy, cyano, and N(RC)2;

[0881] Rcis independently for each occurrence hydrogen or (Ci-Ce)alkyl; or two occurrences of Rctaken together with the nitrogen to which they are attached form a 4- to 7- membered heterocycloalkyl;

[0882] R2is hydrogen or (Ci-Ce)alkyl;

[0883] R3is (Ci-C6)haloalkyl or (Ci-Ce)alkyl substituted with (C3-Cs)cycloalkyl, wherein (C3-Cs)cycloalkyl is optionally substituted with one or more substituents selected from halo, (Ci-Ce)alkyl, and (Ci-C6)haloalkyl

[0884] R4is independently for each occurrence hydrogen or (Ci-Ce)alkyl; or two occurrences of R4taken together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycloalkyl; and

[0885] Rxis hydrogen or (Ci-C6)alkyl.

[0886] In certain embodiments, the compound has the structure of Formula (Xia) or (Xlb):

[0887] - 73 - FH13161920.1 GPX-02525

[0888]

[0889] or a pharmaceutically acceptable salt thereof.

[0890] In certain embodiments, Y is NH2.

[0891] In certain embodiments, R3is n-butyl.

[0892] In certain embodiments, X is CH.

[0893] In certain embodiments, X is N.

[0894] In certain embodiments, R1is (Ci-Ce)alkyl optionally substituted with 4- to 7-membered heterocycloalkyl.

[0895] In certain embodiments, R1is methyl optionally substituted with 4- to 7-membered heterocycloalkyl.

[0896] In certain embodiments, R2is methyl.

[0897] In certain aspects, provided herein is a compound according to Formula (XII):

[0898] Y

[0899]

[0900] R2(XII);

[0901] or a pharmaceutically acceptable salt thereof, wherein:

[0902] X is N or CRX;

[0903] Y is N(R4)2;

[0904] - 74 - FH13161920.1 GPX-02525

[0905] Rlaand Rlbare each independently hydrogen or (Ci-Ce)alkyl, or Rlaand Rlbtaken together with the carbon atom to which they are attached form a 4- to 7-membered heterocycloalkyl or (C3-C8)cycloalkyl.

[0906] R2is hydrogen or (Ci-Ce)alkyl;

[0907] R3is (Ci-C6)haloalkyl or (Ci-Ce)alkyl substituted with (C3-Cs)cycloalkyl, wherein (C3-Cs)cycloalkyl is optionally substituted with one or more substituents selected from halo, (Ci-Ce)alkyl, and (Ci-C6)haloalkyl;

[0908] R4is independently for each occurrence hydrogen or (Ci-Ce)alkyl; or two occurrences of R4taken together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycloalkyl; and

[0909] Rxis hydrogen or (Ci-C6)alkyl.

[0910] In certain embodiments, the compound has the structure of Formula (Xlla) or (Xllb):

[0911]

[0912] or a pharmaceutically acceptable salt thereof.

[0913] In certain embodiments, Y is NH2.

[0914] In certain embodiments, R3is CH2CH2CH2CF3, or cyclopentylmethyl.

[0915] In certain embodiments, X is CH.

[0916] In certain embodiments, X is N.

[0917] In certain embodiments, R1is (Ci-Ce)alkyl substituted with 4- to 7-membered heterocycloalkyl.

[0918] In certain embodiments, R1is methyl substituted with 4- to 7-membered heterocycloalkyl.

[0919] - 75 - FH13161920.1 GPX-02525

[0920] In certain embodiments, R2is hydrogen.

[0921] In certain embodiments, R2is (Ci-C6)alkyl.

[0922] In certain embodiments, R2is methyl.

[0923] In certain aspects, provided herein is a compound according to Formula (XIII)

[0924]

[0925] or a pharmaceutically acceptable salt thereof, wherein:

[0926] R1and R2taken together with the carbon atom to which they are attached form:

[0927] R\.0

[0928]

[0929] Rais hydrogen or (Ci-Ce)alkyl optionally substituted with one or more substituents selected from hydroxy, (Ci-Ce)alkoxy, (Ci-C6)haloalkoxy, halo, cyano, (C3-Cs)cycloalkyl and 4- to 7-membered heterocycloalkyl; wherein (C3-Cs)cycloalkyl, 4- to 7-membered heterocycloalkyl are each optionally substituted with one or more substituents selected from halo, (Ci-C6)alkyl, hydroxy, CO2RC, SO2RC, (Ci-C6)alkoxy, (Ci-C6)alkoxy(Ci-C6)alkyl, (Ci-C6)haloalkyl, (Ci-C6)haloalkoxy, cyano, and N(RC)2;

[0930] Rbis hydrogen or (Ci-Ce)alkyl;

[0931] Rcis independently for each occurrence hydrogen or (Ci-Ce)alkyl; or two occurrences of Rctaken together with the nitrogen to which they are attached form a 4- to 7- membered heterocycloalkyl;

[0932] - 76 - FH13161920.1 GPX-02525

[0933] R3is (Ci-Ce)alkyl optionally substituted with one or more substituents selected from halo and (C3-Cs)cycloalkyl, wherein (C3-C8)cycloalkyl is optionally substituted with one or more substituents selected from (Ci-Ce) alkyl and halo;

[0934] R4is independently for each occurrence hydrogen, (Ci-Ce)alkyl, or two occurrences of R4taken together with the nitrogen atom to which they are attached forms a 4- to 7-membered heterocycloalkyl; and

[0935] R5is hydrogen, (Ci-Ce)alkyl, (Ci-C6)haloalkyl, (Ci-C6)hydroxyalkyl, (Ci-Ce)alkoxyalkyl, (C3-Cs)cycloalkyl, (Ci-Ce)alkoxy alkyl, or (Ci-C6)haloalkoxy(Ci-C6)alkyl.

[0936] In certain embodiments, R1and R2taken together with the carbon atom to which they are attached form:

[0937]

[0938] In certain embodiments, Rais (Ci-Ce)alkyl optionally substituted with one or more substituents selected from hydroxy, (Ci-Ce)alkoxy, (Ci-C6)haloalkoxy, halo, cyano, (C3-Cs)cycloalkyl and 4- to 7-membered heterocycloalkyl; wherein (C3-Cs)cycloalkyl, 4- to 7-membered heterocycloalkyl are each optionally substituted with one or more substituents selected from halo, (Ci-Ce)alkyl, hydroxy, CChR0, SChR0, (Ci-Ce)alkoxy, (Ci-Ce)alkoxy(Ci-Ce)alkyl, (Ci-C6)haloalkyl, (Ci-C6)haloalkoxy, cyano, and N(RC)2.

[0939] In certain embodiments, Rbis hydrogen or (Ci-C6)alkyl.

[0940] In certain embodiments, R3is (Ci-Ce)alkyl optionally substituted with (C3-Cs)cycloalkyl, wherein (C3-Cs)cycloalkyl is optionally substituted with one or more substituents selected from (Ci-Ce) alkyl and halo.

[0941] In certain embodiments, each R4is hydrogen.

[0942] In certain embodiments, R5is (Ci-C6)alkyl.

[0943] In certain aspects, provided herein is a compound having the structure of Formula (XIV):

[0944] - 77 - FH13161920.1 GPX-02525

[0945] RaNH2

[0946] R3(CH2)n

[0947]

[0948] 0(XIV),

[0949] or a pharmaceutically acceptable salt thereof, wherein:

[0950] Rais hydrogen (Ci-Ce)alkyl, (C3-Cs)cycloalkyl, (C3-C8)cycloalkyl(Ci-C6)alkyl, wherein (Ci-Ce)alkyl, (C3-Cs)cycloalkyl, (C3-C8)cycloalkyl(Ci-C6)alkyl are optionally substituted with one or more substituents selected from halo, hydroxy, (Ci-Ce)alkoxy, (Ci-Ce)haloalkoxy and cyano;

[0951] R1and R2taken together with the carbon atom to which they are attached form:

[0952]

[0953] Rbis hydrogen or (Ci-Ce)alkyl optionally substituted with one or more substituents selected from hydroxy, (Ci-Ce)alkoxy, halo, cyano, (C3-Cs)cycloalkyl and 4- to 7-membered heterocycloalkyl; wherein (C3-Cs)cycloalkyl, and 4- to 7-membered heterocycloalkyl are each optionally substituted with one or more substituents selected from halo, (Ci-Ce)alkyl, hydroxy, (Ci-Ce)alkoxy, (Ci-Ce)hydroxy alkyl (Ci-C6)alkoxy(Ci-C6)alkyl, (Ci-C6)haloalkyl, (Ci-C6)haloalkoxy, CO2Rf, 5- to 10-membered heteroaryl, cyano, N(Rf)SO2Rf, SO2Rf, NRf(CO)Rf, and N(Rf)2;

[0954] Rcis hydrogen or (Ci-Ce)alkyl;

[0955] Rfis independently for each occurrence hydrogen or (Ci-Ce)alkyl, wherein (Ci-Ce)alkyl is optionally substituted with phenyl, or two occurrences of Rftaken together with the nitrogen to which they are attached form a 4- to 7- membered heterocycloalkyl;

[0956] R3is (Ci-Ce)alkyl optionally substituted with one or more substituents selected from halo, pentafluoro thio, (C3-Cs)cycloalkyl, and 4- to 10-membered heterocycloalkyl wherein (C3-Cs)cycloalkyl is optionally substituted with one or more substituents selected from halo, (Ci-C6)haloalkyl. and (Ci-Ce)alkyl; and

[0957] n is an integer from 1 to 6.

[0958] - 78 - FH13161920.1 GPX-02525

[0959] In certain aspects, provided herein is a compound of Formula (XXV), (XXVI), (XXVII), (XXVIII) (XXIX), (XXX), or (XXXI):

[0960]

[0961] or a pharmaceutically acceptable salt thereof, wherein:

[0962] R1and R2taken together with the carbon atom to which they are attached form:

[0963] R\,. O

[0964] J N-f

[0965] < Y

[0966] (N-R

[0967]

[0968] a) Ob

[0969] ; or

[0970] - 79 - FH13161920.1 GPX-02525

[0971]

[0972] Rais hydrogen or (Ci-Ce)alkyl optionally substituted with one or more substituents selected from hydroxy, (Ci-Ce)alkoxy, (Ci-C6)haloalkoxy, halo, cyano, (C3-Cs)cycloalkyl, and 4- to 7-membered heterocycloalkyl; wherein (C3-Cs)cycloalkyl and 4- to 7-membered heterocycloalkyl are each optionally substituted with one or more substituents selected from halo, (Ci-C6)alkyl, hydroxy, CO2RC, SO2RC, (Ci-C6)alkoxy, (Ci-C6)alkoxy(Ci-C6)alkyl, (Ci-Ce)haloalkyl, (Ci-C6)haloalkoxy, cyano, and N(RC)2;

[0973] Rbis hydrogen or (Ci-Ce)alkyl;

[0974] Rcis independently for each occurrence hydrogen or (Ci-Ce)alkyl; or two occurrences of Rctaken together with the nitrogen to which they are attached form a 4- to 7- membered heterocycloalkyl;

[0975] R3is (Ci-Ce)alkyl optionally substituted with one or more substituents selected from halo and (C3-Cs)cycloalkyl, wherein (C3-Cs)cycloalkyl is optionally substituted with one or more substituents selected from (Ci-Ce)alkyl and halo;

[0976] R4is independently for each occurrence hydrogen, (Ci-Ce)alkyl, or two occurrences of R4taken together with the nitrogen atom to which they are attached forms a 4- to 7-membered heterocycloalkyl;

[0977] R5is hydrogen, (Ci-Ce)alkyl, (Ci-C6)haloalkyl, (Ci-C6)hydroxyalkyl, (Ci-Ce)alkoxyalkyl, (C3-Cs)cycloalkyl, (C3-C8)cycloalkyl(Ci-C6)alkyl, CN, CO2R6, (Ci-Ce)alkoxyalkyl, (Ci-C6)haloalkoxy(Ci-C6)alkyl, C(O)N(R7)2, or halo; wherein (C3-C8)cycloalkyl(Ci-C6)alkyl is optionally substituted with hydroxy;

[0978] R6is hydrogen or (Ci-Ce)alkyl;

[0979] R7is independently for each occurrence selected from hydrogen and (Ci-Ce)alkyl; and X is CH or N.

[0980] In certain aspects, provided herein is a compound of Formula (XV), (XVI), (XVII), (XVIII) (XIX), (XX), or (XXI):

[0981] - 80 - FH13161920.1 GPX-02525

[0982]

[0983] or a pharmaceutically acceptable salt thereof, wherein:

[0984] R1and R2taken together with the carbon atom to which they are attached form:

[0985] R\,. O

[0986] J N-f

[0987] < Y

[0988] (N-R

[0989]

[0990] a) Ob

[0991] ; or

[0992] - 81 - FH13161920.1 GPX-02525

[0993]

[0994] Rais hydrogen or (Ci-Ce)alkyl optionally substituted with one or more substituents selected from hydroxy, (Ci-Ce)alkoxy, (Ci-C6)haloalkoxy, halo, cyano, (C3-Cs)cycloalkyl and 4- to 7-membered heterocycloalkyl; wherein (C3-Cs)cycloalkyl, 4- to 7-membered heterocycloalkyl are each optionally substituted with one or more substituents selected from halo, (Ci-C6)alkyl, hydroxy, CO2RC, SO2RC, (Ci-C6)alkoxy, (Ci-C6)alkoxy(Ci-C6)alkyl, (Ci-Ce)haloalkyl, (Ci-C6)haloalkoxy, cyano, and N(RC)2;

[0995] Rbis hydrogen or (Ci-Ce)alkyl;

[0996] Rcis independently for each occurrence hydrogen or (Ci-Ce)alkyl; or two occurrences of Rctaken together with the nitrogen to which they are attached form a 4- to 7- membered heterocycloalkyl;

[0997] R3is (Ci-Ce)alkyl optionally substituted with one or more substituents selected from halo and (C3-Cs)cycloalkyl, wherein (C3-Cs)cycloalkyl is optionally substituted with one or more substituents selected from (Ci-Ce)alkyl and halo;

[0998] R4is independently for each occurrence hydrogen, (Ci-Ce)alkyl, or two occurrences of R4taken together with the nitrogen atom to which they are attached forms a 4- to 7-membered heterocycloalkyl;

[0999] R5is hydrogen, (Ci-Ce)alkyl, (Ci-C6)haloalkyl, (Ci-C6)hydroxyalkyl, (Ci-Ce)alkoxyalkyl, (C3-Cs)cycloalkyl, CN, CO2R6, (Ci-Ce)alkoxyalkyl, (Ci-C6)haloalkoxy(Ci-C6)alkyl, C(O)N(R7)2, or halo;

[1000] R6is hydrogen or (Ci-Ce)alkyl;

[1001] R7is independently for each occurrence selected from hydrogen, (Ci-Ce)alkyl; and X is CH or N.

[1002] In certain aspects, provided herein is a compound selected from the following table:

[1003] Compound Structure Compound Structure

[1004]

[1005] - 82 - FH13161920.1 GPX-02525

[1006]

[1007] - 83 - FH13161920.1 GPX-02525

[1008]

[1009] - 84 - FH13161920.1 GPX-02525

[1010]

[1011] - 85 - FH13161920.1 GPX-02525

[1012]

[1013] - 86 - FH13161920.1 GPX-02525

[1014] 19 OH 381 OH

[1015] H2N NH YXNH2

[1016] O^ JL ^O

[1017] Y

[1018] ’ V

[1019] 20 OH 382 OH

[1020] H2N^. NH Y-NH2

[1021] A VAXA / X / ^O

[1022] Y 1 L. ■?. r ay?

[1023] '""j y=O

[1024] YN

[1025] o \

[1026] 21 1

[1027] HN NH2383 ^NH2O^YL ^OH0Y

[1028] W Y r^° ^ V Qy?

[1029] '"•'1 \=o

[1030] N \

[1031] 22 1

[1032] 2384

[1033] HN NH HO Y2oAL ^o

[1034] Y I I. N===\ ■ F -’I- Cly.-0

[1035] ZN~A

[1036] '- 0

[1037] FV

[1038] 0

[1039] 23 1

[1040] H2N NH 385

[1041] 0< YY>0 oYL ^o

[1042] rj0

[1043] '^ V Gy.; '"'L >°

[1044] f '

[1045]

[1046] - 87 - FH13161920.1 GPX-02525

[1047] 24 1

[1048] H2N^ _NH 386

[1049] FsC^^N N„.^

[1050] n 1 1 ^. p

[1051] o \ JI

[1052] '"'3 ^ N—F 1QY ZN^

[1053] '-. o

[1054] Oo ■p 25 387Z^S\<NH2

[1055] _N., NZ,

[1056] T O-V

[1057] p z

[1058] 26 1

[1059] H^2)X rvV° 388Z^S\<NH2

[1060] 0 }l O - '

[1061] FSCCK

[1062] 0

[1063] N::^

[1064] 27 NH2389 ^ \ / NH2

[1065] HN NH2

[1066] FJCX^X^N^N,, ^

[1067] 0■'" T’ CW

[1068] F£T P

[1069] 28 H

[1070] ^N^NHj 390 ^ \, NH2

[1071] 0<s JL^0 ^X^YN"'O ^CP

[1072] LN

[1073] \»"j )P=O

[1074] €HNY 0

[1075]

[1076] - 88 - FH13161920.1 GPX-02525

[1077]

[1078] - 89 - FH13161920.1 GPX-02525

[1079] 33 NH2395

[1080] [> — / o L. NH2

[1081] Oy^yO

[1082] <\ / N^ ',NX) F4 Y r Y.

[1083] 0N*-o

[1084] & 34 F. 396

[1085] )— F L. NH2

[1086] H2N— <( O O

[1087] O0XY

[1088] o=\ 'sl" / 1

[1089] / H "" / N^oFp -“YN'rx,0NO- o

[1090] *— o

[1091] & 35 \ NH2397

[1092] 7p o L / NH2

[1093] Oyly>

[1094] / ' / NX

[1095] O=\N'"\ X X 1 CYNXZN,_

[1096] F< T | u r^?0<< LN 0- 0 N=V *— o

[1097] 36 NH2398

[1098] 7p o L / NH2

[1099] 0 JUo

[1100] / ' / NX

[1101] O=\N'"\ X X 1 o N N,,

[1102] Y Y 'A, r^? 0- 0 ->"'1

[1103] N= / \=0 *-o

[1104] 37 \ NH2399

[1105] 2~-7p o l\yH2

[1106] / ' / NX

[1107] O=\N'"\ X X 1

[1108] P,, / N N„.

[1109] 0- 0 F' n [

[1110] *-o

[1111] Q

[1112] 38 \ NH2400

[1113] \zp 0 L / NH2

[1114] 0< Jy0o^Nn.fVyS' O,, / NX. N;,

[1115] ”,NX) r^9

[1116] F'' ' n 1 U

[1117] 0VYLN FSC ° '"' 1 )=0

[1118] Np

[1119] *-o

[1120]

[1121] - 90 - FH13161920.1 GPX-02525

[1122] 39 \ NH2401

[1123] zp o

[1124] °=\ '

[1125] * N— << ' — ' N-^-j

[1126] . 'o |

[1127] """\ N—H°~L ° OH

[1128] 40 \ NH2402

[1129] zp o

[1130] °=\ ' M" /

[1131] RZM,NA)

[1132] 0k

[1133] L^ TCM o

[1134] / M HOJ00 OH

[1135] 41 NH

[1136] [> —2

[1137] z403

[1138] p 0

[1139] o=\ ' '<” / V*A ~ j*

[1140] R / X,N^4 ' —z z',N^O

[1141] FX>- o

[1142] ‘-0

[1143] / M Y00A°H42 NH 404

[1144] [> —2

[1145] zp o

[1146] * °=\ N— << ' — ' ''' N- J^IX-j

[1147] . <^"" / 'o. k TX,

[1148] / M k0W O 0 k

[1149]

[1150] - 91 - FH13161920.1 GPX-02525 43 NH2405

[1151] 0=( N" ( X A 1

[1152] / N¥\X—Z',NX)

[1153] 0- o

[1154] *-o

[1155] OH

[1156] 44 r° 406ZX ZNH2

[1157] NH2) —1

[1158] >-¥ / p \

[1159] rX GX ANZ N,, / ^^0HO=(NI"\ X A T

[1160] . N—F7 101 1 L N ^•.

[1161] / ' — ' N*\ Y y=o \Z — / 00 \

[1162] n°

[1163] 45 ' — < NH2407

[1164] zp 0

[1165] / ' / NZ

[1166] 0=\N'" \ X X I D^N N,,

[1167] ¥ [ V. O-. M>

[1168] 1 XN <

[1169] / ZK / 0- ° X OH 46 NH2408ZX ZNH2

[1170] [> —zp 0

[1171] °=\ Ji

[1172] ^N5> <*0-¥Y^ r5"Fsc>

[1173] 47 409

[1174] °¥¥>°

[1175] N¥

[1176]

[1177] - 92 - FH13161920.1 GPX-02525

[1178]

[1179] - 93 - FH13161920.1 GPX-02525

[1180]

[1181] - 94 - FH13161920.1 GPX-02525 58 r° 420 F

[1182] \ NH2J —1

[1183] / P \

[1184] N-^° O-Xk. O

[1185] 0=\N'" \ X cK I

[1186] w""N<

[1187] F Fp.f^...

[1188] : 0

[1189] '^OH 59 SMe 421 F

[1190] °=\ ^N" / VTA.1

[1191] r — \ / N~4 ' — /

[1192] O- 0

[1193] Lo • -T Q^.

[1194] F 1 'OH 60 NH2422 F

[1195] H0< / _ X NH2

[1196] °=\ 'n" / i oXL x)

[1197] r-\,NX ' — / ' / Nx)

[1198] O- 0

[1199] L0

[1200] 61 HO NH2423 F

[1201] 7p 0

[1202] / N^z',NT> jXzN N,, / x / ^0H0- 0F7 IT T X r^70XT ^" VVN y=o '-o

[1203] o \ 62 HO^. NH2OH

[1204] 424

[1205] zp O

[1206] °=\ ji

[1207] FP -'" TN- n. r^0" - O- 0

[1208] Lo

[1209]

[1210] - 95 - FH13161920.1 GPX-02525

[1211]

[1212] - 96 - FH13161920.1 GPX-02525

[1213] 68 F-3 NH2430

[1214] 7p o

[1215] ° \ 's|" ( j! p V A / O- o

[1216] *— o

[1217] 69 F, NH2431

[1218] p— / O 0 HO y2

[1219] O^^ A.0

[1220] O=) '

[1221] N / \ / < / ' N

[1222] \ "'\ X X TX

[1223] / N^ ' — ' ',NX) O,. / N N,„

[1224] 0- 0 F' n | X.

[1225] 0

[1226] L-o

[1227] Vx° OH

[1228] 70 F NH2432 A\ ^NH2

[1229] p— oH0H °=\ ' i N,, / ^0H~ZNX)FP T [ L, r^ / A “ '"'L

[1230] 1-0

[1231] 71F'-. NH2433 ^NHH02

[1232] Ip

[1233] °VA^° ^ LQA^,NX X)

[1234] ^Nr'CMN_ r - A. A

[1235] \ 0

[1236] OH

[1237] 72F'. NH2434Z^Xrz-NH2

[1238] oPP> O

[1239] / \ / N^zN^0

[1240] A Y CW.

[1241] 20

[1242] F F LJ)

[1243] A

[1244] Xi 0 0 \ ° s'-^r0. A^NZ"■ H

[1245]

[1246] - 97 - FH13161920.1 GPX-02525

[1247]

[1248] - 98 - FH13161920.1 GPX-02525

[1249] 78 440 A NH;,

[1250] NH2

[1251] zp 0 oA-Ao O=( 'sl" / J*

[1252] / \,NA ',NX) °A -CMc- -Lo

[1253] PZN^ 79 \ 7 — \ NH2441 'A' NHJ

[1254] / ? °\

[1255] °=\ ' / 'y?x ' i

[1256] / NA ~,NX)

[1257] 0- °

[1258] L0

[1259] / s

[1260] H AO

[1261] N*7M C^^ ooz

[1262] 80 442

[1263] 0AA.0

[1264] ^rcu / A V

[1265] OxNH0A 81 NH2443 / A / NH2

[1266] z°0

[1267] HOJM AA / VAN^

[1268] o=\N'"\ X X I

[1269] / NA ' — ' ',NX)

[1270] 0- 0

[1271] I— o / A \ 0

[1272] F3CNH2

[1273]

[1274] - 99 - FH13161920.1 GPX-02525

[1275]

[1276] - 100 - FH13161920.1 GPX-02525

[1277] 86 448

[1278] <. NH2ZYX^NH2

[1279] QYL ^G r zF\F1 \ C\ / N N,, A^N N,„ Y \ Y,0O? M <$ - ' ( * *1Qvv / zH— zN~ ANv ) >°= / o'

[1280] Y F

[1281] 87 L ^NH2449Z— k, NH2

[1282] °Yk x>

[1283] F0VV°

[1284] U^N N,„^

[1285] Y \ |. p ■ ■ ■ - ■ T

[1286] 0JI '""f N== / '""|XN—

[1287] r°

[1288] 88 <X. NH2450

[1289] °YY>°

[1290] F PVLN-^ A" N,„^FY

[1291] 0[ 1^. pF' T CYY Y / YA JI

[1292] 89

[1293] Z NH451 OH

[1294] -Y / 2 k / NH20<; Uk^0

[1295] Y

[1296] • 90 L, NH2452

[1297] OYL ^Q

[1298] > A, N

[1299] Y \ |. p

[1300] F° JI

[1301] '""1 ^ N—

[1302] YY

[1303] V

[1304]

[1305] - 101 - FH13161920.1 GPX-02525

[1306]

[1307] - 102 - FH13161920.1 GPX-02525

[1308]

[1309] - 103 - FH13161920.1 GPX-02525 100 L ^NH2462

[1310] / k^-NH2

[1311] H 1

[1312] F4 Y P G G- / n \ 1^. J 9

[1313] o IFo

[1314] N—

[1315] < / N^>Y o HCY

[1316] r°

[1317] 101 L, NH2463

[1318] Nv\^°

[1319] \ \ 1 1 OH o

[1320] JI ■ f

[1321] o

[1322] r°

[1323] 102 Y. NH2464 X / NH2

[1324] O^ JL ^O NyV0O^NFP^NN,„no F< n i p

[1325] F° Y< VXF0 kA / NY"°

[1326] '"' N—

[1327] zNY

[1328] Y °

[1329] 2 OH

[1330] 103 Y NH2465 ^Y-NH2

[1331] O^ JL ^ONV k20

[1332] F< T | p

[1333] F° ^"rctY z 5N^ o <NI

[1334] c OH G OH

[1335]

[1336] - 104 - FH13161920.1 GPX-02525 104 ^~K, NH2466

[1337] ^70 ^o- / > L.^ N„.

[1338] F< n I 1^. o

[1339] F°

[1340] )

[1341] kx°

[1342] / OH

[1343] 105 ^~K, NH2467

[1344] CX, / N N„.

[1345] F1 T \ o

[1346] F°

[1347] '"'y\ ' N—

[1348] ZO.

[1349] k< Y °=X°

[1350] oU r-V.

[1351] / 'OH

[1352] £

[1353] y z z—

[1354] 106 L- < )C >°=, NH2468

[1355] N / yYPyNH°2

[1356] . N,,H0\A^X9 F'T Y I L-F” 0<< °= / = ‘■X / WN Y \ U 9 '""1 S=o N^ / '"■'\ N—

[1357] p ’

[1358] o ] L y2 / 0

[1359] 107 469

[1360] r^VNH2Ny1^0

[1361] T r P

[1362] Fo

[1363] / N~~^ 0

[1364]

[1365] - 105 - FH13161920.1 GPX-02525 108 NH2470

[1366] £> — / O o 1 ' / \A / N / o=^ o z^xO1ZO=( N" ( X A 1X / L o / \ / NA ~ / NA) _O o

[1367] w

[1368] 0A O.q e - 0

[1369] fyz. z— "

[1370] zz. $ »

[1371] v >ty=^ ^- 109 471 ^L / NH2

[1372] Nz<

[1373] F< Y |

[1374] 0

[1375] / N~^ k '°

[1376] (AOH

[1377] ^^, zA\

[1378] \ NH2< 1 I o=

[1379] 110 472

[1380] ' — 4 / ? °\

[1381] / ' / \A /

[1382] 0=\N" \ _ QMC \ - / X A I

[1383] / \ / NA y Tz z- - '

[1384] y z— ” / °

[1385] > C >\o= A >°=

[1386] 0

[1387] NH

[1388] d

[1389] 111 N. 473

[1390] \\ NH2

[1391] zp 0

[1392] °=\ 's|" ( i

[1393] / A ' — ' ' / NX)? A

[1394] o 0- 0

[1395] Lo

[1396] 112 474 / ^ / NH2

[1397] NLA^O OH JP<-N N / z / Y A) Y

[1398] 0| Y- / '" <<w'"" Lj N ^>=0 o \

[1399]

[1400] - 106 - FH13161920.1 GPX-02525 113 ^\ ZNH2475 J\ / NH2

[1401] °V'V°

[1402] tkzN N,„

[1403] nA

[1404] r | o

[1405] °F^T'QyL ''"'T N— / M A o / 07\ ° k z°H n 0’A 'N H H

[1406] 114Z-T^, NH2476

[1407] .f 0AV

[1408] 1

[1409] ^ / oz

[1410] A—

[1411] / / 'SZ'X

[1412] 0 °

[1413] £ Q _l \ - /

[1414] z

[1415] 115 \ > >°= 477

[1416] L, NH2ZX / NH2O< V' ^0NV

[1417] V X z z —\^°

[1418] 2\ / f O X - z z, —F^rQ / — \

[1419] i / \. ^ V V7p"'-\ / - zVM.

[1420] HO'i T> OA0OZ

[1421] Vo o 1 <?

[1422] / / ''z“\

[1423] 0 °

[1424] 116 478

[1425]

[1426] - 107 - FH13161920.1 GPX-02525 117 479 J\, NH2

[1427] N<5JL^> O P< / N

[1428] F4 Y r T.F 0^ i yN\

[1429] NY

[1430] o

[1431] T V

[1432] ty 'Z—. OH X M / =< / =^ Z zK Z z \'^ I \\ T O c M / —

[1433] ° / - \

[1434] ( ) 2

[1435] \ / O

[1436] 118 \ NH

[1437] ZYS^NH24802

[1438] V 'Y7''*'-z

[1439] OY^O HY°. 1 /

[1440] YY N=^ N" Y X X I I I: XA*°0< o ■,o. N^< '''' N-% F^V''^ ^ 10 <f >— ' 0 40

[1441] -"•y ^=o F F / / .

[1442] ^0 119 Y Y. NH2481 / ^°

[1443] \ NH2

[1444] o. Jk.o

[1445] H- /

[1446] N=< N" < M YAAM 1 ^X / N N,„ \ / VV - VNXn | | o Y / -7 0 0°

[1447] '"'T N— F F

[1448] HOT O

[1449] Y

[1450] 120 482

[1451] \ NH2. Z^Y.

[1452] / P \ \ / — / — \ A.

[1453] N=\ N" < / Y N-Y 1 \_z W « yNx< Y— ' 0 0 F F

[1454]

[1455] - 108 - FH13161920.1 GPX-02525 121 483 \ NH2

[1456] H-7 ▲ 1 / QC O-' i o \='' N=\ N" < X X Iy / ^ L o °z°z / \ '' ix ^wAo / VN\- I \Z ^0"=■''' '^O r?^ A.>"F F 0( \ ° ^0 / * i —

[1457] \ 1 y ° z z '—

[1458] \ > >° y= 2 z—

[1459] c > >°= n

[1460] L^ z, - L x

[1461] ^ Z z \' I i- O c M / —

[1462] ( > z

[1463] \ / O,

[1464] 122 484 NH2

[1465] °vv°

[1466] V°* O

[1467] '""\ N—

[1468] L o

[1469] 123 485 ^X_, NH2ArNH2

[1470] NyK^O

[1471] -»■< ^=0 o^N\a.

[1472] zNS

[1473] 0

[1474] OH

[1475] 124 486 ^\^NH2

[1476] V-^N N,„^^

[1477] T | p

[1478] 0JI

[1479] ;’" T^ N—

[1480] n

[1481] F.$o«

[1482] F F

[1483]

[1484] - 109 - FH13161920.1 GPX-02525

[1485]

[1486] - 110 - FH13161920.1 GPX-02525 129 / -\ _NH2491 Y\ / N H2 1

[1487] N YY - °°ZC k

[1488] ( M \ i ° —

[1489] yzz— ■ / M )0

[1490] HO

[1491] K

[1492] 0 4

[1493] 130 \ NH2492

[1494] ' —zp O YX<NH2

[1495] N

[1496] o=\ '

[1497] Z\ W ~,NA)

[1498] \z — ' ° \ ^ r o^NHO

[1499] < Y o °= 0

[1500] 131 \ NH2

[1501] zp 0 493 ^x / NH2

[1502] z\ i ° — NyLo

[1503] o=0\ ',jy z"— (

[1504] Wc > >°= ~,NA) Ff ^NYN''fV / -OH \z — ° \F 0

[1505] HO'F'"'L >°

[1506] 132 494

[1507] ArN H2NyY° oFP^NTN^r> ^OHF 0M^N '"'L >° 0 \

[1508] 133 495

[1509] OCYYJO

[1510] T \ u 9

[1511] zNY

[1512] H° 4?0

[1513] H

[1514]

[1515] - 111 - FH13161920.1 GPX-02525

[1516] 134 \ NH2496 r^V"NH2i <°

[1517] / L o / ,Nx) A

[1518] ° V / ^ "1"^j rx yX'F

[1519] yzz— ■'\ i ° —

[1520] \ X ° —

[1521] y z z—

[1522] >° >c >°=

[1523] 135 \ NH2

[1524] ' —z497

[1525] p o ^L / NH2

[1526] O=\ 'sl" / ± uNV^V-0

[1527] Z\ / N^ ' — / ,NXD

[1528] \Z — ' °

[1529] ''v z^Ns o ^Oo 136 \ NH2498

[1530] X -oX

[1531] / N^,NX)

[1532] \Z —0''

[1533] ^F

[1534] 137 499

[1535] 0 / \

[1536] LJ-N

[1537] T >°

[1538] ^-N

[1539] 138 500

[1540] XNH2nNT ^°

[1541] F< T I 1.!'"< / F 0k / 'KJN'"'L >=0q / ) \

[1542] — i i

[1543] / )=O

[1544] y- N

[1545] HOX

[1546]

[1547] - 112 - FH13161920.1 GPX-02525

[1548]

[1549] - 113 - FH13161920.1 GPX-02525

[1550] 1 o 144 H2N CI 506 J\.NH2< / r °°

[1551] NAA^0y. or / A < Y \, _ "0N„.

[1552] \ X\ ) x ° ° —

[1553] 0y y z z zz.——' — '

[1554] zN^ 0 4

[1555] 145 NH2507

[1556] / \ Y

[1557] / \ / yN,„ / K / J °

[1558] 0AALN^A

[1559] '" Y'L~N >°

[1560] 0 \

[1561] 146 NH2508

[1562] / =\ z°NAy^rY° OZO N,, X\ AN-S\ Z\ / \^N'- \z — H 1 1 oF 0< YVN

[1563] 0'" T >=° c / Y / Y

[1564] Y

[1565] 147 Cl NH2509

[1566] n -f

[1567] r

[1568] 148 Cl NH2510

[1569] N AyYro

[1570] : 9>

[1571]

[1572] - 114 - FH13161920.1 GPX-02525

[1573]

[1574] - 115 - FH13161920.1 GPX-02525

[1575]

[1576] - 116 - FH13161920.1 GPX-02525

[1577]

[1578] - 117 - FH13161920.1 GPX-02525

[1579]

[1580] - 118 - FH13161920.1 GPX-02525

[1581]

[1582] - 119 - FH13161920.1 GPX-02525 170 NH2532

[1583] oA FaC^ ^ ^ VrNH

[1584] °2 / N N,.

[1585] ° x / Kj

[1586] '"'•r ^=o

[1587] O \

[1588] - >< M=

[1589] 171 X z z— 533

[1590] O: « -. J\,NH2

[1591] r"\ Y T.,o V-S^N N,,^ T^sk o

[1592] F 0YxH N '"'L >° 0 \ Y\ '

[1593] / o / O.

[1594] xV °°

[1595] v X

[1596] ^r)Xz~^°Z

[1597] 172 534 J\,NH2

[1598] N^UL ^O

[1599] Q\ 9q c £ \ - '

[1600] ..p -.^Ytp, r<g y z z— y z z -1—' '—aF 0YxH N v )v > >°== '"'L >° 0 \

[1601] 173 535

[1602] F< T | 0F 0Y^r VJ '""l ^ N— n

[1603] $o

[1604]

[1605] - 120 - FH13161920.1 GPX-02525

[1606]

[1607] - 121 - FH13161920.1 GPX-02525

[1608]

[1609] - 122 - FH13161920.1 GPX-02525

[1610]

[1611] - 123 - FH13161920.1 GPX-02525 186 548

[1612] NAyYNHo2

[1613] o

[1614] N H

[1615] L?v

[1616] 187 Y<< °=

[1617] 549

[1618] J\ / A z ZN—

[1619] ZEH2 ^Jx^ VNH2

[1620] ° — \! NyYo YYN^N'- XX PT ° Y Y | Y p F-'T Y \ ] 0F 0YhVX N—F° YYA A <Nh '"" I N—

[1621] HO V0x c /

[1622] 4 / / W ''-YV ° / 4 O

[1623] zx °

[1624] \TO oT-X°Z°

[1625] 188 fjo 550

[1626] £

[1627] yz. z— ■ z y\ T z— ° - Y- _C)V > }° >==°=

[1628] YK

[1629] o

[1630] YL?0ANH L2

[1631] 189 551

[1632] NAhryC

[1633] Y Y | Y pF 0YhVX '""1XN—HNh 0

[1634] 190 ^•\ XNH2 552

[1635] N^yJL ^O Ar NhyNH

[1636] O2F3C\^VN N„, / X

[1637] yY - zN-<

[1638] 0 s?

[1639] 6'NH

[1640]

[1641] - 124 - FH13161920.1 GPX-02525

[1642] 191 553

[1643] N Ajyr

[1644] ■ ■

[1645] ° \XT VN

[1646] -<" T y=o

[1647] / M \ o o \

[1648] 9" NH 192 CN 554

[1649] J\ / NH2 N Ayk^NHO2

[1650] Y I pF 0\xY tX^, N N,„ '"" VIYXN— / 1 ^ \ Y 9 0: Y 1.

[1651] O kY \ JI

[1652] -rV ex As 6'x, o / O 4

[1653] _FVY° 4 ”

[1654] QN < \ '

[1655] \\ _L

[1656] 193 y z z— 555

[1657] V ) z= N AyYr^O

[1658] F'l

[1659] FY | 1^. p o Y< VY '""l ^ N~ z?NY 0 ^ 6'A o*

[1660] 194r^XV'NH2 556rAxY'NH2

[1661] NYL ^O

[1662] VA^, N.. N,, HO / Y FYFY

[1663] 0I L. nY <^LN '"'1 >°1Q vv o-r 0

[1664] 195 ^\. NH2557

[1665] N YL ^O ArNH2FSC^ / ^N^N,,. V^Nx^N'-rX\

[1666] F^ Y | 1^. pF 0

[1667] ° ^'T V N '""l ' N~ -i'-r ^>=o YY; o \

[1668]

[1669] HO6°

[1670] - 125 - FH13161920.1 GPX-02525 196 558

[1671] NAL ^O MN M

[1672] F< Y \ M / F 0AMLN o '" 't A oA by

[1673] A A<= AZ■z.

[1674] C / —

[1675] 197 559 A ^NH2

[1676] M° o NyVo

[1677] (X

[1678] _oA

[1679] M z Y | A p UF0 AMA ^C r¥°zN~

[1680] / H 0 \

[1681] z1 A Q?; -1i )

[1682] — — ' ° — '

[1683] y z_ _ x

[1684] y z z—

[1685] 198 c > >v° >==

[1686] H AH J A\. NH2560

[1687] N AyMNHo2o Q

[1688] LL? LL? F^ Y [ A oF 0M 'A"' 1 ' N— ■-~YO -V"■•y " / A NV \=°

[1689] V

[1690] 199 561

[1691] F^ Y f A0F 0MA '"' 1 ' N— / A V

[1692]

[1693] - 126 - FH13161920.1 GPX-02525

[1694]

[1695] - 127 - FH13161920.1 GPX-02525

[1696] 204 566

[1697] Fp

[1698] F-NY

[1699] 0 N‘Q_

[1700] N, ' '"'L >° o \

[1701] 205 H2N o 567

[1702] MY N„0

[1703] ' — XINHFY | A p J o r~r^.0YYVX N~ < oJb ZNX 0 / \ z Ax °'"

[1704] 206 \ T ) ° - o— i P 568

[1705] yz. z— ■ A\^NH2

[1706] H2N 0 L-M

[1707] v >= / - \ X N NH P-„ / TN Y N„° OX-OYA F< Y I P ' — ' 0F 0Y<

[1708] 1 0 '"" V1XXN—

[1709] ZNX

[1710] Y 0

[1711] 207 0 569

[1712] \ X\XNH2 IXY v T Y NZ / ° i0AA F< Y r bFo

[1713] Y

[1714] 0

[1715] 208 0 0 570 X\XNH2

[1716] H2N^ 1 v\ N,'"< A X 1

[1717] ' 9 x) T Y°

[1718] 1 0 '

[1719] rP '-NTNY>Fo

[1720] F3CT Y

[1721] 0

[1722]

[1723] - 128 - FH13161920.1 GPX-02525

[1724]

[1725] - 129 - FH13161920.1 GPX-02525

[1726] 214 r° 576,0H

[1727] NH2J — '

[1728] HN— / ,0 (N< JX^O

[1729] O=k rA ANV° JTX-N'S<N'. AXX=\N'"\ A A J, FA ■*' Y r 3 pF 0

[1730] wrN- ''" IsN— [ ) — ' 0 0 ZNA '-. o F

[1731] 215 H \N— C / / N O 577 JDH

[1732] / Zx / NH2

[1733] O=^ ' N" < / Y A I NX

[1734] N< JX>0 z\ W "" / NA)

[1735] O- o PvN N„.^

[1736] F^ Y f A o *— oF 0

[1737] "'" l ' N—

[1738] OH

[1739] 216 578 OH

[1740] p° Zx^NH2

[1741] H2N— VXN <

[1742] >=( / - \ jk N^>°

[1743] O=( N" ( V, V T F'l

[1744] F'^ Y | 0 ° A< YX N— i > —0°

[1745] A

[1746] 217 579,0H

[1747] H2N— vXN o Zx^NH2

[1748] A / M / NA F^ Y I X 0 c- • -}F 0

[1749] N— r 0NX ^

[1750] X

[1751] 218 580 X -'OH

[1752] 1 II Y\<NH2

[1753] D^N N„

[1754] F< Y \ 0F 0

[1755] '"'X ^ N— A

[1756] 0

[1757] OH

[1758]

[1759] - 130 - FH13161920.1 GPX-02525

[1760] 219 581 yOH

[1761] I 11 J\ _NH2

[1762] Ny^V°F3C\Z\ / NX / N'<

[1763] F< T \ 1 ^, 0 •CY._ -""|AN— / ( X z? -— / M

[1764] \ / I 0

[1765] ) ( _M- p I \ OH / X / N> z z X —

[1766] 220 ZH% ° 582 HO^ /

[1767] / y z= / — \ ArNH2

[1768] NyX ^o O^, N N„.

[1769] F4 Y r p

[1770] F0 YKNX / p> <

[1771] F OH

[1772] 221 583 HO / ,. /

[1773] ArNH2

[1774] O^-N N; /

[1775] F4 Y \ 3,Fo YKN^

[1776] F OH

[1777] 222 584 HOy

[1778] NH2o ( ArNH2

[1779] NyiyO

[1780] YV-N N„

[1781] Y Y | Y p t^N,,'Ooy<F 0xx VA '"" Y^ N— ] 0

[1782] p OH

[1783]

[1784] - 131 - FH13161920.1 GPX-02525

[1785] 223 NH2Q o 585 HO,, /

[1786] J^NH2

[1787] NYL A

[1788] PvN N„.^

[1789] Y f 0F 0

[1790] '"'Y^ N— T N> Z v

[1791] ^5< OH

[1792] 224 586 \.>0H

[1793] N ryryNH02P^N N,,.^

[1794] X z— Y [ 1 ^. P \ Q)F 0N— w

[1795] 225 NH2o o 587 \^0H

[1796] N AyyNH02Ny<~ / NAQ

[1797] F P^ ^N Y N,,.^ [ 1 ^. PF 0N— o

[1798] LL?

[1799] 226 588 HO^ /

[1800] JX ^NH2

[1801] PX^N N„. / ^ A / FY Y | Y << / 'OHF 0

[1802] -O'f \=o N= /

[1803] 227 HO^

[1804] NA 0H589 /

[1805] JX^NH

[1806] N2

[1807] AY°

[1808] 1 |T N'"< A A 1

[1809] N \ _ / ''<■ V \

[1810] FY Y \ A.

[1811] J 00

[1812] F3cr

[1813] X / OH

[1814]

[1815] - 132 - FH13161920.1 GPX-02525 228 590 HO,, /

[1816] N Ayyro

[1817] > X^N N,,.^ jV F4 Y f 3 << / 'OHF 0Uv

[1818] \=0 N= / 229 HO,,

[1819] NH20 0 591 / y- N^oY [ Y.

[1820] ° ^ty\

[1821] y X

[1822] 230 HOOC NH2592 HO^ /

[1823] J

[1824] / H,NA Y^-N

[1825] Y | Y 0 O- 0F 0

[1826] '"’T ^ N— ) (M Cuo

[1827] oK K r- LL?

[1828] 231 HOH2C NH2593 HO,,

[1829] tH / N^< T / x0J

[1830] JP^-NYN^ / \

[1831] \ F'l '^ Y | Y pF 0

[1832] '■" T ^ N— r- 232 594 HO^ /

[1833] ArNH2

[1834] / NX ' — ',NX)

[1835] P^N

[1836] 0- 0 Y | l ^. p *-oF 0

[1837] '■" T ^ N—

[1838]

[1839] - 133 - FH13161920.1 GPX-02525 233 595 HO,, /

[1840] ArNH2Ny^yO

[1841] ,NP ' — / / NX) y\^, N N„

[1842] Y [ y p o- •F 0X< VA N—LofNX V

[1843] w

[1844] 1 JMs.

[1845] 234 yi ^ 002 r-0 596 HO^y"

[1846] \ NH2) —1y?kyNH2

[1847] / p \

[1848] N=< N"’< Y X 1

[1849] >N- \Z —0 0

[1850] A

[1851] V

[1852] 235 597 HO,, /

[1853] Y, NH2

[1854] / 0 0N / r

[1855] yKyNH

[1856] °2

[1857] \ ) ' / \S< / N

[1858] N=\ N'"< X X 1X

[1859] ,NP ',NX)

[1860] 0-.

[1861] L-O V 236 r° 598

[1862] - \ NH2\ — 1 ANH2

[1863] Ny^yO yx / p <

[1864] \ / — / - \ X N^° PvN N„i / S

[1865] Y [ V. / N=< N" < K X J.F 0

[1866] . NX ~ yN\ )=0

[1867] N= / \z — / ° °

[1868] 237 599

[1869] N<yNH2

[1870] FP-NYN''YY,F 0< YVN >=0

[1871] N= /

[1872]

[1873] - 134 - FH13161920.1 GPX-02525

[1874]

[1875] - 135 - FH13161920.1 GPX-02525

[1876]

[1877] - 136 - FH13161920.1 GPX-02525 248 610

[1878] N^JL ^G HJN^ N J Q

[1879] L jT

[1880] rl ' / N^Nrctv A

[1881] Fx J

[1882] F^l r" F " O^J 0

[1883] 249 611

[1884] r /

[1885] A-A N^JL ^

[1886] L JI N"' / \< X\ / K G ^N

[1887] / N^bA'N^QVN, z^NFA \ o F

[1888] H0'T^ 0 J XXnv

[1889] 250 612

[1890] nT j j °

[1891] O. N < - '

[1892] N\ i / °z—,^

[1893] y z z—A'N^QVN, C / / h 2 > > — )C

[1894] T°==

[1895] Qvt / M o

[1896] n „„U>.,«• 1 3i 0 4 "

[1897] 251 613

[1898] Ar Nyk^O

[1899] Fn I 1^. p0

[1900] ZN^ i o

[1901] OAOH

[1902] 252 614

[1903] N / < XrNH>02

[1904] ■ ° '"■!"■ Q v

[1905] J

[1906] oX)H

[1907]

[1908] - 137 - FH13161920.1 GPX-02525

[1909]

[1910] - 138 - FH13161920.1 GPX-02525

[1911]

[1912] - 139 - FH13161920.1 GPX-02525

[1913] 260 622

[1914] F' Y O [

[1915] \ I ) ° — '

[1916] \ > >°=

[1917] h A "6 1 T N>

[1918] X z z —

[1919] ? o r / —

[1920] 3 ° 'cnz.

[1921] 261 > TMJ °Ao ooo 623

[1922] NH2i o

[1923] / \ / \^. / ~ N

[1924] O=( N" ( )< J\ T

[1925] N~ N"%

[1926] \Z -0''■

[1927] »u

[1928] 0

[1929] 262 624

[1930] Ar

[1931] Ny^o

[1932] ■. rc ^

[1933] N=h

[1934] 263 625

[1935] Z-!<X / NH2 A""2

[1936] oN7Y°ro„ °. f orF^T' QV. N=h / M

[1937] \ o

[1938] ^c?

[1939] 264 < / NH2626

[1940] AV'NH2

[1941] O „z / N N,„ / \

[1942] F' n \ 7.F^T'Qyv0AAXNX / M

[1943] 10zN~^ f 0 %zHO / \

[1944] OH

[1945]

[1946] - 140 - FH13161920.1 GPX-02525 265 < / NH2627

[1947] Ar

[1948] nNYY° r“ F X ° L \Z XT-tVN / "' °H\=O N=Z

[1949] 266 < / NH2628

[1950] X"Y'NH2

[1951] O.„z / N N„.

[1952] F' I L.

[1953] 0 ^" XVN \ / M o

[1954] '- 0 <0^ HCLL OH

[1955] 1

[1956] 267 ^vp Az- 629

[1957] N A^AN.H02

[1958] y z z—\ ZE °1'

[1959] c > >°=

[1960] 268 L. NH2630

[1961] X\<NH2 A °A° N^AL ^O ^ ■•'NYN-rT. o OA, / N N,_

[1962] 0L-< VJ

[1963] '"'T N— F' I L.

[1964] < / NX>S ' f 0

[1965] OH

[1966] 269 631 J\^NH2

[1967] N^ A^0 oJyO rT F~ Y I i. r^o0M^L Nc^TOv._ '0" YLN Y°

[1968] A

[1969]

[1970] V

[1971] - 141 - FH13161920.1 GPX-02525 270 632 A_NH2

[1972] lyNH2N^AL ^O O..„ / N N,„

[1973] F' n I o0Ap VA. V rov \ I } ° —z

[1974] A zz <NA \ > >°=

[1975] A 0

[1976] 271 L / NH2633 ^X / NH2

[1977] oJyO Ny^y0o O'", / 1''1Nz / . P -Y'' CyrA“ X1Qvv

[1978] AN

[1979] V

[1980] 272 k^NH2634

[1981] oUL^O

[1982] 'Y C^

[1983] 4 °

[1984] A ’ ° O V- ^y o i 273 k^NH2635 ^

[1985] Aw O-, _N. _N,,

[1986] 1 L.

[1987] ° A-HF,c"' '"'r'QvN_ N= /

[1988] 4 °

[1989] 274 L^NH2636

[1990] OyAyO

[1991] •^ YQvt

[1992] A

[1993]

[1994] - 142 - FH13161920.1 GPX-02525 275 L / NH2637

[1995] ^sk xNH2

[1996] A W

[1997] ■°

[1998] AN

[1999] U z — > - 4 ° p M OH

[2000] 2 z

[2001] C O / - 276 638 ^L ^NH2

[2002] / < O

[2003] O..„ / N N„.

[2004] n [ L O

[2005] 1

[2006] o J^OZ \ J., J r^z° J*

[2007] O. N < - yz. z — O; - 277 ~ '

[2008] y z z — 639

[2009] \_ _Jv >=

[2010] ftz— — ' / I ft >z—°= ONA^rNH

[2011] <= / °l„ °z■. rL ~Z ~Z—..o ° AAj^

[2012] o

[2013] 278 640

[2014]

[2015] - 143 - FH13161920.1 GPX-02525 279 641

[2016] Ar \ X ) ° — y zz^z

[2017] \ > >°=

[2018] rJ ^

[2019] 280 642

[2020] N A y^ryo

[2021] P,, N C^n0U 't"’f i \=o N^ /

[2022] 1

[2023] ^^T > VT °°

[2024] ^^ / z —Z

[2025] 281 \ \ / V o"

[2026] / z 643

[2027] O. I CX - - - yz. z — ~

[2028] c

[2029] zCI _j rA> r r>=

[2030] ft — —

[2031] <= /

[2032] J Z z z—

[2033] T V

[2034] ° / - \

[2035] ^Z\ ^>° oz282 644 1

[2036] ^L^NH2

[2037] ^•-z / N N„. p V n F' T I

[2038] °

[2039] y ZNA 0 V

[2040]

[2041] - 144 - FH13161920.1 GPX-02525 283 645 HO,, /

[2042] ^sk xN H2NV^ xz°

[2043] O-„z / N N„.

[2044] F' n I L.

[2045] 0

[2046] F OH

[2047] 284z— < ^NH2646 HO^ /

[2048] °V\^° ^X / N H2

[2049] N xJx^0

[2050] P -, / N N ’ ■ " • " 1 -.”

[2051] N^ / ^0F' 1 L.

[2052] 0

[2053] J^xo

[2054] V zx? P

[2055] OH O O:. NM C C ' - - y y zz z z——

[2056] 285 V > ) >°°= 647 HO,, /

[2057] oLL ^o

[2058] / 1 T ArN

[2059] N„. iU— HOH H2

[2060] Nyk^o

[2061] X T CM

[2062] '"'T

[2063] N^ /

[2064] 286Z648 HO^ /

[2065] -X> / NH2J\XNH2 O^^ JL ^O

[2066] FP-Vrx,

[2067] °

[2068] k°

[2069] 287 649 HO,, /

[2070] / J\XNH2

[2071] NLIX ^O

[2072] J^'-, / N'YN'' / X L^OHF° M -^>'-LfN^

[2073] N=7 x=o

[2074]

[2075] - 145 - FH13161920.1 GPX-02525

[2076]

[2077] - 146 - FH13161920.1 GPX-02525

[2078] 292 L, NH2654 HO.

[2079] ri#^xV'NH2 oPP.0

[2080] O,„J N,„

[2081] O-.„ / N N„.

[2082] F ¥ [ V.

[2083] F° UVNXF' 0 VVVNXN~^ f 0

[2084] F4 FF° « OH

[2085] 293 ^L, NH2655

[2086] OP ^J

[2087] F P< vNv TN"^ n

[2088] F0

[2089] ’¥

[2090] 294 656 HO.

[2091] J\ XNH2 o^JPo NpP°

[2092] 0Nx

[2093] N^1

[2094] P °

[2095] \>

[2096] 295 <XNH2657 HO.

[2097] ' ~n\ OxrPY'NH2NPP>° +‘ V o^?:; O-„z / N N„.

[2098] F' n I L. N==^^° 0

[2099] F OH

[2100]

[2101] - 147 - FH13161920.1 GPX-02525

[2102]

[2103] - 148 - FH13161920.1 GPX-02525

[2104] 300 662

[2105] ^ Q? / \ oxZ °z / Zv Z° Zc' _rX°

[2106] \

[2107] \ T J ° ZZ.—' I ° —

[2108] Z - '

[2109] Z zz '

[2110] X\\ > ° oo=

[2111] (? D> / ^ z< r z N

[2112] (z jzZ ° ° j=

[2113] < ’ZK Z Z z—^.

[2114] T V Z

[2115] 301 o OM / - \ / - \ 663 ""0

[2116] \ X / ° ° ' Z\ z\ — -\\' V Z'Y''NH2o> X O X — — \ \zV vO O NZL ^O

[2117] ZZZZoo o ozzCZ / N N„.

[2118] 1 Z P 110Z-TVA N— ZVr z^°

[2119] r)Z^v°Z4 O. M C - - 302 yz. z — ~ 664

[2120] v7 > Z > ><°=

[2121] Z n z 2 — °=

[2122] ) C)O N

[2123] 303 665

[2124] ZY'NH2NZL ^O CZ / N

[2125] ii \ Z p ° Z-ZVA

[2126] o °

[2127]

[2128] - 149 - FH13161920.1 GPX-02525

[2129]

[2130] - 150 - FH13161920.1 GPX-02525 308 < / NH2670 oix / NH2

[2131] FyFJo<0 N„. / x VN

[2132] FF n \ |. p

[2133] F 0°

[2134] '""1 \ ZE ) ° - y z z— ZN^ / M \ > >°= 0 0

[2135] io- o' NH o

[2136] LL?

[2137] 309 O / - 671

[2138] '‘" =>=A / v - Af"

[2139] A YY2

[2140] 3

[2141] U> \OxO^F F 0

[2142] ZE \ 0 5^y o°z

[2143] ZE V / o - "

[2144] _.r V

[2145] O. N C - '

[2146] 310 *— K, N 672

[2147] y z zH —2

[2148] OxvJ > I= x) N Ayfy"2

[2149] ^ Yrx,FF T \ I. p

[2150] F F 0 L^ OVN\l z '""1

[2151] / M 0 V HCT^

[2152] 311 673

[2153]

[2154] - 151 - FH13161920.1 GPX-02525

[2155]

[2156] - 152 - FH13161920.1 GPX-02525 316 678 ^k^NH2

[2157] F3C'^NYN" <^1< X3°0VTLN YP -'" [ >=0 N= / yz.z— -\ X } ° —

[2158] )\=

[2159] TA p? 0- \ /

[2160] o

[2161] 317 679 ^k / NH2

[2162] A '.

[2163] F3C / ^NYN'" OHMD° Yl ",0

[2164] \=O o N= /

[2165] 318 ^V o°

[2166] \. I / 680

[2167] CyQ^

[2168] O.l O -fo

[2169] y z z —

[2170] v > >° >r ><°= o

[2171] / I fT~ / I nZ.—'=

[2172] o o

[2173] <= / X z z —

[2174] x° / — \

[2175] 319Z— <X^NH2681

[2176] CK JL,0

[2177] Y~ ' o ■ ° 4r^ "

[2178] 320 682

[2179] ri5^V'N H2

[2180] FiC^N°NWN- / M o

[2181]

[2182] - 153 - FH13161920.1 GPX-02525

[2183]

[2184] - 154 - FH13161920.1 GPX-02525

[2185] 326 K, NH2688

[2186] nLL>°

[2187] F C-PP / '-,,. POH0LMVN' '"'L >°

[2188] 327 L HH2689

[2189] oYx, O

[2190] VP-NVN.

[2191] A M CM

[2192] '"' 1 ^ N —

[2193] (M

[2194] V

[2195] F

[2196] 328 690

[2197] L / NH2nLL>°

[2198] O-YMF3C— Yn - P°H0LYLN '" L >°0YYLN J1P c o

[2199] o o

[2200] '"'t >°

[2201] op

[2202] 329 691 I Ippvv

[2203] pKLL< ° °= / X z z— T v L, NH2° / — \ o^PP.o

[2204] Y ’ * P\ / N N.„

[2205] Y | |. p PY1° c0YL \Y I YY

[2206] 4

[2207] cf0

[2208] 330 692

[2209] L ^NH2N YyYNHoIoJCo

[2210] rp i T.,o

[2211] IX JtzN., Ms'

[2212] Y0P LYL. P

[2213] -"■Lr N A

[2214] y=o

[2215] o \

[2216]

[2217] - 155 - FH13161920.1 GPX-02525

[2218] 331 A\, NH2693

[2219] OAA^O N vY A ny y Ov F F '"'Ix) A N-Z 0 V

[2220] 332 VAX^NH2694

[2221] o< AA^oNvY v^V'' rA F K0M^N A zN'%

[2222] 0 V

[2223] 333 695

[2224] ^A<NH2 L. NH2

[2225] IMAL ^Q o< AA^o

[2226] ^ T' Q^

[2227] A / A \ 0

[2228] OH

[2229] 334 696

[2230] L. NH2 rAv'NH2

[2231] nAL ^° o< AA^o

[2232] FAY'AYN_ AN\ 0

[2233] OH

[2234] 335 A / FNH2697

[2235] N AyA^HOaAV’Q^ hC^^N^N,. y.

[2236] 0AAN A '" A >=Oo \ V

[2237]

[2238] - 156 - FH13161920.1 GPX-02525

[2239] 336 698

[2240] o N AJYr

[2241] Fsc\X~X-NX'N'•■ / ¥

[2242] Y

[2243] ° YXL yz. z— ~\ X / ° — / M

[2244] 0 v ) >°=

[2245] xK ^

[2246] ¥

[2247] 337 Y

[2248] Y^NH2699

[2249] Xr

[2250] NyXN

[2251] ^H

[2252] O2F3CXX^X-NV-N'- ° OXYtr" ■ ' N= /

[2253] 4 °

[2254] 338 ^Y _NH2700

[2255] O^YL ^O N Aykr^OF3C^X-NyN'.y\ ^YX^t °

[2256] o H2N< o Y Y °

[2257] '<>

[2258] F

[2259] 339 ^Y, NH2701 Y ’ ‘

[2260] °xYx>° o

[2261] H2N^ o

[2262] F

[2263] 340ZYXNH2702

[2264] O^ JL ^O

[2265] U^N Nz,.^

[2266] FF Y \ |. p

[2267] fo Y-YVY

[2268] ”'""| N—

[2269] / NY

[2270] F^^ 0

[2271] OH

[2272]

[2273] - 157 - FH13161920.1 GPX-02525

[2274]

[2275] - 158 - FH13161920.1 GPX-02525

[2276]

[2277] - 159 - FH13161920.1 GPX-02525

[2278] 349 ^\. NH2711 F3C

[2279] H2N )

[2280] °V YVN>N^ Y' CMC"-T- C^.

[2281] '"'T

[2282] HO-L0¥ 0

[2283] 350 712 CF3

[2284] \ NH O^XL.0

[2285] N,NY2'Yv° XV / N N„

[2286] T

[2287] 0\ ]. o HOJ A0rNS 0

[2288] 351 NH2713

[2289] O^XLxO

[2290] l T X-A ° \z — 1

[2291] A1352 NH2714

[2292] I T T | p rX'" \ N—

[2293] zM

[2294] 0 - A1°0

[2295]

[2296] - 160 - FH13161920.1 GPX-02525 353 ^XS, NH2715 \ NH2

[2297] / T~(

[2298] N, X / O

[2299] N

[2300] ■IS 'Qyt

[2301] X t X

[2302] 354 NH2716

[2303] ^ '■Qvv

[2304] -- 0

[2305] 0

[2306] 355 NH2717 \ NH2

[2307] ,NY

[2308] oXL ^ONvx^°

[2309] CV / N

[2310] n 1 1^. o0x< vx Xs

[2311] p N — HoJ A00 Xx*\ <

[2312] XXO QZ

[2313] 356 X. H 718 \ NH

[2314] N2

[2315] 21

[2316] ,NY

[2317] Nv\^°

[2318] VX / N Nz, / ^o I 1 L ^"rov0XYLN '>" T ^=0 „oH o \ 0

[2319] 357 ^\, H 719 H2N

[2320] N2

[2321] oXX^O

[2322] X ^?N^ Y'Qv n x X '"'Y N—

[2323]

[2324] " X

[2325] - 161 - FH13161920.1 GPX-02525

[2326]

[2327] - 162 - FH13161920.1 GPX-02525

[2328]

[2329] In certain aspects, provided herein is a compound selected from the following table: Compound Structure Compound Structure

[2330] F

[2331] 'Y. NH2Z-XV, NH2

[2332] oYL ^o

[2333] N,„ / \ 726 904 F< T [ 1 ^. p °. r Q vtFo CM JI '"'Y^ N— \ o \ o

[2334] OH F Fx|. F

[2335] 2~k^, NH2Z-^-., / <NH2oYh ^O O.^ JJ\^O

[2336] 727 905

[2337] . r' Qvt

[2338] / M r k k ° \ o

[2339] c OH OH

[2340]

[2341] - 163 - FH13161920.1 GPX-02525

[2342] y

[2343] ^Y NH2O^Yk ^O kYNx / N,. ^

[2344] 728 906 F^ Y y u?

[2345] Fo YY AY '”-y

[2346] if

[2347] p OH QM / - \

[2348] F Y NH2ZY> / NH2

[2349] o^yk ^o O^Pk^O

[2350] > YT° o

[2351] 729 907 F^ Y Y u o '^■r avt '"■ \ N^ zNY YN\ o 0

[2352] OH

[2353] S^OH

[2354] F

[2355] Y. NH2

[2356] Y., NH2

[2357] °< V >?5-0oYY>o

[2358] PvNvN" Z\

[2359] F^ Y [ u 730 908 °L^YVNXzN~k>-. o Q.

[2360] 1 6xo F y

[2361] ^••Z.^NHZ < / NH2

[2362] o<ykx>o o^Jk^o

[2363] P^. N N„. / K YvNN„ F< Y | u 731 FY Y f Y 909 °

[2364] °

[2365] Ny" 3 o ( 0

[2366] Cg^ '" YOH o °

[2367]

[2368] - 164 - FH13161920.1 GPX-02525

[2369] F

[2370] ^~Y / NH2

[2371] Y NH2O^JL^O °Y V° PM N„.

[2372] 732 Y Y [ Y.

[2373] 910 °

[2374] NY 1 o f 0

[2375] Cg^ '"; OH o ° F Y MG< OH, NH2

[2376] Y NH2

[2377] YAz0O^N N„.

[2378] F< PvU". / \ Y [ Y

[2379] 733 9110

[2380] NY '■ 0 f 0

[2381] Q. 00 / 'OH

[2382] F HO.

[2383] ^■.,z. NH2\-Y / NH2 O^YL ^O O^JL^O O^N N„.

[2384] n \ |. o 734 912F° Y-< \ ji *°. r' Qvt '”•3 ^ N—

[2385] YY

[2386] / M \ 0 k °

[2387] OH

[2388] ; OH

[2389] F \^OH

[2390] ^Y NH2H2NXJ YY°OV''YY)

[2391] Jp^N N„.

[2392] F^T Y | 0 735 913F0 Y-Y\ Ji '"'Y^ N— / M

[2393] 1 o i?

[2394] OH

[2395]

[2396] S^OH

[2397] - 165 - FH13161920.1 GPX-02525

[2398] F \,,0H H2NY

[2399] Z-\V, NH2

[2400] O^ JL OD O-YY^O

[2401] 736 914

[2402] 'f<" 5 "' Qyv

[2403] / M

[2404] k °

[2405] a?; OH OH F OH NH2— Y^H2O^ JL oD o^ JL ^o

[2406] N„.

[2407] F<

[2408] 737 915 Y | Y.

[2409] F 0_

[2410] NY^ / M kx° k °

[2411] OH

[2412] ; OH

[2413] F NH2

[2414] YNH2

[2415] ^-,,.1^2 o^^JL ^o °YY

[2416] 738 916F^N’ "" QyY YN

[2417] Y" \ o k0

[2418] OH

[2419] / OH

[2420] F FFAY. NH

[2421] Y-^\^,2

[2422] NH2 ^■■^NH;,

[2423] O^ JL ^O O^^ Jk^O

[2424] Nz<

[2425] 739 Y Y r Y. 917

[2426] F° M Y

[2427] NY Y f o \ 0

[2428] OH OH

[2429]

[2430] - 166 - FH13161920.1 GPX-02525 F V

[2431] Z-\V, NH2

[2432] oYL ^O

[2433] YvNVN,'Zk F^ Y [ Y.

[2434] 740 F< Y n 918F° r\ N0

[2435] N~^

[2436] £x° Y OH YOH FZYV, NH NH2 2

[2437] OPP^O

[2438] F^ Y [ Y.

[2439] 741 Y Y \ Y. 919F° M^VNO

[2440] ( 0

[2441] Y OH YOH F

[2442] Y., NH2Y., / NH2 oYYo Y / °

[2443] °YY

[2444] 742 YPY N,„ 920 p oYJ^vYNi-n>i?F7 Y 1 ]. P Y<YYVY..^FJI F^ O - / >vY N o YX\

[2445] ''"■'IsN—ZNY \0YYFz — k ° \ OHH0OH *YY

[2446] F V Y MH2

[2447] Y NH2

[2448] o^YL ^o °Pp5-O

[2449] 743 YPNN„. F< Y [

[2450] F921

[2451] 7 Y | |. p

[2452] F° YYA JI °

[2453] '"’ IsN—

[2454] / NY

[2455] oFYO °Hopp OHOH

[2456]

[2457] - 167 - FH13161920.1 GPX-02525

[2458]

[2459] - 168 - FH13161920.1 GPX-02525

[2460] o

[2461] YNH

[2462] P-Y, NH2°Yv° P^N N„.

[2463] 748 926FF n i Y pFo YYA J /

[2464] '"' N— P <NY;

[2465] \ o G°

[2466] 1 °X OH OM! - \

[2467] / \ I

[2468] O / \ HOY

[2469] F

[2470] L / NH2 / NH2

[2471] >oY o

[2472] oP^O 1 N„.

[2473] FA Y | Y p 749 O^N N„. 927

[2474] F< Y [ 1 ^. pFo YY-^ JiF-"-f ^ N— ° YpVX

[2475] '"•'I N— / M \ o PP

[2476] „. s OH F

[2477] Z~^X'O

[2478] k / NH2P^2

[2479] o^PL ^o oPP> O

[2480] PvN N,,.^.

[2481] FA Y | Y p 750 928

[2482] Fo YxY\ Jl, r'N N^ 'N'"■l ^ N—

[2483] <NP PA \ o i

[2484] OH OH F

[2485] V-Y / NH2

[2486] A, NH2oPk ^o oPPpo

[2487] YY^N N„.

[2488] F< Y \ Y pFo YYA JI 751 929

[2489] '"’ N—F 0^'PPp

[2490] F^ 0

[2491] p1OH PH

[2492]

[2493] - 169 - FH13161920.1 GPX-02525

[2494]

[2495] - 170 - FH13161920.1 GPX-02525

[2496]

[2497] - 171 - FH13180518.3 GPX-02525

[2498]

[2499] - 172 - FH13180518.3 GPX-02525

[2500]

[2501] - 173 - FH13180518.3 GPX-02525

[2502]

[2503] - 174 - FH13180518.3 GPX-02525

[2504]

[2505] - 175 - FH13180518.3 GPX-02525

[2506]

[2507] - 176 - FH13180518.3 GPX-02525

[2508]

[2509] - 177 - FH13180518.3 GPX-02525

[2510]

[2511] - 178 - FH13180518.3 GPX-02525

[2512] F NH2

[2513] °V V°

[2514] 780 958

[2515] A 7 0

[2516] Q 0 NH

[2517] F N

[2518] Z-k-, / <NH2H2NXJ

[2519] LA N N,.

[2520] 781 959 v ( u 9 o Azr yA '"• \ zNS '. 0

[2521] 6 'NH Q.

[2522] Zx6'° M< / = / ^ zNH CN

[2523] F13x / - \

[2524] HsN^ J

[2525] 0-vA^°yOv,'^o'^,_ IAN N,.

[2526] 782F3 T? 960

[2527] FO \ / T\ JIa.

[2528] / M A '■ ° '. 0 o' NH Q...

[2529] 6 / xo

[2530]

[2531] - 179 - FH13180518.3 GPX-02525

[2532] NT? S

[2533] F

[2534] H2N^ J

[2535] NH2

[2536] °V^Y>0

[2537] 783 961

[2538] ZNS

[2539] 0

[2540] OZ'NH

[2541] o O F NH2L^NH2°Y V° HN-, °< YYs>°

[2542] 784 962 <5^Nro^N_

[2543] / 'M / S '• 0z- o Q Q

[2544] 6'N 0 " ^r0\.

[2545] F

[2546] ^ ■,, YH2 k. NH2

[2547] F P4 vNv YN'- ^\ n\zN N,,. / ^

[2548] r? p

[2549] 785vn \

[2550] F° 963 p ° JI '"' 1 ^ N— / M '. o J Q.

[2551] 6 'N o °

[2552] ^Y, NH2

[2553] L^NH2YYYY

[2554] Nz<

[2555] F< L Y r Y.

[2556] 786 ° 964.

[2557] '• o Jj '• o Q.

[2558] 6'° Q ”"

[2559] 6xo

[2560]

[2561] - 180 - FH13180518.3 GPX-02525

[2562]

[2563] - 181 - FH13161920.1 GPX-02525

[2564]

[2565] - 182 - FH13161920.1 GPX-02525

[2566] F <zOr °°, NH2juO”x°-", Z

[2567] z \ _L\?« • ©? N < ' - N„.

[2568] 794 F< Y r 3 972

[2569] F° o7r L / )^ — r\ )\=

[2570] J

[2571] 6'°

[2572] F

[2573] Z-Y<NH2

[2574] ojjo

[2575] 795 r"\ i Tzo 973

[2576] < > 'z\— / —- F

[2577] / xM< <= /

[2578] ^-.,,^NH2Y \\ c i* NH2

[2579] ° / - \ YJJY

[2580] 7 F P< vM Y ''-Y \ \

[2581] 96 O 974yOV"^ Y" c

[2582] Fo YYA JI ^ YYYV N—

[2583] / U '. 0

[2584] 4 QY o ° 6 o F

[2585] J. NH2O^ JJ x) '" Y. °<yK^O YKXN N„

[2586] 797F1 Y \ U O 975 Y | Y °

[2587] Fo YYA J / ° Y-Y\Y '"'J ' N— N—

[2588] / NY zNY -. o O Q Y

[2589] o °

[2590]

[2591] o °

[2592] - 183 - FH13161920.1 GPX-02525

[2593] F NH2

[2594] oY^O YY^0

[2595] \ / ~^N N,,.

[2596] 798 P n \ o 976 n \ oFo \ Y1 JJ0PXYA Ji p

[2597] G° >”■■ / M / M O 0 oM / - \

[2598] o °

[2599] Ox' / W °>0*\ v

[2600] 1P O >'=-\ -.

[2601] F Y NH21

[2602] pP0

[2603] PvN N,„ zx

[2604] 799 F4 Y f 1 p 977

[2605] F° JI

[2606] / M

[2607] k °

[2608] X

[2609] 6so

[2610] F

[2611] ° z>

[2612] Y P / NH

[2613] NH2( 1 — / 2

[2614] Jv< / =

[2615] y o Y Y z z ft—° ' I V

[2616] ° / — \ PvN N,„ zx

[2617] 800 F< Y \ P 978

[2618] FJI ^ Yp-p o

[2619] '"••[ ' N—

[2620] zNY Y -• o 1 4 ” Q ”" 6so 6xo

[2621] L / NH2

[2622] FyF0 yL ^O

[2623] 801 979 ^ V CpY A

[2624] -. o Q. o0

[2625]

[2626] - 184 - FH13161920.1 GPX-02525

[2627]

[2628] - 185 - FH13161920.1 GPX-02525

[2629]

[2630] - 186 - FH13161920.1 GPX-02525 r T \ \ F yY o°

[2631] 5YT °°Z, NH2PP^xzoP^o

[2632] N,,.^ \\ T i < < O O — —

[2633] 808 9 YY z.zZ.z - ' '

[2634] F7 n i i. p 86

[2635] F° Y-Y VX pp > > > >°°==

[2636] Q > - p

[2637] N H

[2638] F o / - \

[2639] \ O I—o

[2640] Ax

[2641] Pp _ \

[2642] °pP^° z

[2643] N„.

[2644] F4 Y f 1 p 1

[2645] 809F° \ JI 987

[2646] N—

[2647] N

[2648] cPNH2

[2649] p=\

[2650] ' ' z '

[2651] 810 988 ^ °, / — \

[2652] 1"’ / \ - / A' o >-\ -,.

[2653] Y^VSY f Q ^Qo o-z>T1

[2654] F P^ / NH2

[2655] H 1

[2656] P.,,. NH2N-YY^0

[2657] (PY

[2658] PvNvN" Y y

[2659] 811

[2660] F< Y Z

[2661] o \ \ 989

[2662] p

[2663] F\ Y1 / /

[2664] ''"• N— '• o rNP

[2665] >- oyOHH2NF^A°F

[2666] 0

[2667]

[2668] - 187 - FH13161920.1 GPX-02525

[2669]

[2670] - 188 - FH13161920.1 GPX-02525

[2671] F \ ^OH

[2672] , NH2k\ / N H2

[2673] N,„ \ I ° ■ —

[2674] 816FP A \ 1 ^. ° 994 F^ T 1 \ / _1\

[2675] F / \ k o °0°= MTN ZN^

[2676] '• o

[2677] H4 ^

[2678] QHk o

[2679] F

[2680] 817 995

[2681] F^TQyL

[2682] 4

[2683] yNA

[2684] F \.0H

[2685] , NH2k\ / N H2

[2686] 818 996

[2687] h"

[2688] '. O <k k0a0

[2689] 3 OH F HO,, /

[2690] ^■. NH2

[2691] / k-NH2 o^ JL ^o M fl^^s Tk ^O

[2692] 819 997 rO T T. OHF7

[2693] Fo fl \ J 9I

[2694] '"■ 1 N— ■5• ■ cb<k

[2695] k

[2696]

[2697] FAF 0

[2698] - 189 - FH13161920.1 GPX-02525

[2699] F NH2

[2700] 820 O^N N,,. / -x 998

[2701] F7 Y i i. p

[2702] F 0Y-YA J /

[2703] Y Q G° o- L0

[2704] 4F

[2705] ^w ° °K o o / — \ / — \

[2706] HO^ /

[2707] ''A - / ^ \ Y- Z— _ / L^-NH2

[2708] ^A° o H T

[2709] 11N'AX^

[2710] 82 999 I °

[2711] 1 vA T »OH ■5

[2712] \,.'OH ^L / NH2Nv >^°

[2713] F< Y (

[2714] 822 1000 YF)< o o=

[2715] xz

[2716] ° AA / NY^ k YOH F

[2717] N^Y

[2718] Y NH2NH2oY^O P-, / NVN,,^X

[2719] F 1 U 823 10010^AAY

[2720] Y

[2721] 0fOH

[2722]

[2723] HO r

[2724] - 190 - FH13161920.1 GPX-02525

[2725]

[2726] - 191 - FH13161920.1 GPX-02525

[2727] F

[2728] ¥ NH2< PvNH2

[2729] oP-L ^O NPYY

[2730] F4 Y r i p

[2731] 828FY ¥ 1 U*F1006 9 ° Ji F o Y¥ \¥ '"• r ^ N— <N¥ k °F / X °

[2732] OH0HF F

[2733] Z^ -,,<NH2¥V'NH2 oPP> O

[2734] JP^N N„. CV N_N„.

[2735] F4 Y f 1 p FY Y | Yt 9 829F1007

[2736] ° JIF 0Y¥YA '"’X^ N—

[2737] <Nk / H \ O \ 0

[2738] Op NH2HC)

[2739] F

[2740] ¥., _NH2

[2741] / Y / NH2 OPL ^O H T

[2742] N^ Xx^O

[2743] F< Y \ O

[2744] 830Fo YY'A J / 1008

[2745] '"'P' N—

[2746] <Nk

[2747] \ o

[2748] H

[2749] o^O H0P

[2750] o

[2751] F PY'NH2

[2752] N< P\. O

[2753] Y NH2

[2754] 831 YY^ N. _ N,. 1009

[2755] T r p X /

[2756] F0 k J— ■» LN /

[2757] "’ N I == / )=o ¥

[2758] \ o0YNH

[2759]

[2760] - 192 - FH13161920.1 GPX-02525

[2761] F Y NH2

[2762] °Yv° YXV-NH2

[2763] N YY,0 H 832 F<

[2764] FY

[2765] 0( Y. 1010

[2766] N-Y ■W -Otvf f o N^Y

[2767] \ N\

[2768] F Y> / NH2 Y_, NH2

[2769] °YyO

[2770] 833 1011 FY Y r Y / =^F

[2771] F-T Y r >

[2772] Fo k Y-^ VN /

[2773] " Y N=y Y°

[2774] F YNH2J\ XNH2

[2775] N< YL > O YY0

[2776] Y^NXN" r^

[2777] 834 F PY VNYN" / > 10 FY Y \ Y Y \ V. 12

[2778] FY

[2779] ° YYyi IYY; °

[2780] NV YY^

[2781] FY^ O YNH

[2782] X° Y’”

[2783] F F S'A ■,

[2784] / O ZZEZY,,r / NH2

[2785] °V V°

[2786] Y^N N,.. / \

[2787] 835 FY Y | Y p 1013

[2788] F 0YT -"-VyY' N—

[2789] p

[2790]

[2791] F

[2792] - 193 - FH13161920.1 GPX-02525

[2793] F

[2794] J\ / NH2

[2795] ^-k,z_-NH2

[2796] N^Jk^O

[2797] 836 1014Fk^Nr' Q^

[2798] ■F'-r ow

[2799] / M -. 0 4?

[2800] Hk 00OH F NH2J\ / NH2 okko N^Jk^O

[2801] 837 ° 'QyA 1015

[2802] / M > 0

[2803] H^OHFY F F J^-NH2

[2804] ^■. NH2Mv okko Tk °z £ OM_

[2805] 838 1016

[2806] " k * / \ MX zNkUX>-2 S 5 J-o0 ° \ i? iS^ / 0^ HO F

[2807] ^.,, MH2

[2808] O-^Jk^O

[2809] O^, N N„.

[2810] 839

[2811] Fn \ \^. 1017

[2812] 7 o

[2813] F° "'”•[

[2814] \ o

[2815] ° si

[2816]

[2817] - 194 - FH13161920.1 GPX-02525

[2818] F NH2XU^NH2

[2819] NH^Y T ^° Ypo

[2820] P^N N,„ O^N N„. F^

[2821] 840 fl \ |. p 1018 Y [ 1.

[2822] Fo JI °

[2823] Y k’OH ° P‘

[2824] F

[2825] ° 6

[2826] F

[2827] , NH2

[2828] N PxApNH2

[2829] 841 1019 F< Y \ J. P P^HF0\z ^ -vV-fN\=O Y" N=Z P o

[2830] °pY

[2831] NY

[2832] / o

[2833] F

[2834] _. NH2 / k / NH2

[2835] NH

[2836] <5 >^Y T?^° O JL O

[2837] PvN N,,. / ^

[2838] *U F^

[2839] 842F1020 Y \ ].

[2840] 1 A \ Y0

[2841] F 0Y< 5 JI °L'-~'PVNX'’" N—

[2842] Y0 / y " OH ° O^p Y'" F NY

[2843] / 0

[2844] F

[2845] ^■.,,pH2

[2846] YNH> °pp>0 _NY^O

[2847] Jp^N N<rY \ \S^-N 1 N 1„. O -H 843 r / \ i 1021

[2848] F4 Y o F4 Y \ 1.

[2849] Fo Y / Y5 J / F 0< XY

[2850] '"• ~" L\ N N— N Y y=o o^s —1

[2851]

[2852] 0

[2853] - 195 - FH13161920.1 GPX-02525 X X

[2854] u-Y °1" F Y o P ° T i YX^YYz- \ Y o 2Z Toz'Z— YNHJ YTYPPY

[2855] 844 N,,.^ 1022 \ I ° p —

[2856] \\ Y X X z\ X ° -1

[2857] Y zzz ° °

[2858] F< Y Y p Y y z z ' ' — | zz—

[2859] Fo YYY Jl \\\ Y > Y >c > >°° >°==

[2860] HO-^P °

[2861] Y

[2862] F p Y Y

[2863] P^ / MH2P,,, NH2

[2864] NPL ^O °V V°

[2865] 845 1023 F< Y \ Y

[2866] O

[2867] ■ih ' Cy

[2868] / YN°~^ HO-Y\ H° <. OH

[2869] FY / NH2v

[2870] 846 1024

[2871] ° NY "

[2872] < JY o o

[2873] F F F

[2874] Zp,<-NH2

[2875] °< VY°

[2876] 847 1025

[2877] Y Y YY

[2878] \ 0

[2879] OH F

[2880] P,,^NH2

[2881] R oUPo

[2882] Y / P / N N„.

[2883] 848 Y | p 1026

[2884] ° Y-YA J /

[2885] ''" V N—

[2886] <NY

[2887] \ o

[2888]

[2889] OH

[2890] - 196 - FH13161920.1 GPX-02525

[2891] F NH2Jx -NH2

[2892] . oUko N A / HO'^V\ T r

[2893] O^N N,„ / \ 849 1027 FY Y r?

[2894] '■’■s ' ChJ °

[2895] k ° Y OH

[2896] F

[2897] kx / NH2

[2898] Y NH2H 1

[2899] NYV>° oY"! ] T O^N N,., / x FY Y \ p 850 Y 'CM 1028Fo YYA Y zM -. o Oxo-s J r

[2900] OH HI\H F

[2901] / k / NH2

[2902] Y NH2n T

[2903] NxY^0

[2904] \ --*<O;3vo

[2905] 851 1029

[2906] •V C^

[2907] A

[2908] Y

[2909] o%b OH HN^ F

[2910] kx / NH2

[2911] , NH2

[2912] N<kL ^° O^N N„.

[2913] U\, N N,„ / x.

[2914] 852 4XOYY^°

[2915] 0| p 1030

[2916] YY '" V' lY' N—

[2917] '- o \ 0

[2918] Z£NH

[2919]

[2920] OH

[2921] - 197 - FH13161920.1 GPX-02525

[2922] F

[2923] . NH2

[2924] OHN^JJ\^O

[2925] 853 T \ Y 0 1031

[2926] 0

[2927] 'l” |XN— zNY \ 0

[2928] ? AS'NH ° °Y OH F Y NH2N^JJ\^O

[2929] 854FT Y f Y 1032

[2930] F 0YYV

[2931] 1 zNY o\* k °

[2932] , OXnd * °Y F

[2933] r?zxY'NH2

[2934] Y. NH2N^JJ\^O O^Jk^O

[2935] FXv- ^ >, / N N

[2936] 855 1033

[2937] F°

[2938] zNY kx°

[2939] ? AS'N. ° H<5 ^ °Y F

[2940] Y\, / NH2 M^UL ^O O^N N, - FVK / N Nz„ F^

[2941] 856Fn 3FY

[2942] 1 Y. 10 4 o YY^VN0

[2943] N-Y

[2944] Y ’ o

[2945]

[2946] OH

[2947] - 198 - FH13161920.1 GPX-02525

[2948] F

[2949] , NH2

[2950] / rNH’ YYY

[2951] 857fL F T T u / ? 1035 ^vy

[2952] 0n, V N— < Y -- NY >-V

[2953] N fN Y \=FO

[2954] V OH F HO^ /

[2955] 2“XV-NH2^\z-N H2°V' v>0

[2956] F’ n i i. o 858 1036 o A 'A'TX> U '"’ 1 ^ N—

[2957] \ 0 k

[2958] OH OH HO,,. /

[2959] ^\, NH2zsJ\ / N H2O^^ JL^O N^U-L ZO

[2960] P -z / N^N,,

[2961] F’ n i i. o 859 'A'T 0A, 1037 o it '"■y\ ' N— \ 0 V OH OH F HO^ /

[2962] ^■. NH2YP'NH2 °pv°NPL ZO F^^ / N N,,

[2963] 860 1038

[2964] ’ ■ ' I C-y < °. ■ f ' Y v z M k0k

[2965] c OH

[2966]

[2967] OH

[2968] - 199 - FH13161920.1 GPX-02525

[2969] F HO,,. /

[2970] ^? U / NH2 ^'VNH?

[2971] o^U-L^o N^Uk ^O

[2972] 861 1039

[2973] "A. f ' Qy? °. T' Qyt z M k0

[2974] OH c OH F HO^ /

[2975] , NH2Z;? U / NH2

[2976] Nv^<0

[2977] N,„

[2978] 862 n [ p 1040 °. T' O-v,

[2979] 0

[2980] / M

[2981] \ 0 <N^N

[2982] OH 1 OH F HO,, /

[2983] ^.,,, NH2r^XY'NH2

[2984] N^Uk^OFA,z / N N,. / .

[2985] 863 n | p 1041 k'-V Q u.

[2986] 0

[2987] / M A \ 0

[2988] ‘i OH 1 OH F

[2989] ,xOH ^■.,Z<NH2

[2990] zX / NH2

[2991] FN^JLX> O V ^\^N N„.

[2992] 864 n [ p 1042 O.,zXN N„.

[2993] 0F [ U

[2994] f°

[2995] / M

[2996] \ 0

[2997] zN^ O

[2998]

[2999] OH

[3000] - 200 - FH13161920.1 GPX-02525

[3001] F

[3002] \ ^OH

[3003] NH2

[3004] < YV'NH2

[3005] F °YA° NYY>0

[3006] 865 V" CU 9 1043 O. / zXN N„.

[3007] o F Y [ Y.

[3008] N— ZF 0

[3009] ZNY 0> V OH FNH2 Y\ / NH2

[3010] nYY>° oYL >°

[3011] 866. vcq, 1044

[3012] < / NY>kx° kx°

[3013] OH

[3014] ; OH

[3015] F Y Y\ / NH2

[3016] NH2

[3017] N YY>° oY. O

[3018] F Y r

[3019] 867 1045

[3020] Y V'Y0

[3021] < / NY>Lx° kx°

[3022] OH

[3023] / OH

[3024] F Y NH2YV'NH2o- LoN

[3025] O.,^N N,„

[3026] 868. 'r‘kq. 1046

[3027] '1O v¬

[3028] kx°

[3029] Y ikN H2

[3030]

[3031] < OH

[3032] - 201 - FH13161920.1 GPX-02525

[3033] F A NH2

[3034] YX^-NH2 oY ^O

[3035] NY-L^O

[3036] 869 1047

[3037] Y'Nro^ A0 H2k °

[3038] / OH

[3039] F HO.

[3040] A.. / zNH2

[3041] N YY>°

[3042] 870 1048 P -, / N N,

[3043] '''''. F' Y \

[3044] o AYVNXYN

[3045] k0

[3046] o c OH

[3047] OH F

[3048] Y*OH

[3049] Y NH2Y> / NH2 oY ^o N YY>o F^A^N N„ N„.

[3050] 871 1049 F4 Y [ 1^. PF° YAYAF° QYL

[3051] YNAY k0k ° 3 OH OH OH

[3052] F k.'OH

[3053] Y.., NH2 IYY'NH2oU voN YY>°

[3054] FV^-. / N N„.

[3055] 872 F IT r o 1050FA Y I 1 ^. o o YAAYF° AX-YVY ''"•v N—

[3056] / k AY k ° V ° / 'OH OH

[3057]

[3058] - 202 - FH13161920.1 GPX-02525

[3059] F HO.

[3060] / V / NH2NH2

[3061] N H^^ Tk ^O O^ JL.0

[3062] O^N N„.

[3063] F^A^N N„

[3064] 873 1051

[3065] F° Q^k1Q^v Z M

[3066] kx° k0

[3067] / OH OH F HO.

[3068] NH2

[3069] H / L / NH2

[3070] T

[3071] N^^k zO pk\ k ZN>.

[3072] 874 1052

[3073] ^k zo ^

[3074] J \HN / '-QVN0AN(k

[3075] O FAkF° H F

[3076] M >=<> X. / NH2

[3077] O] k< H - NH2NV

[3078] NyiL.0

[3079] L?LJ-^<

[3080] 875 1053 F' " T'

[3081] 0CV^__

[3082] ' / M k 0

[3083] V OH OH HO.

[3084] N\NH2

[3085] 876 1054P'"'N°N" QV / MN- k0

[3086] OH

[3087]

[3088] - 203 - FH13161920.1 GPX-02525

[3089] 1 \. T / yY o°r_rx>2:

[3090] \ T C '

[3091] 877 1055

[3092] \I >=

[3093] 4 ^

[3094] KIJX / NH F2

[3095] ? T

[3096] YY^°

[3097] ^■.,zNH2

[3098] PVNVN'< M- F< Y \ O 878 1056Fo YYA JI '"'Y^ N— c-M Y

[3099] 4 o ° F - M ^

[3100] 879.r.. Y,, NH2

[3101] 4. 1057

[3102] F Y [ 1 ^.

[3103] iY

[3104] Y< °= /

[3105] - I v - O; w, —

[3106] F^ k

[3107] FF°

[3108] f V NX / 2NH2A ^••,,^NH>1oo Y< YY<> kJkj>0

[3109] 880 ^ Y'CM? 1058

[3110] A'YM \ rs

[3111] \ o Y °

[3112] / 'PH

[3113]

[3114] OH

[3115] - 204 - FH13161920.1 GPX-02525

[3116] F NXYH2

[3117] Y NH2

[3118] °w °

[3119] 881FY^ Y -n. o 1059

[3120] Fo YYY\ Y

[3121] V

[3122] zNY Y \ °

[3123] OH i 6"o F

[3124] ^Y

[3125] Y NH2

[3126] oYY> O O^N N„.

[3127] Y \ Y p 882 1060

[3128] Fo YY y Y '"■ IsN—

[3129] '"• y N" / M O

[3130] zNY

[3131] vx°

[3132] Cg^ '" 6so OH HO^ /

[3133] X Y YY X JP^Nx A Y^ ^

[3134] F< Y | p 883 Y f Y. 1061

[3135] F NFo YY^A Y ° YYy

[3136] Y < \N^ o

[3137] x° OH OH HO,,. /

[3138] YF

[3139] O" T X

[3140] Y

[3141] oYY^O X

[3142] Y | p 884 PX N„

[3143] Y f Y 1062Fo Y / YA YF 0YYYyNxV_

[3144] Y < \N^ o

[3145] OH

[3146]

[3147] OH

[3148] - 205 - FH13161920.1 GPX-02525

[3149] 1 F F

[3150] Yr °°z

[3151] L, NH2

[3152] \ I C °V'V° y zz^

[3153] 885 PvNN„. 1063

[3154] F4 Y r i o

[3155] Fo \ YA Ji OZ \ \=

[3156] T /

[3157] \ o

[3158] OH HO.

[3159] F^L / NH2X¥YH2

[3160] f¥ H ¥

[3161] M^Y^O °YY

[3162] F^p Y 1 Y O 886 1064Fo YY-'A Ji Y -r p^. '"'Y^ N—

[3163] / H \ o \ 0

[3164] F OH HO.

[3165] F— ¥ ^NH2

[3166] f¥NXYNH2°v¥^o ¥¥¥^>o O^N N„. C^N N„.

[3167] F4 Y r i p F< Y | Y 887Fo Y / YA J / 1065

[3168] '""'l ' N— °

[3169] / M YY\* \ o

[3170] vx° OH OH HO.

[3171] / -\> / NH2¥\YH2OV^Y YK / N N„

[3172] JY^-N N„. FY Y |

[3173] 888f¥ n i Y o 1066FO k / YVF° ¥YYVA

[3174] zN~^ YY; 5 o \ o

[3175] YNH

[3176]

[3177] OH

[3178] - 206 - FH13161920.1 GPX-02525

[3179]

[3180] - 207 - FH13161920.1 GPX-02525

[3181]

[3182] - 208 - FH13161920.1 GPX-02525

[3183] ^ zOL p z ^■-,Z<NH2o^ JL ^o

[3184] \ I °

[3185] 897 1075 z

[3186] v )=

[3187] > O

[3188] T rZ.—' - \ 0

[3189] OH

[3190] F\ ^F

[3191] Z-XV, NH2HO.

[3192] O. Jk.0 NJYNH2

[3193] 898 1076

[3194] \ 0

[3195] OH

[3196] F\ / FNH2

[3197] NH2

[3198] O^ Jk x)

[3199] N,,

[3200] 899 n \ o 107

[3201] F0[7

[3202] \^\ 11

[3203] '"'Y^ N—

[3204] \ o

[3205] V OH

[3206] F^, F

[3207] Z-X> / NH2

[3208] NH2O O O. Jk.0

[3209] 900 1078 J H °

[3210] '^ T::qv

[3211] R J

[3212] / H

[3213] \ 0FT

[3214]

[3215] OH

[3216] - 209 - FH13161920.1 GPX-02525

[3217] T A^ / NH2

[3218] NA^O oA^O

[3219] F A A 1 L.

[3220] 901 F4 Y 1 A o 1079FO AYAFo YAY A

[3221] YA* \ 0

[3222] OH OH FYF

[3223] / -Y / NH2NVv°oAkoYANA / \ 902 F4 Y \ o 1080 YY

[3224] Fo YYY A

[3225] N—

[3226] \ o Y OH OH AFA NH2

[3227] oA^O

[3228] 903 N,„ / \

[3229] FF n i A p

[3230] Fo YYY A

[3231] <NA

[3232] \ o

[3233]

[3234] OH

[3235] or a pharmaceutically acceptable salt thereof.

[3236] Methods of Treatment

[3237] One aspect of the invention provides a method for treating or preventing osteoporosis, fracture, osteomalacia, arthritis, thrombocytopenia, hypoparathyroidism, hyperphosphatemia or tumoral calcinosis, comprising administering to a subject in need thereof an effective amount of a compound according to the present invention, or a pharmaceutically acceptable salt thereof.

[3238] Another aspect of this invention is a method for preventing or treating a condition mediated by PTH which comprises administering to a mammal in need thereof an effective amount of a compound a compound according to the present invention, or a pharmaceutically

[3239] - 210 - FH13161920.1 GPX-02525

[3240] acceptable salt thereof, either alone or in admixture with a pharmaceutically excipient.

[3241] Another aspect of the invention includes compounds of the present invention, or a pharmaceutically acceptable salt thereof, for use in the treatment and prevention of diseases and conditions characterized by loss of bone mineral density, mass, or strength, as well as in conditions wherein PTH would have a beneficial pharmacological effect. The invention includes administering compounds of formula (I) or (II) for use as a PTH mimetic. Another aspect of the invention includes use of the compounds of the present invention in the manufacture of a medicament for use in the treatment of osteopenia and osteoporosis in men and women for reduction in the risk of fractures, both vertebral and nonvertebral.

[3242] Another aspect of the invention provides a method of:

[3243] a) reducing of HbA1c;

[3244] b) treating or preventing type 2 diabetes, hyperglycemia, impaired glucose tolerance, or non-insulin dependent diabetes, and / or obesity;

[3245] c) reducing body weight and / or food intake, and / or inducing satiety; and / or d) treating or preventing Alzheimer's disease, nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), and / or cardiovascular diseases;

[3246] comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to the present invention.

[3247] In certain embodiments, the compound is administered orally to the subject.

[3248] In certain embodiments, the compound is administered parenterally to the subject. In certain embodiments, the disease is prevented. In other embodiments, the disease is treated.

[3249] Pharmaceutical Compositions, Routes of Administration, and Dosing

[3250] In certain embodiments, the invention is directed to a pharmaceutical composition, comprising a compound of the invention, e.g. a compound according to the present invention, and a pharmaceutically acceptable carrier.

[3251] In certain embodiments, the invention is directed to a pharmaceutical composition, comprising a compound of any of the disclosed embodiments, and a pharmaceutically acceptable carrier.

[3252] In certain embodiments, the pharmaceutical composition comprises a plurality of compounds of the invention and a pharmaceutically acceptable carrier.

[3253] - 211 - FH13161920.1 GPX-02525

[3254] Pharmaceutical compositions of the invention can be prepared by combining one or more compounds of the invention with a pharmaceutically acceptable carrier and, optionally, one or more additional pharmaceutically active agents.

[3255] As stated above, an “effective amount” refers to any amount that is sufficient to achieve a desired biological effect. Combined with the teachings provided herein, by choosing among the various active compounds and weighing factors such as potency, relative bioavailability, patient body weight, severity of adverse side-effects and mode of administration, an effective prophylactic or therapeutic treatment regimen can be planned which does not cause substantial unwanted toxicity and yet is effective to treat the particular subject. The effective amount for any particular application can vary depending on such factors as the disease or condition being treated, the particular compound of the invention being administered, the size of the subject, or the severity of the disease or condition. One of ordinary skill in the art can empirically determine the effective amount of a particular compound of the invention and / or other therapeutic agent without necessitating undue experimentation. A maximum dose may be used, that is, the highest safe dose according to some medical judgment. Multiple doses per day may be contemplated to achieve appropriate systemic levels of compounds. Appropriate systemic levels can be determined by, for example, measurement of the patient’s peak or sustained plasma level of the drug. “Dose” and “dosage” are used interchangeably herein.

[3256] In certain embodiments, intravenous administration of a compound may typically be from 0.1 mg / kg / day to 20 mg / kg / day. In one embodiment, intravenous administration of a compound may typically be from 0.1 mg / kg / day to 2 mg / kg / day. In one embodiment, intravenous administration of a compound may typically be from 0.5 mg / kg / day to 5 mg / kg / day. In one embodiment, intravenous administration of a compound may typically be from 1 mg / kg / day to 20 mg / kg / day. In one embodiment, intravenous administration of a compound may typically be from 1 mg / kg / day to 10 mg / kg / day.

[3257] Generally, daily oral doses of a compound will be, for human subjects, from about 0.01 milligrams / kg per day to 1000 milligrams / kg per day. It is expected that oral doses in the range of 0.5 to 50 milligrams / kg, in one or more administrations per day, will yield therapeutic results. Dosage may be adjusted appropriately to achieve desired drug levels, local or systemic, depending upon the mode of administration. For example, it is expected that intravenous administration would be from one order to several orders of magnitude lower dose per day. In the event that the response in a subject is insufficient at such doses, even higher doses (or effective higher doses by a different, more localized delivery route) may be - 212 - FH13161920.1 GPX-02525

[3258] employed to the extent that patient tolerance permits. Multiple doses per day are contemplated to achieve appropriate systemic levels of the compound.

[3259] For any compound described herein the therapeutically effective amount can be initially determined from animal models. A therapeutically effective dose can also be determined from human data for compounds which have been tested in humans and for compounds which are known to exhibit similar pharmacological activities, such as other related active agents. Higher doses may be required for parenteral administration. The applied dose can be adjusted based on the relative bioavailability and potency of the administered compound. Adjusting the dose to achieve maximal efficacy based on the methods described above and other methods as are well-known in the art is well within the capabilities of the ordinarily skilled artisan.

[3260] The formulations of the invention can be administered in pharmaceutically acceptable solutions, which may routinely contain pharmaceutically acceptable concentrations of salt, buffering agents, preservatives, compatible carriers, adjuvants, and optionally other therapeutic ingredients.

[3261] For use in therapy, an effective amount of the compound can be administered to a subject by any mode that delivers the compound to the desired surface. Administering a pharmaceutical composition may be accomplished by any means known to the skilled artisan. Routes of administration include but are not limited to intravenous, intramuscular, intraperitoneal, intravesical (urinary bladder), oral, subcutaneous, direct injection (for example, into a tumor or abscess), mucosal (e.g., topical to eye), inhalation, and topical.

[3262] For intravenous and other parenteral routes of administration, a compound of the invention can be formulated as a lyophilized preparation, as a lyophilized preparation of liposome-intercalated or -encapsulated active compound, as a lipid complex in aqueous suspension, or as a salt complex. Lyophilized formulations are generally reconstituted in suitable aqueous solution, e.g., in sterile water or saline, shortly prior to administration.

[3263] For oral administration, the compounds can be formulated readily by combining the active compound(s) with pharmaceutically acceptable carriers well known in the art. Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a subject to be treated. Pharmaceutical preparations for oral use can be obtained as solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or - 213 - FH13161920.1 GPX-02525

[3264] sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate. Optionally the oral formulations may also be formulated in saline or buffers, e.g., EDTA for neutralizing internal acid conditions or may be administered without any carriers.

[3265] Also specifically contemplated are oral dosage forms of the above component or components. The component or components may be chemically modified so that oral delivery of the derivative is efficacious. Generally, the chemical modification contemplated is the attachment of at least one moiety to the component molecule itself, where said moiety permits (a) inhibition of acid hydrolysis; and (b) uptake into the blood stream from the stomach or intestine. Also desired is the increase in overall stability of the component or components and increase in circulation time in the body. Examples of such moieties include: polyethylene glycol, copolymers of ethylene glycol and propylene glycol, carboxymethyl cellulose, dextran, polyvinyl alcohol, polyvinyl pyrrolidone and polyproline. Abuchowski and Davis, “Soluble Polymer-Enzyme Adducts”, In: Enzymes as Drugs, Hocenberg and Roberts, eds., Wiley-Interscience, New York, N. Y., pp. 367-383 (1981); Newmark et al., J Appl Biochem 4:185-9 (1982). Other polymers that could be used are poly-l,3-dioxolane and poly-l,3,6-tioxocane. For pharmaceutical usage, as indicated above, polyethylene glycol moieties are suitable.

[3266] For the component (or derivative) the location of release may be the stomach, the small intestine (the duodenum, the jejunum, or the ileum), or the large intestine. One skilled in the art has available formulations which will not dissolve in the stomach, yet will release the material in the duodenum or elsewhere in the intestine. Preferably, the release will avoid the deleterious effects of the stomach environment, either by protection of the compound of the invention (or derivative) or by release of the biologically active material beyond the stomach environment, such as in the intestine.

[3267] To ensure full gastric resistance a coating impermeable to at least pH 5.0 is essential. Examples of the more common inert ingredients that are used as enteric coatings are cellulose acetate trimellitate (CAT), hydroxypropylmethylcellulose phthalate (HPMCP), HPMCP 50, HPMCP 55, polyvinyl acetate phthalate (PVAP), Eudragit L30D, Aquateric, cellulose acetate phthalate (CAP), Eudragit L, Eudragit S, and shellac. These coatings may be used as mixed films.

[3268] - 214 - FH13161920.1 GPX-02525

[3269] A coating or mixture of coatings can also be used on tablets, which are not intended for protection against the stomach. This can include sugar coatings, or coatings which make the tablet easier to swallow. Capsules may consist of a hard shell (such as gelatin) for delivery of dry therapeutic (e.g., powder); for liquid forms, a soft gelatin shell may be used. The shell material of cachets could be thick starch or other edible paper. For pills, lozenges, molded tablets or tablet triturates, moist massing techniques can be used.

[3270] The therapeutic can be included in the formulation as fine multi-particulates in the form of granules or pellets of particle size about 1 mm. The formulation of the material for capsule administration could also be as a powder, lightly compressed plugs or even as tablets. The therapeutic could be prepared by compression.

[3271] Colorants and flavoring agents may all be included. For example, the compound of the invention (or derivative) may be formulated (such as by liposome or microsphere encapsulation) and then further contained within an edible product, such as a refrigerated beverage containing colorants and flavoring agents.

[3272] One may dilute or increase the volume of the therapeutic with an inert material.

[3273] These diluents could include carbohydrates, especially mannitol, oc-lactose, anhydrous lactose, cellulose, sucrose, modified dextrans and starch. Certain inorganic salts may also be used as fillers including calcium triphosphate, magnesium carbonate and sodium chloride. Some commercially available diluents are Fast-Flo, Emdex, STA-Rx 1500, Emcompress and Avicell.

[3274] Disintegrants may be included in the formulation of the therapeutic into a solid dosage form. Materials used as disintegrates include but are not limited to starch, including the commercial disintegrant based on starch, Explotab. Sodium starch glycolate, Amberlite, sodium carboxymethylcellulose, ultramylopectin, sodium alginate, gelatin, orange peel, acid carboxymethyl cellulose, natural sponge and bentonite may all be used. Another form of the disintegrants are the insoluble cationic exchange resins. Powdered gums may be used as disintegrants and as binders and these can include powdered gums such as agar, Karaya or tragacanth. Alginic acid and its sodium salt are also useful as disintegrants.

[3275] Binders may be used to hold the therapeutic agent together to form a hard tablet and include materials from natural products such as acacia, tragacanth, starch and gelatin. Others include methyl cellulose (MC), ethyl cellulose (EC) and carboxymethyl cellulose (CMC). Polyvinyl pyrrolidone (PVP) and hydroxypropylmethyl cellulose (HPMC) could both be used in alcoholic solutions to granulate the therapeutic.

[3276] - 215 - FH13161920.1 GPX-02525

[3277] An anti-frictional agent may be included in the formulation of the therapeutic to prevent sticking during the formulation process. Lubricants may be used as a layer between the therapeutic and the die wall, and these can include but are not limited to; stearic acid including its magnesium and calcium salts, polytetrafluoroethylene (PTFE), liquid paraffin, vegetable oils and waxes. Soluble lubricants may also be used such as sodium lauryl sulfate, magnesium lauryl sulfate, polyethylene glycol of various molecular weights, Carbowax 4000 and 6000.

[3278] Glidants that might improve the flow properties of the drug during formulation and to aid rearrangement during compression might be added. The glidants may include starch, talc, pyrogenic silica and hydrated silicoaluminate.

[3279] To aid dissolution of the therapeutic into the aqueous environment a surfactant might be added as a wetting agent. Surfactants may include anionic detergents such as sodium lauryl sulfate, dioctyl sodium sulfosuccinate and dioctyl sodium sulfonate. Cationic detergents which can be used and can include benzalkonium chloride and benzethonium chloride. Potential non-ionic detergents that could be included in the formulation as surfactants include lauromacrogol 400, polyoxyl 40 stearate, polyoxyethylene hydrogenated castor oil 10, 50 and 60, glycerol monostearate, polysorbate 40, 60, 65 and 80, sucrose fatty acid ester, methyl cellulose and carboxymethyl cellulose. These surfactants could be present in the formulation of the compound of the invention or derivative either alone or as a mixture in different ratios.

[3280] Pharmaceutical preparations which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and / or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. Microspheres formulated for oral administration may also be used. Such microspheres have been well defined in the art. All formulations for oral administration should be in dosages suitable for such administration.

[3281] For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.

[3282] For topical administration, the compound may be formulated as solutions, gels, ointments, creams, suspensions, etc. as are well-known in the art. Systemic formulations include those designed for administration by injection, e.g., subcutaneous, intravenous,

[3283] - 216 - FH13161920.1 GPX-02525

[3284] intramuscular, intrathecal or intraperitoneal injection, as well as those designed for transdermal, transmucosal oral or pulmonary administration.

[3285] For administration by inhalation, compounds for use according to the present invention may be conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichloro tetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of e.g., gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.

[3286] Also contemplated herein is pulmonary delivery of the compounds disclosed herein (or salts thereof). The compound is delivered to the lungs of a mammal while inhaling and traverses across the lung epithelial lining to the blood stream. Other reports of inhaled molecules include Adjei et al., PharmRes 7:565-569 (1990); Adjei et al., Int J Pharmaceutics 63:135-144 (1990) (leuprolide acetate); Braquet et al., J Cardiovasc Pharmacol 13(suppl. 5):143-146 (1989) (endothelin-1); Hubbard et al., Annal Int Med 3:206-212 (1989) (Dl-antitrypsin); Smith et al., 1989, J Clin Invest 84:1145-1146 (a- 1 -proteinase); Oswein et al., 1990, " Aerosolization of Proteins", Proceedings of Symposium on Respiratory Drug Delivery II, Keystone, Colorado, March, (recombinant human growth hormone); Debs et al., 1988, J Immunol 140:3482-3488 (interferon-gamma and tumor necrosis factor alpha) and Platz et al., U. S. Pat. No. 5,284,656 (granulocyte colony stimulating factor; incorporated by reference). A method and composition for pulmonary delivery of drugs for systemic effect is described in U. S. Pat. No. 5,451,569 (incorporated by reference), issued Sep. 19, 1995 to Wong et al.

[3287] Contemplated for use in the practice of this invention are mechanical devices designed for pulmonary delivery of therapeutic products, including but not limited to nebulizers, metered dose inhalers, and powder inhalers, all of which are familiar to those skilled in the art.

[3288] Some specific examples of commercially available devices suitable for the practice of this invention are the Ultravent nebulizer, manufactured by Mallinckrodt, Inc., St. Louis, Mo.; the Acorn II nebulizer, manufactured by Marquest Medical Products, Englewood, Colo.; the Ventolin metered dose inhaler, manufactured by Glaxo Inc., Research Triangle Park, North Carolina; and the Spinhaler powder inhaler, manufactured by Fisons Corp., Bedford, Mass.

[3289] - 217 - FH13161920.1 GPX-02525

[3290] All such devices require the use of formulations suitable for the dispensing of the compounds of the invention. Typically, each formulation is specific to the type of device employed and may involve the use of an appropriate propellant material, in addition to the usual diluents, adjuvants and / or carriers useful in therapy. Also, the use of liposomes, microcapsules or microspheres, inclusion complexes, or other types of carriers is contemplated. Chemically modified compound of the invention may also be prepared in different formulations depending on the type of chemical modification or the type of device employed.

[3291] Formulations suitable for use with a nebulizer, either jet or ultrasonic, will typically comprise a compound of the invention (or derivative) dissolved in water at a concentration of about 0.1 to 25 mg of biologically active compound of the invention per mL of solution. The formulation may also include a buffer and a simple sugar (e.g., for inhibitor stabilization and regulation of osmotic pressure). The nebulizer formulation may also contain a surfactant, to reduce or prevent surface induced aggregation of the compound of the invention caused by atomization of the solution in forming the aerosol.

[3292] Formulations for use with a metered-dose inhaler device will generally comprise a finely divided powder containing the compound of the invention (or derivative) suspended in a propellant with the aid of a surfactant. The propellant may be any conventional material employed for this purpose, such as a chlorofluorocarbon, a hydrochlorofluorocarbon, a hydrofluorocarbon, or a hydrocarbon, including trichlorofluoromethane, dichlorodifluoromethane, dichlorotetrafluoroethanol, and 1,1,1,2-tetrafluoroethane, or combinations thereof. Suitable surfactants include sorbitan trioleate and soya lecithin. Oleic acid may also be useful as a surfactant.

[3293] Formulations for dispensing from a powder inhaler device will comprise a finely divided dry powder containing a compound of the invention (or derivative) and may also include a bulking agent, such as lactose, sorbitol, sucrose, or mannitol in amounts which facilitate dispersal of the powder from the device, e.g., 50 to 90% by weight of the formulation. The compound of the invention (or derivative) should advantageously be prepared in particulate form with an average particle size of less than 10 micrometers (pm), most preferably 0.5 to 5 pm, for most effective delivery to the deep lung.

[3294] Nasal delivery of a pharmaceutical composition of the present invention is also contemplated. Nasal delivery allows the passage of a pharmaceutical composition of the present invention to the blood stream directly after administering the therapeutic product to

[3295] - 218 - FH13161920.1 GPX-02525

[3296] the nose, without the necessity for deposition of the product in the lung. Formulations for nasal delivery include those with dextran or cyclodextran.

[3297] For nasal administration, a useful device is a small, hard bottle to which a metered dose sprayer is attached. In one embodiment, the metered dose is delivered by drawing the pharmaceutical composition of the present invention solution into a chamber of defined volume, which chamber has an aperture dimensioned to aerosolize and aerosol formulation by forming a spray when a liquid in the chamber is compressed. The chamber is compressed to administer the pharmaceutical composition of the present invention. In a specific embodiment, the chamber is a piston arrangement. Such devices are commercially available.

[3298] Alternatively, a plastic squeeze bottle with an aperture or opening dimensioned to aerosolize an aerosol formulation by forming a spray when squeezed is used. The opening is usually found in the top of the bottle, and the top is generally tapered to partially fit in the nasal passages for efficient administration of the aerosol formulation. Preferably, the nasal inhaler will provide a metered amount of the aerosol formulation, for administration of a measured dose of the drug.

[3299] The compounds, when it is desirable to deliver them systemically, may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents, such as suspending, stabilizing and / or dispersing agents.

[3300] Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.

[3301] Alternatively, the active compounds may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

[3302] - 219 - FH13161920.1 GPX-02525

[3303] The compounds may also be formulated in rectal or vaginal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.

[3304] In addition to the formulations described above, a compound may also be formulated as a depot preparation. Such long-acting formulations may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.

[3305] The pharmaceutical compositions also may comprise suitable solid or gel phase carriers or excipients. Examples of such carriers or excipients include but are not limited to calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.

[3306] Suitable liquid or solid pharmaceutical preparation forms are, for example, aqueous or saline solutions for inhalation, microencapsulated, encochleated, coated onto microscopic gold particles, contained in liposomes, nebulized, aerosols, pellets for implantation into the skin, or dried onto a sharp object to be scratched into the skin. The pharmaceutical compositions also include granules, powders, tablets, coated tablets, (micro)capsules, suppositories, syrups, emulsions, suspensions, creams, drops or preparations with protracted release of active compounds, in whose preparation excipients and additives and / or auxiliaries such as disintegrants, binders, coating agents, swelling agents, lubricants, flavorings, sweeteners or solubilizers are customarily used as described above. The pharmaceutical compositions are suitable for use in a variety of drug delivery systems. For a brief review of methods for drug delivery, see Langer R, Science 249:1527-33 (1990).

[3307] The compound of the invention and optionally other therapeutics may be administered per se (neat) or in the form of a pharmaceutically acceptable salt or cocrystal. When used in medicine the salts or cocrystals should be pharmaceutically acceptable, but non-pharmaceutically acceptable salts or cocrystals may conveniently be used to prepare pharmaceutically acceptable salts or cocrystals thereof. Such salts include, but are not limited to, those prepared from the following acids: hydrochloric, hydrobromic, sulphuric, nitric, phosphoric, maleic, acetic, salicylic, p -toluene sulphonic, tartaric, citric, methane sulphonic, formic, malonic, succinic, naphthalene-2-sulphonic, and benzene sulphonic. Also, such salts can be prepared as alkaline metal or alkaline earth salts, such as sodium, potassium or calcium salts of the carboxylic acid group.

[3308] Suitable buffering agents include: acetic acid and a salt (1-2% w / v); citric acid and a salt (1-3% w / v); boric acid and a salt (0.5-2.5% w / v); and phosphoric acid and a salt (0.8-2%

[3309] - 220 - FH13161920.1 GPX-02525

[3310] w / v). Suitable preservatives include benzalkonium chloride (0.003-0.03% w / v); chlorobutanol (0.3-0.9% w / v); parabens (0.01-0.25% w / v) and thimerosal (0.004-0.02% w / v).

[3311] Pharmaceutical compositions of the invention contain an effective amount of a compound as described herein and optionally therapeutic agents included in a pharmaceutically acceptable carrier. The term “pharmaceutically acceptable carrier” means one or more compatible solid or liquid filler, diluents or encapsulating substances which are suitable for administration to a human or other vertebrate animal. The term “carrier” denotes an organic or inorganic ingredient, natural or synthetic, with which the active ingredient is combined to facilitate the application. The components of the pharmaceutical compositions also are capable of being commingled with the compounds of the present invention, and with each other, in a manner such that there is no interaction which would substantially impair the desired pharmaceutical efficiency.

[3312] The therapeutic agent(s), including specifically but not limited to a compound of the invention, may be provided in particles. Particles as used herein means nanoparticles or microparticles (or in some instances larger particles) which can consist in whole or in part of the compound of the invention or the other therapeutic agent(s) as described herein. The particles may contain the therapeutic agent(s) in a core surrounded by a coating, including, but not limited to, an enteric coating. The therapeutic agent(s) also may be dispersed throughout the particles. The therapeutic agent(s) also may be adsorbed into the particles. The particles may be of any order release kinetics, including zero-order release, first-order release, second-order release, delayed release, sustained release, immediate release, and any combination thereof, etc. The particle may include, in addition to the therapeutic agent(s), any of those materials routinely used in the art of pharmacy and medicine, including, but not limited to, erodible, nonerodible, biodegradable, or nonbiodegradable material or combinations thereof. The particles may be microcapsules which contain the compound of the invention in a solution or in a semi-solid state. The particles may be of virtually any shape.

[3313] Both non-biodegradable and biodegradable polymeric materials can be used in the manufacture of particles for delivering the therapeutic agent(s). Such polymers may be natural or synthetic polymers. The polymer is selected based on the period of time over which release is desired. Bioadhesive polymers of particular interest include bioerodible hydrogels described in Sawhney H S et al. (1993) Macromolecules 26:581-7, the teachings of which are incorporated herein. These include polyhyaluronic acids, casein, gelatin, glutin, polyanhydrides, polyacrylic acid, alginate, chitosan, poly(methyl methacrylates), poly(ethyl - 221 - FH13161920.1 GPX-02525

[3314] methacrylates), poly (butylmethacrylate), poly (isobutyl methacrylate),

[3315] poly (hexylmethacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), and poly (octadecyl acrylate).

[3316] The therapeutic agent(s) may be contained in controlled release systems. The term “controlled release” is intended to refer to any drug-containing formulation in which the manner and profile of drug release from the formulation are controlled. This refers to immediate as well as non-immediate release formulations, with non-immediate release formulations including but not limited to sustained release and delayed release formulations. The term “sustained release” (also referred to as “extended release”) is used in its conventional sense to refer to a drug formulation that provides for gradual release of a drug over an extended period of time, and that preferably, although not necessarily, results in substantially constant blood levels of a drug over an extended time period. The term “delayed release” is used in its conventional sense to refer to a drug formulation in which there is a time delay between administration of the formulation and the release of the drug there from. “Delayed release” may or may not involve gradual release of drug over an extended period of time, and thus may or may not be “sustained release.”

[3317] Use of a long-term sustained release implant may be particularly suitable for treatment of chronic conditions. “Long-term” release, as used herein, means that the implant is constructed and arranged to deliver therapeutic levels of the active ingredient for at least 7 days, and preferably 30-60 days. Long-term sustained release implants are well-known to those of ordinary skill in the art and include some of the release systems described above.

[3318] It will be understood by one of ordinary skill in the relevant arts that other suitable modifications and adaptations to the compositions and methods described herein are readily apparent from the description of the invention contained herein in view of information known to the ordinarily skilled artisan, and may be made without departing from the scope of the invention or any embodiment thereof. Having now described the present invention in detail, the same will be more clearly understood by reference to the following examples, which are included herewith for purposes of illustration only and are not intended to be limiting of the invention.

[3319] - 222 - FH13161920.1 GPX-02525

[3320] EXAMPLES

[3321] The invention is further described in the following examples, which do not limit the scope of the invention described in the claims.

[3322] Chemical Abbreviations

[3323] The following abbreviations are used for chemical reagents used in preparation of examples of the disclosure:

[3324] ACN Acetonitrile

[3325] AC2O Acetic anhydride

[3326] AcOH Acetic acid

[3327] AmB Ammonium bicarbonate

[3328] AmF Ammonium formate

[3329] Ar Argon

[3330] BPO Benzoyl peroxide

[3331] B0C2O Di-tert-butyl dicarbonate

[3332] CataCXiumA Pd G3 Mesylate[(di(l-adamantyl)-n-butylphosphine)-2-(2'-amino-l,l'- biphenyl)]palladium(II), [(Di(l-adamantyl)-butylphosphine)-2- (2 '-amino- 1, 1 '-biphenyl)] palladium(II) methanesulfonate CDI 1, 1 '-Carbonyldiimidazole

[3333] CS2 Carbon disulfide

[3334] CS2CO3 Cesium carbonate

[3335] CDCI3 Deuterated chloroform

[3336] CHCI3 Chloroform

[3337] CF3CH2OH 2,2,2-Trifluoroethanol

[3338] CMBP (Cyanomethylene)tributylphosphorane

[3339] DBU l,8-Diazabicyclo(5.4.0)undec-7-ene

[3340] DCC N, N'-dicyclohexylcarbodiimide

[3341] DCE Dichloroethane

[3342] DCM Dichloromethane

[3343] DIAD Diisopropyl azodicarboxylate

[3344] DIPEA or DIEA A, A-diisopropylethylamine

[3345] DMA Dimethylacetamide

[3346]

[3347] -223- FoleyHoagUS13180487.1 GPX-02525

[3348] DMAP 4-Dimethylaminopyridine

[3349] DMF Dimethylformamide

[3350] DMSO Dimethyl sulfoxide

[3351] DPPP 1,3-Bis(diphenylphosphino)propane

[3352] EtOAc Ethyl acetate

[3353] EtOH Ethanol

[3354] FA Formic acid

[3355] GPhos Pd G6 TES Palladium, bromo[dicyclohexyl[3-( 1, 1 -dimethylethoxy)-6- methoxy-2 ',6 ' - bi s ( 1 -methylethyl) [1,1 '-biphenyl] -2-yl- KC1'] pho sphine-KP] [4- [ [2 - (trimethylsilyl)ethoxy]carbonyl]phenyl]-, (SP-4-2)- (ACI) h Hour

[3356] H2Hydrogen

[3357] HATU Hexafluorophosphate azabenzotriazole tetramethyluronium HFIP Hexafluoroisopropanol

[3358] HNO3Nitric acid

[3359] H2SO4 Sulfuric acid

[3360] IC1 Iodine monochloride

[3361] iPrOH Isopropanol

[3362] Ir[(ppy)2(dtbbpy)]PF6(4,4'-Di-tert-butyl-2,2'-bipyridine)bis[(2- pyridinyl)phenyl]iridium(III) Hexafluorophosphate K2CO3 Potassium carbonate

[3363] KCN Potassium cyanide

[3364] K3PO4 Potassium phosphate

[3365] K2OSO4 Potassium Osmate

[3366] LiOH Lithium hydroxide

[3367] m-CPBA Meta-chloroperbenzoic acid

[3368] MeCN Acetonitrile

[3369] Mel Methyl iodide

[3370] MeOH Methanol

[3371] MgSO4Magnesium sulfate

[3372] min Minute

[3373] MnO2Manganese dioxide

[3374]

[3375] -224- FoleyHoagUS13180487.1 GPX-02525

[3376] MsCl Mesyl chloride

[3377] MTBE Methyl tert-butyl ether

[3378] NaIO4Sodium periodate

[3379] N2Nitrogen

[3380] NaBH4Sodium borohydride

[3381] NaBH3CN Sodium cyanoborohydride

[3382] NaBH(OAc)3Sodium triacetoxyborohydride

[3383] NBS N-bromo succinimide

[3384] NCS N-chloro succinimide

[3385] NaClO Sodum hypochlorite

[3386] NaH Sodium hydride

[3387] NaHCO3Sodium bicarbonate

[3388] NaOH Sodium hydroxide

[3389] NaOMe Sodium methoxide

[3390] Na2SO3Sodium sulfite

[3391] Na2SO4Sodium sulfate

[3392] NH3Ammonia

[3393] NH4CI Ammonium chloride

[3394] (NH4)2CO3Ammonium carbonate

[3395] NH4OAC Ammonium acetate

[3396] NH4OH Ammonium hydroxide

[3397] NiBr2dtbbpy Bis(l,l-dimethylethyl)-2,2'-bipyridine] nickel (II) dichloride NMP N-methly-2-pyrrolidine

[3398] Pd / C Palladium on carbon

[3399] Pd(OAc)2Palladium acetate

[3400] Pd(OH)2Palldium hydroxide

[3401] Pd-PEPPSI-iPentCl(O- Dichloro[l,3-bis(2,6-Di-3-pentylphenyl)imidazol-2-ylidene](3- picoline) chloropyridyl)palladium(II)

[3402] p-NsCl 4-Nitrobenzenesulfonyl chloride

[3403] POC13Phosphorus oxychloride

[3404] PPh3Triphenylphosphine

[3405]

[3406] -225- FoleyHoagUS13180487.1 GPX-02525

[3407] PYAOP ((7-Azabenzotriazol-l-yloxy)tripyrrolidinophosphonium hexafluoropho sphate)

[3408] rt Room temperature

[3409] RuCh Ruthenium chloride

[3410] SEMC1 2- (Trimethylsilyl)ethoxymethyl chloride

[3411] S1O2 Silica

[3412] SOCI2 Thionyl chloride

[3413] TBAF Tetrabutylammonium fluoride

[3414] TBSC1 tert-Butyldimethylsilyl chloride

[3415] TEA Triethylamine

[3416] TFA Trifluoroacetic acid

[3417] THF Tetrahydrofuran

[3418] TMSCN Trimethylsilyl cyanide

[3419] TosCl / 2-Toluenesulfonyl chloride

[3420] TsOH p-Toliienesulfonic acid

[3421] TTMSS Tris(trimethylsilyl)silane

[3422] XantPhos Pd G4 (5P-4-3)-[[5-(diphenylphosphino)-9,9-dimethyl-9 / / -xanthen-4- yl] diphenylphosphine-KP] ( methanesu Ifonato-KO) [2 '- (methylamino-KJV) [1,1 '-biphenyl] -2-yl-KC] - Palladium Zn(CN)2Zinc cyanide

[3423] ACN Acetonitrile

[3424] AC2O Acetic anhydride

[3425] AcOH Acetic acid

[3426] AmB Ammonium bicarbonate

[3427] AmF Ammonium formate

[3428] Ar Argon

[3429] BPO Benzoyl peroxide

[3430] B0C2O Di-tert-butyl dicarbonate

[3431] CDI 1, 1 '-Carbonyldiimidazole

[3432] CS2 Carbon disulfide

[3433] CS2CO3 Cesium carbonate

[3434] CDCI3 Deuterated chloroform

[3435]

[3436] -226- FoleyHoagUS13180487.1 GPX-02525

[3437] CHC13 Chloroform

[3438] CF3CH2OH 2,2,2-Trifluoroethanol

[3439] CMBP (Cyanomethylene)tributylphosphorane

[3440] DBU l,8-Diazabicyclo(5.4.0)undec-7-ene

[3441] DCC N, N'-dicyclohexylcarbodiimide

[3442] DCE Dichloroethane

[3443] DCM Dichloromethane

[3444] DIAD Diisopropyl azodicarboxylate

[3445] DIPEA iVuV-diisopropylethylamine

[3446] DMA Dimethylacetamide

[3447] DMAP 4-Dimethylaminopyridine

[3448] DMF Dimethylformamide

[3449] DMSO Dimethyl sulfoxide

[3450] DPPP 1,3-Bis(diphenylphosphino)propane

[3451] EtOAc Ethyl acetate

[3452] EtOH Ethanol

[3453] FA Formic acid

[3454] h Hour

[3455] H2Hydrogen

[3456] HATU Hexafluorophosphate azabenzotriazole tetramethyluronium HFIP Hexafluoroisopropanol

[3457] HNO3 Nitric acid

[3458] H2SO4 Sulfuric acid

[3459] IC1 Iodine monochloride

[3460] iPrOH Isopropanol

[3461] K2CO3 Potassium carbonate

[3462] KCN Potassium cyanide

[3463] K3PO4 Potassium phosphate

[3464] K2OSO4 Potassium Osmate

[3465] LiOH Lithium hydroxide

[3466] m-CPBA Meta-chloroperbenzoic acid

[3467] MeCN Acetonitrile

[3468]

[3469] -227- FoleyHoagUS13180487.1 GPX-02525

[3470] Mel Methyl iodide

[3471] MeOH Methanol

[3472] MgSO4 Magnesium sulfate

[3473] min Minute

[3474] MnO2Manganese dioxide

[3475] MsCl Mesyl chloride

[3476] MTBE Methyl tert-butyl ether NaIO4Sodium periodate

[3477] N2Nitrogen

[3478] NaBH4Sodium borohydride NaBH3CN Sodium cyanoborohydride NaBH(OAc)3Sodium triacetoxyborohydride NBS N -bromo succinimide

[3479] NaClO Sodum hypochlorite

[3480] NaH Sodium hydride

[3481] NaHCO3Sodium bicarbonate

[3482] NaOH Sodium hydroxide

[3483] NaOMe Sodium methoxide

[3484] Na2SO3Sodium sulfite

[3485] Na2SO4Sodium sulfate

[3486] NH3Ammonia

[3487] NH4CI Ammonium chloride (NH4)2CO3Ammonium carbonate NH4OAC Ammonium acetate

[3488] NH4OH Ammonium hydroxide

[3489] NMP N -methly- 2-pyrrolidine

[3490] Pd / C Palladium on carbon Pd(OAc)2Palladium acetate

[3491] Pd(OH)2Palldium hydroxide

[3492] p-NsCl 4-Nitrobenzenesulfonyl chloride POC13Phosphorus oxychloride PPh3Triphenylpho sphine

[3493]

[3494] -228- FoleyHoagUS13180487.1 GPX-02525

[3495] rt Room temperature

[3496] RuCh Ruthenium chloride

[3497] SEMC1 2-(Trimethylsilyl)ethoxymethyl chloride

[3498] SiO2Silica

[3499] SOCI2 Thionyl chloride

[3500] TBAF Tetrabutylammonium fluoride

[3501] TBSC1 tert-Butyldimethylsilyl chloride

[3502] TEA Triethylamine

[3503] TFA Trifluoroacetic acid

[3504] THF Tetrahydrofuran

[3505] TMSCN Trimethylsilyl cyanide

[3506] TosCl p-Toliienesulfonyl chloride

[3507] TsOH p-Toliienesulfonic acid

[3508] Zn(CN)2Zinc cyanide

[3509]

[3510] Intermediate 1. (2,2-difluorocyclobutyl)methyl 4-methylbenzenesulfonate

[3511] Synthetic scheme:

[3512] TsCI, pyr

[3513]

[3514] To a solution of (2,2-difluorocyclobutyl)methanol (150 mg, 1.23 mmol) and 4-methylbenzenesulfonyl chloride (281 mg, 1.47 mmol) in DCM (1.5 mL) was added pyridine (318 mg, 4.02 mmol). The mixture was stirred at 20 °C for 16 h. The reaction mixture was partitioned between DCM (40.0 mL) and H2O (40.0 mL). The organic phase was separated, washed with saturated NH4CI, dried over Na2SO4, filtered, and concentrated under reduced pressure to give (2,2-difhiorocyclobutyl)methyl 4-methylbenzenesulfonate (263 mg, 77.5%) as a white solid. MS (ESI): mass calcd. for: C12H14F2O3S: 276.07, found: 277.1 [M+H]+.

[3515] Intermediates 2A-D.

[3516] Synthetic scheme:

[3517] -229- FoleyHoagUS13180487.1 GPX-02525

[3518] TosCI, Py

[3519] DCM

[3520]

[3521] (2-fluorocyclobutyl)methyl 4-methylbenzenesulfonate

[3522] ^OTs

[3523]

[3524] F

[3525] To a solution of (2-fluorocyclobutyl)methanol (0.5 g, 4.8 mmol) in DCM (5 mL) was added pyridine (1.24 g, 15.7 mmol) and TosCI (1.10 g, 5.76 mmol) at 0 °C. The mixture was stirred at 25 °C for 12 h under N2. The reaction was quenched with H2O (10 mL) and extracted with DCM (10 mL x 3). The combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO₂, petroleum ether: ethyl acetate = 100: 1 to 1: 100) to give (2-fluorocyclobutyl)methyl 4-methylbenzenesulfonate (0.75 g, 59.3%) as a colorless oil.1H NMR (400 MHz, DMSO-d6) 8 ppm 7.80 (m, J= 8.0 Hz, 2H), 7.49 (m, J = 8.0 Hz, 2H), 4.53-5.24 (m, 1H), 4.02-4.26 (m, 2H), 2.60-2.87 (m, 1H), 2.41-2.44 (m, 3H), 2.07-2.31 (m, 2H), 1.49-2.01 (m, 2H), 1.10-1.19 (m, 1H).

[3526] Intermediates 2A-D.

[3527] 2-fluorocyclobutyl)methyl 4-methylbenzenesulfonate (300 mg) was separated by chiral SFC (column: DAICEL CHIRALPAK IG, (250mm*30mm,10um); mobile phase: CCL-EtOH (0.1% NH3H2O); gradient: 5%- 15% B with isocratic elution) to give a mixture of Intermediate 2A-C (177 mg) as a colorless oil and Intermediate 2D (90 mg) as a colorless oil.

[3528] The mixture of Intermediate 2A-C (177 mg) was separated by chiral SFC (column: DAICEL CHIRALPAK IC (250mm*30mm, lOum); mobile phase: CO2-IPA (0.1% NH3H2O); gradient: 27% B with isocratic elution) to give a mixture of Intermediate 2A-B (84 mg) as a colorless oil and Intermediate 2C (80 mg) as a colorless oil.

[3529] Finally, the mixture of Intermediate 2A-B (84 mg) was separated by chiral SFC (column: DAICEL CHIRALPAK AD (250mm*30mm, lOum); mobile phase: CCL-MeOH

[3530] -230- FoleyHoagUS13180487.1 GPX-02525

[3531] (0.1% NH3H2O); gradient: 10% B with isocratic elution) to give Intermediate 2A (34 mg) and Intermediate 2B (41 mg) as colorless oils.

[3532] Relative stereochemistry was determined by1H NMR, and absolute stereochemistry was assigned arbitrarily. Characterization:

[3533] [(lR,2S)-2-fluorocyclobutyl]methyl 4-methylbenzenesulfonate (Intermediate 2A)

[3534] 1H NMR (400 MHz, DMSO-d6) 8 ppm 7.79 (d, J = 8.4 Hz, 2H), 7.49 (d, J = 8.0 Hz, 2H), 4.58-4.81 (m, 1H), 4.05 (d, J = 6.0 Hz, 2H), 2.58-2.73 (m, 1H), 2.43 (s, 3H), 2.10-2.20 (m, 1H), 1.85-2.01 (m, 1H), 1.68-1.79 (m, 1H), 1.05-1.24 (m, 1H).

[3535] [(lS,2R)-2-fluorocyclobutyl]methyl 4-methylbenzenesulfonate (Intermediate 2B)

[3536] 1H NMR (400 MHz, DMSO-d6) 6 ppm 7.79 (d, J = 8.4 Hz, 2H), 7.49 (d, J = 8.0 Hz, 2H), 4.59-4.78 (m, 1H), 4.05 (d, J = 6.0 Hz, 2H), 2.56-2.73 (m, 1H), 2.43 (s, 3H), 2.09-2.20 (m, 1H), 1.85-2.05 (m, 1H), 1.67-1.80 (m, 1H), 1.07-1.24 (m, 1H).

[3537] [(lR,2R)-2-fluorocyclobutyl]methyl 4-methylbenzenesulfonate (Intermediate 2C)

[3538] 1H NMR (400 MHz, DMSO-d6) 6 ppm 7.79 (d, J = 8.0 Hz, 2H), 7.49 (d, J = 8.0 Hz, 2H), 5.00-5.18 (m, 1H), 4.21-4.26 (m, 2H), 4.12-4.16 (m, 1H), 2.81-2.84 (m, 1H), 2.43 (s, 3H), 2.07-2.33 (m, 2H), 1.50-1.75 (m, 2H).

[3539] [(lS,2S)-2-fluorocyclobutyl]methyl 4-methylbenzenesulfonate (Intermediate 2D)

[3540] ‘H NMR (400 MHz, DMSO-d6) 6 ppm 7.78-7.81 (d, J= 8.0 Hz, 2H), 7.49 (d, J= 8.0 Hz, 2H), 4.99-5.20 (m, 1H), 4.20-4.27 (m, 1H), 4.11-4.17 (m, 1H), 2.81-2.84 (m, 1H), 2.43 (s, 3H), 2.06-2.31 (m, 2H), 1.49-1.73 (m, 2H).

[3541] Intermediate 3. ((ls,3s)-3-methylcyclobutyl)methanamine

[3542] O.,|

[3543]

[3544] NH2

[3545] Synthetic scheme:

[3546] -231- FoleyHoagUS13180487.1 GPX-02525

[3547] NH3H2O

[3548] SOCI2toluene

[3549] BH3 Me2S

[3550] THF

[3551]

[3552] NH2NH2

[3553] (ls,3s)-3-methylcydobutane-l-carboxamide

[3554]

[3555] A solution of 3-methylcyclobutanecarboxylic acid (1 g, 8.76 mmol) in SOCI2 (10 mL) was stirred at 85 °C for 1 h. The solution was concentrated under reduced pressure to give 3-methylcyclobutanecarbonyl chloride (1.16 g, 100%) as a colorless oil, which was used without further purification.

[3556] (ls,3s)-3-methylcyclobutane-l-carboxamide

[3557]

[3558] NH2

[3559] To a solution of 3-methylcyclobutanecarbonyl chloride (1.16 g, 8.75 mmol) in toluene (10 mL) was added NH3·H2O (7.36 g, 52.5 mmol, 25% purity) at 20 °C. The solution was stirred at 20 °C for 0.5 h. The reaction was concentrated under reduced pressure to provide 3-methylcyclobutanecarboxamide (1.3 g, 99.8%) as a white solid, which was used without further purification. ‘H NMR (400 MHz, DMSO-d6) 8 ppm 7.10 (s, 1H), 6.62 (s, 1H), 2.67-2.80 (m, 1H), 2.05-2.29 (m, 3H), 1.56-1.75 (m, 2H), 0.97 (d, J = 6.4 Hz, 3H).

[3560] ((ls,3s)-3-methylcyclobutyl)methanamine

[3561]

[3562] To a solution of 3-methylcyclobutanecarboxamide (600 mg, 4.03 mmol) in THF (6 mL) was added BHs-Me2S (10 M in THF, 1.21 mL, 12.1 mmol) at 0 °C. The solution was stirred at 20 °C for 30 min and then at 80 °C for 16 h. The mixture was cooled to 0 °C and MeOH (0.5 mL) was added drop wise. The solution was stirred at 0 °C for 10 min and concentrated under reduced pressure to give (3-methylcyclobutyl)methanamine (670 mg, 58.7%) as a colorless oil,

[3563] -232- FoleyHoagUS13180487.1 GPX-02525

[3564] which was used without further purification. MS (ESI): mass calcd. for CeHisN: 99.10, found: 100.3 [M+H]+.

[3565] Intermediate 4. (l-((benzyloxy)methyl)-5-oxopyrrolidin-3-yl)methyl 4-nitrobenzenesulfonate

[3566]

[3567] 4-(((terr-butyldimethylsilyl)oxy)methyl)pyrrolidin-2-one

[3568] o

[3569]

[3570] TBSO

[3571] To a mixture of 4-(hydroxymethyl)pyrrolidin-2-one (698 mg, 5.94 mmol) and imidazole (613 mg, 8.91 mmol) in DCM (29.7 mL) was added TBSC1 (1.18 g, 7.72 mmol) before stirring at rt for 20 h. The resulting mixture was quenched with MeOH (3 mL) and stirred at rt for 40 min. The mixture was diluted with H2O and the layers were separated. The aqueous layer was extracted with DCM (3x). The combined organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The product was purified by column chromatography (silica, 0-12% MeOH, DCM) to afford the title compound (1.33 g, 98%) as a yellow solid. MS (ESI): mass calcd. for CnH23NOSi: 229.15, found: 230.4 [M+H]+.

[3572] l-((benzyloxy)methyl)-4-(((terr-butyldimethylsilyl)oxy)methyl)pyrrolidin-2-one

[3573] o

[3574]

[3575] -233- FoleyHoagUS13180487.1 GPX-02525

[3576] To a solution of 4-(((tert-butyldimethylsilyl)oxy)methyl)pyrrolidin-2-one (1.33 g, 5.78 mmol) in THF (28.9 mL) was added NaH, 60% dispersion in mineral oil (137 mg, 3.44 mmol) at 0 °C, and the mixture was stirred at that temperature for 30 min. BOMC1 (983 pL, 6.36 mmol) was added dropwise to the mixture and stirred at 0 °C for 30 min and then at rt for 4.5 h. The resulting mixture was cooled to 0 °C and carefully quenched with H2O and diluted with EtOAc (30 mL). After the layers were separated, the aqueous layer was extracted with EtOAc (3 x 30 mL). The combined organic layer was washed with brine (40 mL), dried over Na2SO4, and concentrated in vacuo to give a crude mixture. The product was purified by column chromatography (silica, 5-50% EtOAc / heptane) to afford the title compound (1.75 g, 87%) as a colorless oil. MS (ESI): mass calcd. for CigHsiNCLSi: 349.21, found: 242.4 [M-OBn]+. l-((benzyloxy)methyl)-4-(hydroxymethyl)pyrrolidin-2-one

[3577] o

[3578] H

[3579]

[3580] O— '

[3581] To a solution of l-((benzyloxy)methyl)-4-(((tert-butyldimethylsilyl)oxy)methyl)pyrrolidin-2-one (1.75 g, 5.01 mmol) in THF (25.0 mL) was added TBAF (6.01 mL, 6.01 mmol) before stirring at rt for 30 min. The resulting mixture was quenched with saturated aqueous NH4CI. After the layers were separated, the aqueous layer was extracted with EtOAc (4 x 10 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The product was purified by column chromatography (silica, 20-100% EtOAc / heptane) to afford the title compound (1.03 g, 87%) as a colorless oil. MS (ESI): mass calcd. for C13H17NO3: 235.12, found: 258.4 [M+Na]+.

[3582] (l-((benzyloxy)methyl)-5-oxopyrrolidin-3-yl)methyl 4-nitrobenzenesulfonate

[3583]

[3584] To a mixture of l-((benzyloxy)methyl)-4-(hydroxymethyl)pyrrolidin-2-one (1.03 g, 4.38 mmol) and EtsN (1.47 mL, 10.5 mmol) in DCM (21.9 mL) was added p-NsCl (1.19 g, 5.25 mmol). The reaction mixture was stirred at rt for 30 min and quenched with H2O (30 mL). After the layers were separated, the aqueous layer was extracted with DCM (3 x 30 mL). The combined organic layer was washed with brine (50 mL), dried over Na2SO4, filtered, and

[3585] -234- FoleyHoagUS13180487.1 GPX-02525

[3586] concentrated in vacuo. The crude residue was purified by column chromatography (silica, 20- 100% EtOAc / heptane) to afford the title compound (1.46 g, 79%) as a white solid. MS (ESI): mass calcd. for C19H20N2O7S: 420.10, found: 443.4 [M+Na]+.

[3587] Intermediate 5. ((ls,3s)-3-hydroxy-3-methylcyclobutyl)methyl 4-nitrobenzenesulfonate

[3588]

[3589] The title compound was synthesized following analogous procedures to those described for Intermediate 12 using cA-3-hydroxy-3-methylcyclobutanecarboxylic acid as starting material instead of methyl 3-((t -butyldimethylsilyl)oxy)bicyclo[l.l.l]pentane-l-carboxylate.

[3590] Intermediate 6. ((lr,3r)-3-hydroxy-3-methylcyclobutyl)methyl 4-nitrobenzenesulfonate was prepared following analogous procedures to those described for Intermediate 12.

[3591] Intermediate 7. (3-((tert-butoxycarbonyl)amino)bicyclo[l.l.l]pentan-l-yl)methyl 4-nitrobenzenesulfonate

[3592] NsO

[3593] NHBoc

[3594] Synthetic scheme

[3595] NsCI

[3596] HO NEt3NsO

[3597]

[3598] NHBoc DCM NHBoc

[3599] p-NsCl (159 mg, 703 pmol) was dissolved in DCM (5.86 mL) and tert-butyl (3- (hydroxymethyl)bicyclo [1.1.1] pentan- l-yl)carbamate (102 mg, 469 pmol) was added. The mixture was cooled to 0 °C and Et? N (197 pL, 1.41 mmol) was added. After 30 min, the cooling bath was removed, and the reaction was stirred at rt for 3 h. The reaction was diluted with DCM (5 mL) and quenched with water (15 mL). The aqueous phase was extracted with DCM (2 x 15 mL). The organic phase was dried with MgSCU, concentrated onto silica and purified by column chromatography (silica, 10-60% EtOAc / Heptanes) to give the title compound (170 mg, 91%) as a yellow solid.1H NMR (400 MHz, CDCh) 8 ppm 8.40 (d, J = 8.8 Hz, 2H), 8.09 (d, J= 8.8 Hz, 2H), 4.93 (s, 1H), 4.23 (s, 2H), 1.96 (s, 6H), 1.42 (s, 9H).

[3600] Intermediate 8. tert-butyl 3-methoxy-3-((((4-nitrophenyl)sulfonyl)oxy)methyl)azetidine-

[3601] -235- FoleyHoagUS13180487.1 GPX-02525

[3602] 1 -carboxylate

[3603] , NO2

[3604] N

[3605] Boc

[3606] Synthetic scheme:

[3607] , NO2

[3608] NsCI

[3609] NEt3

[3610] N

[3611]

[3612] Boc

[3613] The title compound was synthesized following analogous procedures to those described for Intermediate 7 using tert-butyl 3-(hydroxymethyl)-3-methoxyazetidine-l -carboxylate. ’H NMR (400 MHz, CDC13) 8 ppm 8.42 (d, J = 8.8 Hz, 2H), 8.13 (d, J = 8.8 Hz, 2H), 4.33 (s, 2H), 3.93 (d, J = 9.8 Hz, 2H), 3.71 (d, J = 9.7 Hz, 2H), 3.23 (s, 3H), 1.42 (s, 9H).

[3614] Intermediate 9. (3-Hydroxyoxetan-3-yl)methyl 4-nitrobenzenesulfonate

[3615] Synthetic scheme:

[3616] pNsCI, NEt3

[3617]

[3618] The title compound was synthesized following analogous procedures to those described for Intermediate 7 using 3-(hydroxymethyl)oxetan-3-ol.1H NMR (400 MHz, CDCI3) 6 8.44 (d, J = 8.9 Hz, 1H), 8.18 - 8.13 (m, 1H), 4.62 (d, J = 7.7 Hz, 1H), 4.47 - 4.42 (m, J = 7.2 Hz, 2H).

[3619] Intermediate 10. Rac-((lS,2S)-2-cyanocyclopropyl)methyl 4-nitrobenzenesulfonate

[3620] -236- FoleyHoagUS13180487.1 GPX-02525

[3621] Synthetic scheme:

[3622]

[3623] The title compound was synthesized following analogous procedures to those described for Intermediate 7 using rac-(lR,2R)-2-(hydroxymethyl)cyclopropane-l-carbonitrile. ’H NMR (400 MHz, CDCh) 8 8.43 (d, J = 8.8 Hz, 2H), 8.12 (d, J = 8.8 Hz, 2H), 4.19 (dd, J = 11.1, 6.1 Hz, 1H), 3.97 (dd, 7= 11.1, 7.5 Hz, 1H), 1.91 - 1.82 (m, 1H), 1.46 - 1.35 (m, 2H), 1.11 - 1.06 (m, 1H).

[3624] Intermediate 11. tert-butyl(3-(iodomethyl)-l- (trifluoromethyl)cyclobutoxy)dimethylsilane

[3625]

[3626] Synthetic scheme:

[3627] TMSCF3TBSCI

[3628] CsF Imidazole

[3629] THF DCM

[3630] imidazole h LAH PPh3

[3631] Et2O, O°C DCM, 0°C

[3632]

[3633] Methyl 3-hydroxy-3-(trifluoromethyl)cyclobutanecarboxylate

[3634]

[3635] A solution of methyl 3-oxocyclobutanecarboxylate (1.00 g, 7.80 mmol) and cesium fluoride (713 mg, 4.55 mmol) (freshly dried at 120 °C for 2 h) in dry THF (28.9 mL) was

[3636] -237- FoleyHoagUS13180487.1 GPX-02525

[3637] cooled in an ice bath under an argon atmosphere. Trimethyl(trifluoromethyl)silane, 99% (1.34 mL, 8.59 mmol) was added to the cooled solution while stirring. The ice bath was removed, and the reaction mixture was stirred for 15 h at rt. Saturated aqueous NH4CI solution (10 mL) was added, the mixture was stirred for 15 min, and 1 M solution of tetrabutylammonium fluoride in THF (7 mL) was added. The resulting mixture was stirred for 1 h, and the reaction was extracted with EtOAc (2 x 20 mL). The combined organic layer was washed with brine (2 x 10 mL), dried over Na2SO4, and filtered through a silica gel pad. Evaporation of the filtrate gave the title compound (1.44 g, 93%) as a viscous yellow oil. ’H NMR (400 MHz, CDCI3) 8 ppm 3.73 (s, 3H), 2.99 - 2.85 (m, 2H), 2.82 - 2.73 (m, 2H), 2.50 - 2.40 (m, 2H).

[3638] methyl 3-((tert-butyldimethylsilyl)oxy)-3-(trifluoromethyl)cyclobutanecarboxylate

[3639]

[3640] To methyl 3-hydroxy-3-(trifluoromethyl)cyclobutanecarboxylate (500 mg, 2.52 mmol) in DCM (12.6 mL) was added imidazole (260 mg, 3.79 mmol) followed by tert-butyldimethylsilyl chloride (574 pL, 3.28 mmol). The solution was stirred at rt for 30 h. The reaction was diluted with EtOAc, washed twice with water and NaHCO?, dried with Na2SO4, filtered, and concentrated to give title compound (443 mg, 56%) as a colorless oil.1H NMR (400 MHz, CDCh) 8 ppm 3.71 (s, 3H), 2.91 - 2.81 (m, 1H), 2.77 - 2.66 (m, 2H), 2.52 (ddd, J = 12.1, 6.1, 1.5 Hz, 2H), 0.89 (s, 9H), 0.15 (s, 6H).

[3641] (3-((tert-butyldimethylsilyl)oxy)-3-(trifluoromethyl)cyclobutyl)methanol

[3642]

[3643] To a solution of methyl 3-((tert-butyldimethylsilyl)oxy)-3- (trifhioromethyl)cyclobutanecarboxylate (443 mg, 1.42 mmol) in Et2O (9.50 mL) at 0 °C was added lithium aluminum hydride (851 pL, 1.7 mmol). The solution was stirred at rt for 21 h. The mixture was cooled to 0 °C and sodium sulfate decahydrate was added very slowly until no more bubbling occurred and the mixture was stirred at 0 °C for 15 min. The solid was filtered, rinsed with Et2O, and concentrated to give the title compound (1.70 g, 95%) as a clear

[3644] -238- FoleyHoagUS13180487.1 GPX-02525

[3645] oil. ’H NMR (400 MHz, CDCh) 6 ppm 3.62 (t, J = 5.6 Hz, 2H), 2.62 - 2.51 (m, 2H), 2.31 - 2.19 (m, 1H), 2.10 - 1.98 (m, 2H), 1.39 - 1.32 (m, 1H), 0.89 (s, J = 2.9 Hz, 9H), 0.12 (s, 6H). tert-butyl(3-(iodomethyl)-l-(trifluoromethyl)cyclobutoxy)dimethylsilane

[3646] V-4-OTBS

[3647]

[3648] To triphenylphosphine (466 mg, 1.76 mmol) and imidazole (233 mg, 3.38 mmol) in DCM (5.10 mL) at 0 °C was added iodine (443 mg, 1.75 mmol) and the solution was stirred until all the iodine dissolved. (3-((tert-butyldimethylsilyl)oxy)-3- (trifluoromethyl)cyclobutyl)methanol (385 mg, 1.35 mmol) in DCM (1.70 mL) was added, and the mixture was slowly warmed up to rt and stirred for 18 h. The reaction was poured in EtOAc, washed with 10% aqueous sodium thiosulfate solution, water, and brine, dried over Na2SO4, filtered, and concentrated. To the resulting solid was added 50 mL of 20% EtOAc / heptanes, stirred for 5 min then filtration to remove triphenylphosphine oxide. The filtrate was concentrated onto silica gel and the product purified by column chromatography (silica, 5-30% EtOAc / heptane) to afford the title compound (410 mg, 77%) as a clear oil.1H NMR (400 MHz, CDCh) 8 ppm 3.22 (d, J = 7.5 Hz, 2H), 2.70 - 2.58 (m, 2H), 2.36 (dt, J = 16.2, 8.1 Hz, 1H), 1.90 - 1.77 (m, 2H), 0.89 (s, 9H), 0.13 (s, 6H).

[3649] Intermediate 12. (3-((tert-butyldimethylsilyl)oxy)bicyclo[l.l.l]pentan-l-yl)methyl 4-nitrobenzenesulfonate

[3650] OTBS

[3651] Synthetic scheme:

[3652]

[3653] Methyl 3-((tert-butyldimethylsilyl)oxy)bicyclo[l.l.l]pentane-l-carboxylate

[3654]

[3655] OTBS

[3656] -239- FoleyHoagUS13180487.1 GPX-02525

[3657] Methyl 3-hydroxybicyclo[l.l.l]pentane-l-carboxylate (100 mg, 689 pmol) was dissolved in DMF (980 pL) and imidazole (94.8 mg, 1.38 mmol) was added followed by tertbutyldimethylsilyl chloride (126 mg, 827 pmol). The reaction was stirred at rt for 18 h. The mixture was diluted with EtOAc (5 mL) and washed with water (1 x 5 mL) and 10% LiCl (1 x 5 mL). The organic phase was dried with MgSCU and concentrated in vacuo, which was carried forward to the next step.

[3658] (3-((tert-butyldimethylsilyl)oxy)bicyclo[l.l.l]pentan-l-yl)methanol

[3659] H0''^

[3660] OTBS

[3661] Methyl 3-((tert-butyldimethylsilyl)oxy)bicyclo[l.l.l]pentane-l-carboxylate (177 mg, 689 pmol) was dissolved in THF (2.3 mL) and cooled to 0 °C. Lithium aluminum hydride (689 pL, 1.38 mmol) was added, and the reaction mixture was stirred at 0 °C for 1 h. To the reaction was added sodium sulfate decahydrate, and the mixture was warmed to rt, filtered, and concentrated in vacuo giving the title compound as a colorless oil, which was carried forward to the next step.

[3662] (3-(( / e / 7-butyldiniethylsilyl)oxy)bicyclo| 1.1.1 ]pentan-l-yl)methyl 4-nitrobenzenesulfonate

[3663]

[3664] OTBS

[3665] p-NsCl (233 mg, 1.03 mmol) was dissolved in DCM (8.59 mL) and (3-((tert-butyldimethylsilyl)oxy)bicyclo[l.l.l]pentan-l-yl)methanol (157 mg, 687 pmol) was added. The solution was cooled to 0 °C and Et? N (289 pL, 2.06 mmol) was added. After 30 min, the cooling bath was removed, and stirring was continued at rt for 3 h. The reaction was diluted with DCM (5 mL) and quenched with water (15 mL). The aqueous phase was extracted with DCM (2 x 15 mL). The organic phase was dried with MgSCU, concentrated onto silica, and purified by column chromatography (silica, 0-40% EtOAc / heptanes) giving the title compound (228 mg, 80%) as a yellow solid.1H NMR (400 MHz, CDCh) 8 ppm 8.40 (d, J= 9.1 Hz, 2H), 8.09 (d, J = 9.1 Hz, 2H), 4.25 (s, 2H), 1.86 (s, 6H), 0.85 (s, 9H), 0.05 (s, 6H).

[3666] Intermediate 13.3-(iodomethyl)-l,l-dimethoxycyclopentane

[3667] -240- FoleyHoagUS13180487.1 GPX-02525

[3668] Synthetic scheme:

[3669] LAH

[3670] Et2O, 0°C

[3671]

[3672] Ethyl 3,3-dimethoxycyclopentanecarboxylate

[3673] MeO. OEt

[3674]

[3675] MeO'

[3676] To ethyl 3-oxocyclopentanecarboxylate (500 mg, 3.11 mmol) in MeOH (7.76 L) were added trimethylorthoformate (2.12 mL, 19.4 mmol) and p-toluenesulfonic acid monohydrate (18.1 mg, 93.2 pmol) and the solution was stirred at rt for 16 h. MeOH was removed and the residue was diluted with EtOAc, washed with saturated aqueous NaHCO? solution, water, dried over Na2SO4, filtered and concentrated to give the title compound (575 mg, 92%) as a brown oil.

[3677] tert-butyl (3-(hydroxymethyl)bicyclo[l.l.l]pentan-l-yl)carbamate

[3678] MeOx / ^ / 'OH

[3679] MeO^ J

[3680] To a solution of ethyl 3, 3 -dimethoxycyclopentanecarboxylate (575 mg, 2.84 mmol) in Et2O (14.2 mL) at 0 °C was added lithium aluminum hydride (1.68 mL, 3.35 mmol) and the mixture was stirred at rt for 4 h. It was cooled down to 0 °C and sodium sulfate decahydrate was added very slowly until no more bubbling occurred and the mixture was stirred at 0 °C for 15 min. The solid was filtered, rinsed with Et2O and concentrated to give the title compound (475 mg, 104%) as a clear oil.

[3681] 3-(iodomethyl)-l,l-dimethoxycyclopentane

[3682] -241- FoleyHoagUS13180487.1 GPX-02525

[3683] MeO.

[3684] M

[3685]

[3686] eO'

[3687] To triphenylphosphine (3.65 g, 13.8 mmol) and imidazole (1.82 g, 26.5 mmol) in DCM (39.7 mL) at 0 °C was added iodine (3.47 g, 13.7 mmol) and the solution was stirred until all the iodine was dissolved. Tert-butyl (3-(hydroxymethyl)bicyclo[l.l.l]pentan-l-yl)carbamate (1.70 g, 10.6 mmol) in DCM (13.2 mL) was added, and the mixture was slowly warmed up to rt and stirred for 18 h. The reaction was added EtOAc, washed with 10% aqueous sodium thiosulfate solution, water, and brine, dried over Na2SO4, filtered, and concentrated to give a wet solid. To the solid was added 50 mL of 20% EtOAc / heptanes, and the mixture was stirred for 5 min followed by filtration to remove triphenylphosphine oxide. The filtrate was concentrated onto silica gel and purified by column chromatography (silica, 5-20% EtOAc / heptane) to afford the title compound (1.38 g, 48%) as a clear oil.1H NMR (400 MHz, CDCh) 8 ppm 3.21 (d, J = 1.8 Hz, 1H), 3.20 (s, 3H), 3.20 (d, J = 1.9 Hz, 1H), 3.19 (s, 3H), 2.39 - 2.25 (m, 1H), 2.09 (dd, J = 13.3, 8.0 Hz, 1H), 1.98 - 1.76 (m, 3H), 1.54 - 1.45 (m, 1H), 1.45 - 1.31 (m, 1H).

[3688] Intermediate 14.3-(Iodomethyl)-l,l-dimethoxycyclobutane

[3689] . OMe

[3690]

[3691] OMe

[3692] The title compound was prepared following analogous procedures to those described for Intermediate 13.1H NMR (400 MHz, CDCh) 8 ppm 3.28 (d, J = 7.9 Hz, 2H), 3.15 (s, 3H), 3.13 (s, 3H), 2.51 - 2.40 (m, 1H), 2.37 - 2.29 (m, 2H), 1.80 - 1.71 (m, 2H).

[3693] Intermediate 15. N-benzyl-3-(iodomethyl)-l-(trifluoromethyl)cyclobutanamine

[3694]

[3695] Synthetic scheme:

[3696] -242- FoleyHoagUS13180487.1 GPX-02525

[3697] DMF TMSCF3MgSO4TFA BnNH2KHF2DCM MeCN, 0°C

[3698] PPh3(resin)

[3699] h NaBH4Imidazole MeOH DCM

[3700]

[3701] Methyl 3-(benzylimino)cyclobutanecarboxylate

[3702] O

[3703]

[3704] Bn

[3705] To a solution of methyl 3-oxocyclobutanecarboxylate (3.00 g, 22.2 mmol) in DCM (65.1 mL) was added magnesium sulfate (16.1 g, 133 mmol) followed by benzylamine (2.58 mL, 23.4 mmol), and the reaction was stirred for 5 days. The mixture was filtered, rinsed with dry DCM, and concentrated to provide the title compound (4.83 g, 100%).

[3706] Methyl 3-(benzylamino)-3-(trifluoromethyl)cyclobutanecarboxylate

[3707]

[3708] Trifluoroacetic acid (2.24 mL, 28.9 mmol) was added to a mixture of methyl 3-(benzylimino)cyclobutanecarboxylate (4.83 g, 22.2 mmol) and potassium hydrogen fluoride, 99+% (1.4 g, 17.8 mmol) in MeCN (44.5 mL) and dimethylformamide (5.17 mL, 66.7 mmol) at 0 °C. The suspension was stirred for 5 min. Trimethyl(trifhioromethyl)silane, 99% (5.19 mL, 33.3 mmol) was added and the mixture was stirred at rt for 16 h. The mixture was quenched with saturated aqueous Na2CO3 solution, and the mixture was stirred for 5 min. More water was added, and the mixture was extracted three times with EtOAc. The combined organic phase

[3709] -243- FoleyHoagUS13180487.1 GPX-02525

[3710] was washed twice with brine, dried over Na2SO4, filtered and concentrated. The crude was purified by column chromatography (Silica, 10-50% EtOAc / heptane) to give the title compound (724 mg, 11%) as a clear oil. MS (ESI): masscalcd. forCnHieFsNCh: 287.11, found: 288.4 [M+H]+.

[3711] (3-(benzylamino)-3-(trifluoromethyl)cyclobutyl)methanol

[3712]

[3713] To a solution of methyl 3-(benzylamino)-3-(trifluoromethyl)cyclobutanecarboxylate (712 mg, 2.48 mmol) in MeOH (10.7 mL) at 0 °C was added sodium borohydride (478 mg, 12.4 mmol) and the solution was stirred at rt for 40 min. It was diluted with EtOAc, washed with water and brine, dried over Na2SO4, filtered and concentrated. The product was purified by column chromatography (Silica, 10-70% EtOAc / heptane) to afford the title compound (539 mg, 84%) as a clear oil. MS (ESI): mass calcd. for C13H16F3NO: 259.12, found: 260.4 [M+H]+.

[3714] N-benzyl-3-(iodomethyl)-l-(trifluoromethyl)cyclobutanamine

[3715]

[3716] To triphenylphosphine resin (834 mg, 1.33 mmol, 1.6 mmol / g) and imidazole (176 mg, 2.56 mmol) in DCM (7.69 mL) at 0 °C was added iodine (336 mg, 1.32 mmol) and the solution was stirred until all the iodine dissolved. (3-(benzylamino)-3-(trifhioromethyl)cyclobutyl)methanol (266 mg, 1.03 mmol) in DCM (2.56 mL) was added, and the mixture was slowly warmed to rt and stirred for 18 h. The resin was filtrated and rinsed with EtOAc. The organic phase was washed with 10% aqueous sodium thiosulfate solution, water, and brine, dried over Na2SO4, filtered, and concentrated to give the title compound (260 mg, 69%).

[3717] Intermediate 16. (3-cyanooxetan-3-yl)methyl 4-methylbenzenesulfonate

[3718] -244- FoleyHoagUS13180487.1 GPX-02525

[3719] OTs

[3720]

[3721] Synthetic scheme:

[3722] OH OTs

[3723] TsCI, pyridine

[3724]

[3725] To a solution of 3-(hydroxymethyl)oxetane-3-carbonitrile (0.45 g, 3.98 mmol) in DCM (4.5 mL) was added pyridine (629 mg, 7.96 mmol) and 4-methylbenzenesulfonyl chloride (1.14 g, 5.97 mmol) at 0 °C. The mixture was stirred at 25 °C for 16 h, after which the mixture was poured into water (10 mL) and extracted with DCM (15 mL x 3). The combined organic phase was dried with anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiCL, petroleum ether: ethyl acetate = 100: 1 to 3: 1) to afford (3-cyanooxetan-3-yl)methyl 4-methylbenzenesulfonate (0.57 g, 53.6%) as a white solid.

[3726] 1H NMR (400 MHz, DMSO-d6) 8 ppm 17.83-7.86 (m, 2H), 7.52 (d, J = 8.0 Hz, 2H), 4.76 (d, J = 6.8 Hz, 2H), 4.56 (s, 2H), 4.44 (d, J = 6.8 Hz, 2H), 2.44 (s, 3H).

[3727] Intermediate 17. 10-Amino-2-methyl-2,4-diazadispiro[4.1.57.l5]tridecane-l, 3-dione o

[3728] H

[3729] Synthetic scheme:

[3730] TMSCN, (NH4)2CO3MeOH, H2O, 90°C

[3731] H2(15 psi), Pd / C, TSOH. H2O MeOH acetone, H2O NHyMeOH

[3732]

[3733] 11, 14-Dioxa-2,4-diazatrispiro[4.1.2.410.27.l5]heptadecane-l, 3-dione

[3734]

[3735] -245- FoleyHoagUS13180487.1 GPX-02525

[3736] To a mixture of 8,1 l-dioxadispiro[3.2.47.24]tridecan-2-one (15 g, 76.4 mmol) in MeOH (150 mL) andfhO (150 mL) was added TMSCN (15.17 g, 152.9 mmol) and (NEU CCh (29.38 g, 305.7 mmol) in one portion at 25 °C under N2. After heating at 90 °C for 12 h, the reaction was concentrated under reduced pressure to remove MeOH. The precipitate was collected by filtration, washed with H2O (3 x 100 mL), and dried under vacuum to provide the title compound (13.65 g, 67.1%) as a white solid, which was used directly in the next step without further purification.1H NMR (400 MHz, DMSO- e) 6 ppm 8.38 (s, 1H), 3.83 (s, 4H), 2.27 (d, J = 13.6 Hz, 2H), 1.95 (d, J = 13.6 Hz, 2H), 1.68-1.77 (m, 2H), 1.63 (t, J = 6.4 Hz, 2H), 1.43-1.48 (m, 4H).

[3737] 2-Methyl-ll,14-dioxa-2,4-diazatrispiro[4.1.2.410.27.l5]heptadecane-l, 3-dione

[3738] V N HN— L

[3739]

[3740] To a mixture of ll,14-dioxa-2,4-diazatrispiro[4.1.2.410.27.l5]heptadecane- 1,3-dione (6 g, 22.5 mmol) in DMF (50 mL) was added Mel (3.52 g, 24.8 mmol) and K2CO3 (3.43 g, 24.8 mmol) in one portion at 0 °C under N2. The reaction was stirred at 25 °C for 12 h. After completion, the crude residue was poured into water (20 mL) and the aqueous layer was extracted with EtOAc (3 x 25 mL). The combined organic layer was washed with brine (3 x 30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (petroleum ether: EtOAc = 20: 1 to 0: 1) to afford the title compound (5.99 g, 94.8%) as a white solid.1H NMR (400 MHz, DMSO- e) 6 ppm 8.65 (s, 1H), 3.83 (s, 4H), 2.79 (s, 3H), 2.27 (d, J = 12.8 Hz, 2H), 1.97 (d, J = 13.6 Hz, 2H), 1.75 (m, 1.71-1.79, 2H), 1.64 (t, J= 6.4 Hz, 2H), 1.43-1.48 (m, 4H).

[3741] 2-Methyl-2,4-diazadispiro[4.1.57.l5]tridecane-l, 3, 10-trione

[3742] N

[3743]

[3744] To a mixture of 2-methyl-ll,14-dioxa-2,4-diazatrispiro[4.1.2.410.27.l5]heptadecane-1, 3-dione (5.99 g, 21.4 mmol) in acetone (40 mL) and H2O (20 mL) was added TSOH. H2O (8.13 g, 42.7 mmol) in one portion at 25 °C under N2. After stirring for 12 h, the mixture was poured into water (50 mL). The aqueous phase was extracted with EtOAc (3 x 30 mL). The combined organic phase was washed with brine, dried with anhydrous Na2SO4, filtered and

[3745] -246- FoleyHoagUS13180487.1 GPX-02525

[3746] concentrated. The crude residue was purified by silica gel column chromatography (petroleum ether: EtOAc = 10: 1 to 0: 1) to afford the title compound (3.19 g, 63.2%) as a white solid.

[3747] 10-Amino-2-methyl-2,4-diazadispiro[4.1.57.l5]tridecane- 1,3-dione

[3748]

[3749] To a mixture of 2-methyl-2,4-diazadispiro[4.1.57.l5]tridecane-l, 3, 10-trione (3.19 g, 13.5 mmol) in MeOH (30 mL) was added ammonia (7 M in MeOH, 19.29 mL) at 25 °C. After stirring for 1 h, 10% Pd / C (502.9 mg) was added in one portion. The reaction was stirred at 25 °C for 3 h under H2 (15 Psi). Then it was filtered though a Celite pad and the filtrate was concentrated under reduced pressure to provide the title compound (3 g) as a white solid, which was used in the next step without further purification.

[3750] Intermediate 18. 10-hydroxy-2-methyl-2,4-diazadispiro[4.1.57.l5]tridecane- 1,3-dione

[3751] N H

[3752] Synthetic scheme

[3753] NaBH4, EtOH

[3754] N N N N

[3755]

[3756] H H

[3757] To a mixture of 2-methyl-2,4-diazadispiro[4.1.57.l5]tridecane-l, 3, 10-trione (2 g, 8.47 mmol) in EtOH (20 mL) was added NaBfE (96.1 mg, 2.54 mmol) at 0 °C under N2. The mixture was stirred at 25 °C for 1 h. The reaction mixture was quenched with H2O (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give 10-hydroxy-2-methyl-2,4-diazadispiro[4.1.57.l5]tridecane- 1,3-dione (1.8 g, 89.2%) as a white solid, which was used without further purification. MS (ESI): mass calcd. for C12H18N2O3: 238.13, found: 239.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) 8 ppm 8.64 (s, 1H), 4.41 (d, J = 4.0 Hz, 1H), 3.34-3.45 (m, 1H), 2.79 (s, 3H), 2.24 (t, J = 12.4 Hz, 2H), 1.89-2.04 (m, 3H), 1.74 (d, J = 12.8 Hz, 1H), 1.59 (dd, J = 8.4, 3.6 Hz, 2H), 1.22-1.41 (m, 2H), 1.05-1.21 (m, 2H).

[3758] Intermediate 19. 10-amino-3-methyl-l-(oxetan-3-ylmethyl)-l,3-

[3759] -247- FoleyHoagUS13180487.1 GPX-02525

[3760] diazadispiro[4.1.57.l5]tridecane-2, 4-dione

[3761] o

[3762]

[3763] 3-methyl-l-(oxetan-3-ylmethyl)-l,3-diazadispiro[4.1.57.l5]tridecane-2, 4, 10-trione

[3764] o

[3765] 0

[3766]

[3767] To a solution of 2-methyl-2,4-diazadispiro[4.1.57.l5]tridecane-l, 3, 10-trione (See Intermediate 17) (50 g, 212 mmol) in DMF (500 mL) was added 3-(iodomethyl)oxetane (46.1 g, 233 mmol) and CS2CO3 (138 g, 423 mmol). The mixture was stirred at 40 °C for 12 h under N2. The mixture was poured into water (2 L) and extracted with ethyl acetate (1 L x 2). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiCL, petroleum ether: ethyl acetate = 5: 1 to 0: 1) to give the title compound (44 g, 68%) as a white solid. MS (ESI): mass calcd. for C16H22N2O4: 306.16, found: 307.1 [M+H]+.

[3768] 10-amino-3-methyl-l-(oxetan-3-ylniethyl)-l,3-diazadispiro[4.1.57.l5]tridecane-2, 4-dione

[3769] o

[3770]

[3771] Three reactions were carried out in parallel. To a solution of 2-methyl-4-(oxetan-3-ylmethyl)-2,4-diazadispiro[4.1.57.l5]tridecane-l, 3, 10-trione (22 g, 71.8 mmol) in NH MeOH (200 mL) was added Raney-Ni (6.15 g, 71.8 mmol) under N2. The suspension was degassed and purged with H23 times. The mixture was stirred under H2 (15 psi) at 25 °C for 12 h. The

[3772] -248- FoleyHoagUS13180487.1 GPX-02525

[3773] three parallel reactions were combined and worked-up together. The mixture was filtered through a pad of Celite, and the filtrate was concentrated under reduced pressure to give the title compound (65 g, crude) as a green oil, which was used in the next step without further purification. MS (ESI): mass calcd. for C16H25N3O3: 307.19, found: 308.1 [M+H]+.

[3774] Intermediate 20. 10-amino-2-methyl-4-[[(3R)-tetrahydrofuran-3-yl]methyl]-l,4-diazadispiro[4.1.57.l5]tridec-l-en-3-one

[3775] Synthetic scheme:

[3776] MnO2, DCE

[3777]

[3778] 2-methyl-ll,14-dioxa-l,4-diazatrispiro[4.1.2.410.27.l5]heptadecan-3-one

[3779] H

[3780]

[3781] To a solution of 8,ll-dioxadispiro[3.2.47.24]tridecan-2-one (4 g, 20.4 mmol) and 2-aminopropanamide hydrochloride (3.81 g, 30.6 mmol) in MeOH (40 mL) was added TEA (6.19 g, 61.2 mmol). The mixture was stirred at 100 °C for 16 h under N2. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography

[3782] -249- FoleyHoagUS13180487.1 GPX-02525

[3783] (SiCL, ethyl acetate: methanol = 100: 1 to 95: 5) to give the title compound (3.5 g, 64.5%) as a yellow solid. MS (ESI): mass calcd. for C14H22N2O3: 266.16, found: 267.0 [M+H]+.

[3784] 3-methyl-ll,14-dioxa-l,4-diazatrispiro[4.1.2.410.27.l5]heptadec-3-en-2-one

[3785]

[3786] To a solution of 2-methyl-ll,14-dioxa-l,4-diazatrispiro[4.1.2.410.27.l5]heptadecan-3-one (3.5 g, 13.1 mmol) in DCE (35 mL) was added MnCL (34.3 g, 394 mmol). The mixture was stirred at 80 °C for 18 h. The mixture was cooled to rt and MnCL (11.4 g, 131 mmol) was added. The mixture was stirred at 80 °C for 16 h. The reaction mixture was diluted with DCM (80 mL) and filtered through a pad of silica gel. The filter cake was washed with DCM (600 mL), and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiCL, petroleum ether: ethyl acetate = 1: 0 to 0: 1) to give the title compound (2.75 g, 79.2%) as a yellow solid. MS (ESI): mass calcd. for C14H20N2O3: 264.15, found: 265.4 [M+H]+.

[3787] 2-methyl-4-[[(3R)-tetrahydrofuran-3-yl]methyl]-ll,14-dioxa-l,4-diazatrispiro[4.1.2.410.27.l5]heptadec-l-en-3-one

[3788]

[3789] To a solution of 3-methyl-ll,14-dioxa-l,4-diazatrispiro[4.1.2.410.27.l5]heptadec-3-en- 2-one (825 mg, 3.12 mmol) in DMF (9 mL) was added CS2CO3 (2.03 g, 6.24 mmol) and (3S)- 3-(bromomethyl)tetrahydrofuran (670 mg, 4.06 mmol). The mixture was stirred at 45 °C for 16 h. (3S)-3-(bromomethyl)tetrahydrofuran (103 mg, 624 pmol) was added and stirred at 45 °C for 24 h. An additional aliquot of (3S)-3-(bromomethyl)tetrahydrofuran (103 mg, 624 pmol) was added and the mixture was stirred at 50 °C for 24 h. The reaction was quenched with H2O (100 mL) and extracted with ethyl acetate (40 mL x 3). The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC to give the title compound (470 mg, 43.2%) as a yellow solid. MS (ESI): mass calcd. for C19H28N2O4: 348.20, found: 349.3 [M+H]+.

[3790] -250- FoleyHoagUS13180487.1 GPX-02525

[3791] 2-methyl-4-[[(3R)-tetrahydrofuran-3-yl]methyl]-l,4-diazadispiro[4.1.57.l5]tridec-l-ene-3, 10-dione

[3792] / — \ z\

[3793] o=< XX I

[3794] W V N^O

[3795]

[3796] c°

[3797] A solution of 2-methyl-4-[[(3R)-tetrahydrofuran-3-yl]methyl]-ll,14-dioxa-l,4-diazatrispiro[4.1.2.410.27.l5]heptadec-l-en-3-one (400 mg, 1.15 mmol) in THF (4 mL) and HC1 (1 M, 4 mL) was stirred at 60 °C for 2 h. The reaction mixture was partitioned between saturated aqueous Na2CCh (10 mL) and ethyl acetate (20 mL). The organic phase was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (330 mg, 94.4%) as a light-yellow oil, which was used without further purification. MS (ESI): mass calcd. for C17H24N2O3: 304.18, found: 305.4 [M+H]+.

[3798] 10-amino-2-methyl-4-[[(3R)-tetrahydrofuran-3-yl]methyl]-l,4-diazadispiro[4.1.57.l5]tridec-l-en-3-one

[3799] / — \ Z\N-=Z

[3800] H2N\ W X VX N^ 1o

[3801]

[3802] Co

[3803] To a solution of 2-methyl-4-[[(3R)-tetrahydrofuran-3-yl]methyl]-l,4-diazadispiro[4.1.57.l5]tridec-l-ene-3, 10-dione (330 mg, 1.08 mmol) in Nffc / MeOH (3.3 mL) was added Raney-Ni (186 mg) in one portion at 20 °C under N2. The mixture was degassed and purged with H2 three times. The mixture was stirred under H2 (15 psi) at 20 °C for 16 h. The mixture was filtered through a Celite pad. The filtrate was concentrated under reduced pressure to give the title compound (360 mg, crude) as a light-yellow oil, which was used without further purification. MS (ESI): mass calcd. for C17H27N3O2: 305.21, found: 306.4 [M+H]+.

[3804] Intermediate 21. 10-amino-3-methyl-l-(oxetan-3-ylmethyl)-l,4-diazadispiro[4.1.57.l5]tridec-3-en-2-one was prepared following analogous procedures to those described for Intermediate 20.

[3805] -251- FoleyHoagUS13180487.1 GPX-02525

[3806] Intermediate 22. dispiro[cyclohexane-l,l'-cyclobutane-3',7"-pyrrolo[3,4-b]pyridine]- 4,5"(6" H)-dione

[3807] Synthetic scheme:

[3808]

[3809] 8,ll-dioxadispiro[3.2.47.24]tridecan-2-ol

[3810]

[3811] •OH

[3812] To a solution of 8,ll-dioxadispiro[3.2.47.24]tridecan-2-one (40 g, 204 mmol) in THF (400 mL) was added LiAlfL (2.5 M, 97.8 mL) at 0 °C under N2. The mixture was stirred at 0

[3813] -252- FoleyHoagUS13180487.1 GPX-02525

[3814] °C for 1 h under N2. After completion, the mixture was quenched with H2O (10 mL) and 15% NaOH (10 mL) at 0 °C and stirred at 0 °C for 30 min. The mixture was diluted with H2O (25 mL), ethyl acetate (200 mL), and filtered through a celite pad. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiCh, petroleum ether: ethyl acetate = 100: 1 to 1: 100) to give the title compound (32 g, 79%) as a yellow oil.

[3815] 1H NMR (400 MHz, CDCh) 6 ppm 4.23-4.30 (m, 1H), 3.86-3.97 (m, 4H), 2.20-2.32 (m, 2H), 2.08 (s, 1H), 1.60-1.68 (m, 4H), 1.52-1.59 (m, 6H).

[3816] 8, H-dioxadispiro[3.2.47.24]tridecan-2-yl methanesulfonate

[3817] / ~-o

[3818]

[3819] '■' xDMs

[3820] To a solution of 8,ll-dioxadispiro[3.2.47.24]tridecan-2-ol (32 g, 161 mmol) in DCM (320 mL) was added TEA (65.3 g, 646 mmol) and MsCl (37.0 g, 323 mmol) at 0 °C. The mixture was stirred at 0 °C for 1 h under N2. After completion, the mixture was poured into ice- water (100 mL) and extracted with DCM (100 mL x 3). The combined organic phase was washed with brine, dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiCh, petroleum ether: ethyl acetate = 100: 1 to 1: 100) to give the title compound (23.6 g, 52.9%) as a white solid. ’H NMR (400 MHz, CDCh) 5 ppm 4.96-5.03 (m, 1H), 3.92 (s, 4H), 2.97 (s, 3H), 2.34-2.43 (m, 2H), 2.01-2.09 (m, 2H), 1.66-1.71 (m, 2H), 1.62-1.69 (m, 2H), 1.54-1.61 (m, 4H).

[3821] 8, H-dioxadispiro[3.2.47.24]tridecane-2-carbonitrile

[3822]

[3823] To a solution of 8,ll-dioxadispiro[3.2.47.24]tridecan-2-yl methanesulfonate (23.6 g, 85.4 mmol) in DMSO (240 mL) were added 18-crown-6 (22.6 g, 85.4 mmol), Nal (12.8 g, 85.4 mmol) and KCN (8.34 g, 128 mmol). The mixture was stirred at 80 °C for 12 h under N2. After completion, the reaction was diluted with H2O (250 mL) and extracted with ethyl acetate (250 mL x 3). The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether: ethyl acetate = 100: 1 to 1: 100) to give the title compound (5.67 g, 32%) as a colorless oil.1H NMR (400 MHz, CDCh) 8 ppm 3.92 (s, 4H), 2.98-3.07 (m, 1H),

[3824] -253- FoleyHoagUS13180487.1 GPX-02525

[3825] 2.12-2.26 (m, 4H), 1.72-1.77 (m, 2H), 1.63-1.69 (m, 2H), 1.53-1.60 (m, 4H).

[3826] 2-(3-bromopyridin-2-yl)-8,ll-dioxadispiro[3.2.47.24]tridecane-2-carbonitrile

[3827]

[3828] A mixture of 8,ll-dioxadispiro[3.2.47.24]tridecane-2-carbonitrile (8.4 g, 40.5 mmol) in toluene (85 mL) was degassed and purged with N2 three times. NaHMDS (1 M, 44.6 mL) was added to the mixture dropwise at 0 °C. The mixture was stirred at 0 °C for 30 min. 3-bromo-2-fluoro-pyridine (7.13 g, 40.5 mmol) was added to the mixture at 0 °C. The mixture was stirred at 20 °C for 30 min under N2. After completion, the reaction was quenched with saturated NH4CI (50 mL) at 0 °C, diluted with H2O (50 mL), and extracted with ethyl acetate (80 mL x 3). The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether: ethyl acetate = 9: 1 to 7: 3) to give the title compound (9.5 g, 88%) as a white solid. ‘H NMR (400 MHz, DMSO-d6) 8 ppm 8.58-8.65 (m, 1H), 8.17-8.24 (m, 1H), 7.33-7.46 (m, 1H), 3.81-3.86 (m, 4H), 2.65-2.82 (m, 4H), 1.82-1.94 (m, 2H), 1.58-1.65 (m, 2H), 1.40-1.44 (m, 4H).

[3829] 2-(3-bromopyridin-2-yl)-8,ll-dioxadispiro[3.2.47.24]tridecane-2-carboxamide

[3830] Br,

[3831]

[3832] To a solution of 2-(3-bromopyridin-2-yl)-8,ll-dioxadispiro[3.2.47.24] tridecane-2-carbonitrile (10.5 g, 28.9 mmol) in DMSO (100 mL) was added K2CO3 (7.99 g, 57.8 mmol), then H2O2 (9.83 g, 86.7 mmol, 8.33 mL, 30% w / w in water) was added at 0 °C under N2. The mixture was stirred at 20 °C for 48 h. After completion, the mixture was quenched with saturated Na2SOs (30 mL), diluted with H2O (50 mL), and extracted with DCM (50 mL x 3). The combined organic phase was washed with brine, dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether: ethyl acetate = 5: 1 to 1: 1) to give the title compound (9.7 g, 88%) as a white solid.1H NMR (400 MHz, DMSO-d6) 6 ppm 8.55-8.58 (m, 1H), 8.00-8.03 (m, 1H), 7.22-7.26 (m, 1H), 6.90 (s, 1H), 6.22 (s, 1H), 3.79-3.82 (m, 4H), 2.52 (s, 4H), 1.60-1.76 (m,

[3833] -254- FoleyHoagUS13180487.1 GPX-02525

[3834] 2H), 1.44-1.53 (m, 2H), 1.34-1.42 (m, 2H), 1.25-1.34 (m, 2H).

[3835] 2-(3-bromopyridin-2-yl)-8, H-dioxadispiro[3.2.47.24]tridecan-2-amine

[3836]

[3837] To a solution of 2-(3-bromopyridin-2-yl)-8,ll-dioxadispiro[3.2.47.24] tridecane-2- carboxamide (10.4 g, 27.3 mmol) in n-BuOH (100 mL) was added NaOH (2.18 g, 54.6 mmol) and NaClO (40.2 mL, 68.2 mmol, 10.5% purity). The mixture was stirred at 25 °C for 16 h. After completion, the mixture was poured into saturated NH4CI (100 mL), extracted with ethyl acetate (100 mL x 2). The combined organic phase was washed with brine, dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiCL, petroleum ether: ethyl acetate = 4: 1 to 1: 1) to give the title compound (8 g, 83%) as a yellow solid.4H NMR (400 MHz, DMSO- e) 8 ppm 8.46-8.49 (m, 1H), 8.00-8.03 (m, 1H), 7.17-7.21 (m, 1H), 3.81-3.84 (m, 4H), 2.57 (d, J= 12.8 Hz, 2H), 2.18 (s, 2H), 1.95-2.04 (m, 2H), 1.79-1.91 (m, 2H), 1.47-1.57 (m, 2H), 1.37-1.45 (m, 2H), 1.25- 1.35 (m, 2H).

[3838] tert-butyl N-[2-(3-bromo-2-pyridyl)-8, H-dioxadispiro[3.2.47.24]tridecan-2-yl]carbamate

[3839]

[3840] To a solution of 2-(3-bromo-2-pyridyl)-8,ll-dioxadispiro[3.2.47.24]tridecan-2-amine (1.4 g, 3.96 mmol) in DCM (15 mL) was added B0C2O (1.04 g, 4.76 mmol) and TEA (1.00 g, 9.91 mmol). The mixture was stirred at 25 °C for 16 h. The reaction was diluted with H2O (30 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiCL, petroleum ether: ethyl acetate = 95: 5 to 80: 20) to give the title compound (1.4 g, 75%) as a white solid. MS (ESI): mass calcd. for C2iH29N2BrO4: 452.13, found: 453.2 / 455.2 [M+H]+.

[3841] 2-(2-amino-8, H-dioxadispiro [3.2.47.24] tridecan-2-yl) pyridine-3-carbonitrile

[3842] -255- FoleyHoagUS13180487.1 GPX-02525

[3843]

[3844] A mixture of tert-butyl N-[2-(3-bromo-2-pyridyl)-8,l l-dioxadispiro[3.2.47.24]tridecan-2-yl] carbamate (1.4 g, 3.09 mmol), Zn(CN)2 (802 mg, 6.83 mmol), Pd(PPhs)4 (535 mg, 463 pmol) in DMF (2 mL) was degassed and purged with N2 three times. The mixture was stirred at 120 °C for 16 h under N2, cooled down, poured into water (30 mL), and extracted with ethyl acetate (50 mL x 2). The combined organic phase was washed with brine, dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiCL, petroleum ether: ethyl acetate = 0: 1 to ethyl acetate: methanol = 0: 1) to give the title compound (300 mg, 32%) as a white solid. MS (ESI): mass calcd. for C17H21N3O2: 299.16, found: 300.1 [M+H]+.

[3845] trispiro[pyrrolo[3,4-b]pyridine-7, 1 ' -cyclobutane-3', 1 ' ' -cyclohexane-4' ',2" ' - [ l,3]dioxolan] -5(6H)-one

[3846]

[3847] To a solution of 2-(2-amino-8,ll-dioxadispiro[3.2.47.24]tridecan-2-yl)pyridine-3-carbonitrile (300 mg, 1.0 mmol) in DMSO (2 mL) was added NaOH (4 M, 6 mL). The mixture was stirred at 100 °C for 16 h. The reaction was adjusted to pH = 7 with 1 N HC1, diluted with H2O (20 mL) and extracted with DCM (30 mL x 2). The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiCL, petroleum ether: ethyl acetate = 30: 70 to ethyl acetate: methanol = 50: 50) to give the title compound (200 mg, 65%) as a white solid.

[3848] 1H NMR (400 MHz, CDCh) 8 ppm 8.73 (dd, J = 1.6, 4.8 Hz, 1H), 7.98 (dd, J = 1.6, 7.6 Hz, 1H), 7.30 (dd, J = 4.8, 7.6 Hz, 1H), 6.49 (s, 1H), 3.90 (s, 4H), 2.65 (d, J = 14.0 Hz, 2H), 2.19 (d, J= 13.6 Hz, 2H), 1.94-2.07 (m, 2H), 1.72-1.84 (m, 2H), 1.56-1.64 (m, 4H).

[3849] dispiro[cyclohexane-l,l'-cyclobutane-3',7"-pyrrolo[3,4-b]pyridine]-4,5"(6" H)-dione

[3850]

[3851] -256- FoleyHoagUS13180487.1 GPX-02525

[3852] To a solution of trispiro[pyrrolo[3,4-b]pyridine-7,r-cyclobutane-3',l"-cyclohexane-4",2"'-[l,3]dioxolan]-5(6H)-one (200 mg, 666 pmol) in H2O (1 mL) was added acetone (1 mL) followed by TsOH.fhO (253 mg, 1.33 mmol). The mixture was stirred at 25 °C for 16 h. The reaction was diluted with H2O (20 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (140 mg, 82%) as a white solid.1H NMR (400 MHz, DMSO-d6) 6 ppm 9.31 (s, 1H), 8.81 (dd, J= 1.6, 6.4 Hz, 1H), 7.99 (dd, J= 1.2, 7.6 Hz, 1H), 7.49 (dd, J= 5.2, 7.6 Hz, 1H), 2.44 (d, J= 13.2 Hz, 4H), 2.28-2.37 (m, 2H), 2.22 (d, J= 12.8 Hz, 2H), 1.69-1.71 (m, 2H), 1.57 (s, 2H).

[3853] Intermediate

[3854]

[3855] ll-amino-3-methyl-l-(oxetan-3-ylmethyl)-l,3-diazadispiro[4.2.58.25]pentadecane-2, 4-dione

[3856]

[3857] H2, Raney Ni NH3MeOH

[3858] 12, 15-dioxa-l,3-diazatrispiro[4.2.2.4n.28.25]nonadecane-2, 4-dione

[3859]

[3860] To a solution of l,4-dioxadispiro[4.2.58.25]pentadecan-ll-one (500 mg, 2.23 mmol) in

[3861] -257- FoleyHoagUS13180487.1 GPX-02525

[3862] MeOH (17 mL) was added H2O (17 mL) and (NEU CCh (857 mg, 8.92 mmol). The mixture was degassed and purged with N2 three times. TMSCN (442 mg, 4.46 mmol) was added under N2. The mixture was stirred at 90 °C for 5 h under N2, cooled to 25°C, and concentrated under reduced pressure. The residual mixture was filtered, washed with H2O (10 mL x 3), and dried under vacuum to give the title compound (530 mg, 80.8%) as a white solid.1H NMR (400 MHz, DMSO-d6) 6 ppm 10.53 (s, 1H), 8.43 (s, 1H), 3.83 (s, 4H), 1.65-1.78 (m, 2H), 1.43-1.59 (m, 8H), 1.31-1.42 (m, 6H).

[3863] 3-methyl-12,15-dioxa-l,3-diazatrispiro[4.2.2.4n.28.25]nonadecane-2, 4-dione

[3864]

[3865] To a solution of 12, 15-dioxa-l,3-diazatrispiro[4.2.2.4n.28.25]nonadecane-2, 4-dione (250 mg, 849 pmol) in DMF (2.5 mL) was added Mel (121 mg, 849 pmol) and CS2CO3 (443 mg, 1.36 mmol) at 0 °C. The mixture was purged with N2 three times and stirred at 0 °C for 1 h under N2. The reaction mixture was quenched with H2O (10 mL). The residual mixture was filtered, washed with H2O (10 mL x 3), and dried under vacuum to give the title compound (137 mg, 52.3%) as a white solid. MS (ESI): mass calcd. for C16H24N2O4: 308.17, found: 309.2 [M+H]+.

[3866] 3-methyl-l,3-diazadispiro[4.2.58.25]pentadecane-2, 4, 11-trione

[3867]

[3868] To a solution of 3-methyl-12,15-dioxa-l,3-diazatrispiro[4.2.2.411.28.25]nonadecane-2, 4-dione (137 mg, 444 pmol) in THF (2 mL) was added HC1 (1 M, 1.37 mL). The mixture was stirred at 60 °C for 1 h. After completion, the mixture was adjusted to pH=9 with aqueous Na2COs and extracted with ethyl acetate (30 mL x 2). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (110 mg, 93.7%) as a white solid. MS (ESI): mass calcd. for C14H20N2O3: 264.15, found: 265.3[M+H]+.

[3869] 3-methyl-l-(oxetan-3-ylmethyl)-l,3-diazadispiro[4.2.58.25]pentadecane-2, 4, 11-trione

[3870] -258- FoleyHoagUS13180487.1 GPX-02525

[3871]

[3872] A solution of 3-methyl-l,3-diazadispiro[4.2.58.25]pentadecane-2,4,ll-trione (110 mg, 416 pmol), 3-(iodomethyl)oxetane (90.6 mg, 458 pmol), and CS2CO3 (271 mg, 832 pmol) in DMF (1.5 mL) was degassed and purged with N2 three times. The reaction was stirred at 40 °C for 16 h under N2. The reaction was quenched with water (10 mL), and the mixture was extracted with ethyl acetate (30 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiCL, petroleum ether: ethyl acetate = 1: 0 to 0: 1) to give the title compound (100 mg, 71.9%) as a white solid. MS (ESI): mass calcd. C18H26N2O4: 334.19, found: 335.2 [M+H]+.

[3873] ll-amino-3-methyl-l-(oxetan-3-ylmethyl)-l,3-diazadispiro[4.2.58.25]pentadecane-2,4-dione

[3874]

[3875] solution 3-methyl- 1 -(oxetan-3-ylmethyl)- 1,3-diazadispiro[4.2.58.25]pentadecane-2, 4, 11-trione (100 mg, 299 pmol) in Nffc / MeOH (7 M, 1.00 mL) was stirred at 25 °C for 3 h. To the mixture was added Raney-Ni (5.12 mg, 59.8 pmol) in one portion under Ar. The mixture was degassed with H2 three times and purged with H2. The mixture was stirred under H2 (15 psi) at 25 °C for 13 h. After completion, the mixture was filtered through a celite pad. The filtrate was concentrated under reduced pressure to give the title compound (100 mg, 99.7%) as a colorless oil. MS (ESI): mass calcd. C18H29N3O3: 335.22, found: 336.3 [M+H]+.

[3876] Intermediate 24. 10-hydroxy-2-methyl-4-[[(3R)-tetrahydrofuran-3-yl]methyl]-2,4-diazadispiro[4.1.57.15] tridecane- 1,3-dione

[3877] -259- FoleyHoagUS13180487.1 GPX-02525

[3878] NaBH4, EtOH CS2CO3, DMF

[3879]

[3880] 2-methyl-4-[[(3R)-tetrahydrofuran-3-yl]methyl]-2,4-diazadispiro[4.1.57.l5]tridecane- 1, 3 0-trione

[3881]

[3882] To a solution of 2-methyl-2,4-diazadispiro[4.1.57.l5]tridecane-l, 3, 10-trione (155 mg, 656 pmol) in DMF (2 mL) was added CS2CO3 (641 mg, 1.97 mmol) and (3S)-3- (bromomethyl)tetrahydrofuran (162 mg, 984 pmol). The mixture was stirred at 50 °C for 32 h. The reaction mixture was diluted with H2O (20 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether: ethyl acetate = 99: 1 to 46: 54) to give the title compound (620 mg, crude) as a colorless oil. MS (ESI): mass calcd. for C17H24N2O4: 320.17, found: 321.2 [M+H]+.

[3883] 10-hydroxy-2-methyl-4-[[(3R)-tetrahydrofuran-3-yl]methyl]-2,4-diazadispiro[4.1.57.l5]tridecane-l, 3-dione

[3884]

[3885] To a solution of 2-methyl-4-[[(3R)-tetrahydrofuran-3-yl]methyl]-2,4-diazadispiro[4.1.57.l5]tridecane-l, 3, 10-trione (540 mg, 1.69 mmol) in EtOH (6 mL) was added NaBH4 (19.1 mg, 506 pmol). The mixture was stirred at 20 °C for 1 h. The reaction was quenched with H2O (20 mL), and the mixture was extracted with ethyl acetate (25 mL x 4). The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, dichloromethane: methanol = 99: 1 to 97.4: 2.6) to give the title compound (420 mg, 74.6%) as a colorless oil. MS (ESI): mass calcd. for C17H26N2O4: 322.19, found: 323.2 [M+H]+.

[3886] -260- FoleyHoagUS13180487.1 GPX-02525

[3887] Intermediate 25A. (5R,7r,10R)-10-hydroxy-3-methyl-l-(((R)-tetrahydrofuran-3-yl)methyl)-l,3-diazadispiro[4.1.57.l5]tridecane-2, 4-dione and Intermediate 25B. (5S,7s,10S)-10-hydroxy-3-methyl-l-(((R)-tetrahydrofuran-3-yl)methyl)-l,3-diazadispiro[4.1.57.l5]tridecane-2, 4-dione

[3888] HO / ,

[3889]

[3890] A diastereomeric mixture of (R)-10-hydroxy-3-methyl-l-((tetrahydrofuran-3-yl)methyl)-l,3-diazadispiro[4.1.57.l5]tridecane-2, 4-dione (1.0 g, 3.1 mmol) was purified by chiral SFC (Stationary Phase: Amylose tris(3-chloro-5-methylphenylcarbamate), Mobile Phase: 30% (ACN: EtOH (1:1) + 0.1% FA) / 70% supercritical CO2) and the first peak to elute afforded (5R,7r,10R)-10-hydroxy-3-methyl-l-(((R)-tetrahydrofuran-3-yl)methyl)-l,3-diazadispiro[4.1.57.l5]tridecane-2, 4-dione as a white solid (382 mg, 38%). MS (ESI): mass calcd. for C17H26N2O4: 322.19 found: 323.4 [M+H]+The second peak to elute afforded (5S,7s,10S)-10-hydroxy-3-methyl-l-(((R)-tetrahydrofuran-3-yl)methyl)-l,3-diazadispiro[4.1.57.l5]tridecane-2, 4-dione as a white solid (390 mg, 39%). MS (ESI): mass calcd. for C17H26N2O4: 322.19 found: 323.4 [M+H]+

[3891] Intermediate 26. 10-hydroxy-3-methyl-l-(oxetan-3-ylmethyl)-l,3-diazadispiro[4.1.57.l5]tridecane-2, 4-dione

[3892]

[3893] The title compound was prepared following analogous procedures to those described for Intermediate 24. MS (ESI): mass calcd. for C16H24N2O4: 308.17, found: 309.1 [M+H]+.

[3894] Intermediate 27. 10-hydroxy-l,3-dimethyl-l,3-diazadispiro[4.1.57.l5]tridecane-2, 4-dione

[3895]

[3896] o

[3897] -261- FoleyHoagUS13180487.1 GPX-02525

[3898] The title compound was prepared following analogous procedures to those described for Intermediate 24. MS (ESI): mass calcd. for C13H20N2O3: 252.15, found: 253.2 [M+H]+.

[3899] Intermediate 28. 10-hydroxy-3-methyl-l-(oxetan-3-ylmethyl)-l,4-diazadispiro[4.1.57.l5]tridec-3-en-2-one

[3900]

[3901] 3-methyl-ll,14-dioxa-l,4-diazatrispiro[4.1.2.410.27.l5]heptadecan-2-one

[3902]

[3903] To a solution of 8,ll-dioxadispiro[3.2.47.24]tridecan-2-one (4.5 g, 22.9 mmol) and 2-aminopropanamide (4.28 g, 34.4 mmol, HC1 salt) in MeOH (72 mL) was added TEA (6.96 g, 68.8 mmol) at 20 °C. The reaction was stirred at 60 °C for 16 h. 2-aminopropanamide (1.14 g, 9.17 mmol, 0.4 eq, HC1 salt) was added to the reaction at 20 °C and the reaction was stirred at 60 °C for 24 h. The reaction was concentrated under reduced pressure. The residue was purified by column chromatography (SiCh, petroleum ether: ethyl acetate = 80: 1 to 0: 1) to give the title compound (4.7 g, 50.8%) as a white solid. MS (ESI): mass calcd. for C14H22N2O3: 266.16, found: 267.4 [M+H]+.

[3904] 3-methyl-ll,14-dioxa-l,4-diazatrispiro[4.1.2.410.27.l5]heptadec-3-en-2-one

[3905]

[3906] Mn02 (15.3 g, 176 mmol) was added to a solution of 3-methyl-ll,14-dioxa-l,4-diazatrispiro[4.1.2.410.27.l5]heptadecan-2-one (2.35 g, 8.82 mmol) in DCE (25 mL) at 20 °C.

[3907] -262- FoleyHoagUS13180487.1 GPX-02525

[3908] The reaction was stirred at 80 °C for 16 h, after which it was filtered and concentrated to provide the title compound (4.1 g, 80%) as yellow solid. MS (ESI): mass calcd. for C14H20N2O3: 264.15, found: 265.4 [M+H]+.

[3909] 3-methyl-l,4-diazadispiro[4.1.57.l5]tridec-3-ene-2, 10-dione

[3910] e 0x.

[3911] N HN

[3912]

[3913] 0

[3914] HC1 (15 mL) was added to a solution of 3-methyl-ll,14-dioxa-l,4-diazatrispiro[4.1.2.410.27.l5]heptadec-3-en-2-one (1.5 g, 5.67 mmol) in THF (15 mL) at 20 °C. The reaction was stirred at 60 °C for 4 h. The mixture was adjusted to pH = 9 with aqueous Na2COs and extracted with DCM / i-PrOH=3:l (10 mL x 3). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to give 3-methyl-l,4-diazadispiro[4.1.57.l5]tridec-3-ene-2, 10-dione (530 mg, 39.9%) as a white solid. MS (ESI): mass calcd. for C12H16N2O2: 220.12, found: 221.3 [M+H]+.

[3915] 3-methyl-l-(oxetan-3-ylmethyl)-l,4-diazadispiro[4.1.57.l5]tridec-3-ene-2, 10-dione

[3916] N

[3917]

[3918] CS2CO3 (1.18 g, 3.61 mmol) was added to a solution of 3-methyl-l,4-diazadispiro[4.1.57.l5]tridec-3-ene-2, 10-dione (530 mg, 2.41 mmol) and 3- (iodomethyl)oxetane (571.71 mg, 2.89 mmol) in DMF (5 mL) at 20 °C. Then the reaction was stirred at 50 °C for 16 h, after which the mixture was cooled to 20 °C, diluted with H2O (15 mL), and extracted with DCM / i-PrOH (20 mL x 3). The combined organic layer was washed with brine, dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC (mobile phase: H2O (lOmM NH4HCO3)-ACN; gradient: 5%-35% B over 8.0 min) to give the title compound (978 mg) as a white solid. MS (ESI): mass calcd. for C16H22N2O3: 290.16, found:291.3 [M+H]+.

[3919] 10-hydroxy-3-methyl-l-(oxetan-3-ylmethyl)-l,4-diazadispiro[4.1.57.l5]tridec-3-en-2-one

[3920] -263- FoleyHoagUS13180487.1 GPX-02525

[3921]

[3922] To a solution of 3-methyl-l-(oxetan-3-ylmethyl)-l,4-diazadispiro[4.1.57.l5]tridec-3-ene-2, 10-dione

[3923] (200 mg, 689 pmol) in EtOH (2 mL) was added NaBfE (7.82 mg, 207 pmol) under N2. The mixture was stirred at 25 °C for 1 h. The reaction was quenched with saturated aqueous NH4CI (15 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic layer was washed with brine, dried Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by prep-TLC (SiCL, petroleum ether: ethyl acetate = 10: 1) to give the title compound (106 mg, 52.6%) as a yellow oil. MS (ESI): mass calcd. for C16H24N2O3: 292.1, found: 293.2 [M+H]+.

[3924] Intermediate 29. l-((3-fluorooxetan-3-yl)methyl)-10-hydroxy-3-methyl-l,4-diazadispiro[4.1.57.l5]tridec-3-en-2-one

[3925]

[3926] The title compound was prepared following analogous procedures to those described for Intermediate 28.1H NMR (400 MHz, DMSO- e) 8 ppm 4.70-4.85 (m, 2H), 4.55-4.66 (m, 2H), 4.46 (d, J = 4.0 Hz, 1H), 3.96-4.10 (m, 2H), 3.38-3.46 (m, 1H), 2.25-2.37 (m, 2H), 2.20-2.23 (m, 1H), 2.07 (s, 3H), 1.99-2.06 (m, 1H), 1.90-1.97 (m, 1H), 1.72 (d, J = 12.4 Hz, 1H), 1.55-1.68 (m, 2H), 1.40-1.48 (m, 1H), 1.32-1.43 (m, 1H), 1.11-1.30 (m, 2H).

[3927] Intermediate 30.3-((10-hydroxy-3-methyl-2,4-dioxo-l,3-diazadispiro[4.1.57.l5]tridecan-l-yl)methyl)oxetane-3-carbonitrile

[3928]

[3929] -264- FoleyHoagUS13180487.1 GPX-02525

[3930] The title compound was prepared following analogous procedures to those described for Intermediate 24 using Intermediate 16. MS (ESI): mass calcd. for C17H23N3O4: 333.17, found: 334.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) 6 ppm 4.66-4.91 (m, 4H), 3.93 (s, 2H), 3.38-3.46 (m, 2H), 2.84 (s, 3H), 2.10-2.27 (m, 5H), 1.82 (d, J= 12.8 Hz, 1H), 1.53-1.68 (m, 2H), 1.30-1.41 (m, 2H), 1.11-1.22 ppm (m, 2H).

[3931] Intermediate 31. l-((l,l-dioxidothietan-3-yl)methyl)-10-hydroxy-3-methyl-l,3-diazadispiro[4.1.57.l5]tridecane-2, 4-dione

[3932] o

[3933] r-N'

[3934]

[3935] The title compound was prepared following analogous procedures to those described for Intermediate 24. MS (ESI): mass calcd. for C16H24N2O5S: 356.14, found: 357.2 [M+H]+. ’H NMR (400 MHz, DMSO-d6) 8 ppm 4.46 (d, J = 3.6 Hz, 1H), 4.19-4.30 (m, 2H), 3.93-4.01 (m, 2H), 3.64 (d, J = 8.0 Hz, 2H), 2.97-3.05 (m, 1H), 2.82 (s, 3H), 2.08-2.23 (m, 6H), 1.69- 1.77 (m, 1H), 1.61 (d, J = 11.6 Hz, 2H), 1.35 (t, J = 10.8 Hz, 2H), 1.07-1.18 ppm (m, 2H).

[3936] Intermediate 32. 4-[(4-amino-l-methyl-cyclohexyl)methyl]-5-methyl-2-(2-trimethylsilylethoxymethyl)-l,2,4-triazol-3-one

[3937] H2N

[3938]

[3939] Synthetic scheme:

[3940] -265- FoleyHoagUS13180487.1 GPX-02525

[3941]

[3942] methyl 3-(8, H-dioxadispiro[3.2.47.24]tridecan-2-ylamino)oxetane-3-carboxylate

[3943]

[3944] To a solution of 8,1 l-dioxadispiro[3.2.47.24]tridecan-2-one (1 g, 5.1 mmol) and methyl 3-aminooxetane-3-carboxylate (869 mg, 6.62 mmol) in DCM (10 mL) was added AcOH (306 mg, 5.1 mmol). NaBH(OAc)3 (3.24 g, 15.3 mmol) was added at 0 °C. The mixture was stirred at 25 °C for 16 h. After completion, the residue was poured into H2O (10 mL) and extracted with DCM (10 mL x 2). The combined organic phase was washed with brine, dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiCL, petroleum ether: ethyl acetate=l: 0 to 1: 1) to give the title compound (1.1 g, 69%) as a yellow solid. MS (ESI): masscalcd. forCieffeNOs: 311.17, found: 312.1 [M+H]+.

[3945] 3-(8, H-dioxadispiro[3.2.47.24]tridecan-2-ylamino)oxetane-3-carboxamide

[3946] -266- FoleyHoagUS13180487.1 GPX-02525

[3947]

[3948] Methyl 3-(8, 1 l-dioxadispiro[3.2.47.24]tridecan-2-ylamino)oxetane-3-carboxylate (1.1 g, 3.53 mmol) and NH MeOH (11 mL) were combined. The mixture was stirred in a sealed tube at 95 °C for 12 h, after which it was concentrated under reduced pressure to give the title compound (0.81 g, 78%) as a white solid. MS (ESI): mass calcd. for C15H24N2O4: 296.17, found: 297.1 [M+H]+.

[3949] 5-(8,ll-dioxadispiro[3.2.47.24]tridecan-2-yl)-2-oxa-5,7-diazaspiro[3.4]octane-6, 8-dione

[3950]

[3951] To a solution of 3-(8,ll-dioxadispiro[3.2.47.24]tridecan-2-ylamino)oxetane-3-carboxamide (0.81 g, 2.74 mmol) in ACN (8 mL) was added CDI (889 mg, 5.48 mmol) and DIPEA (1.06 g, 8.22 mmol). The reaction was stirred at 90 °C for 16 h. The residue was poured into H2O (10 mL) and extracted with ethyl acetate (10 mL x 2). The combined organic phase was washed with brine, dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiCL, petroleum ether: ethyl acetate = 1: 0 to 1: 1) to give the title compound (0.4 g, 45%) as a white solid. MS (ESI): mass calcd. for C16H22N2O5: 322.15, found: 323.2 [M+H]+.

[3952] 5-(7-oxospiro[3.5]nonan-2-yl)-2-oxa-5,7-diazaspiro[3.4]octane-6, 8-dione

[3953]

[3954] To a solution of 5-(8,ll-dioxadispiro[3.2.47.24]tridecan-2-yl)-2-oxa-5,7-diazaspiro[3.4]octane-6, 8-dione (0.4 g, 1.24mmol) in H2O and acetone (4 mL) was added TSOH. H2O (472 mg, 2.48 mmol). The mixture was stirred at 50 °C for 5 h. After completion, the mixture was diluted with H2O (10 mL) and extracted with DCM (10 mL x 3). The combined

[3955] -267- FoleyHoagUS13180487.1 GPX-02525

[3956] organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiCh, petroleum ether: ethyl acetate = 1: 0 to 1: 1) to give the title compound (310 mg, 90%) as a white solid. MS (ESI): mass calcd. for C14H18N2O4: 278.13, found: 279.1 [M+H]+.

[3957] 5-(7-oxospiro[3.5]nonan-2-yl)-7-(2-trimethylsilylethoxymethyl)-2-oxa-5,7-diazaspiro[3.4]octane-6, 8-dione

[3958]

[3959] To a solution of 5-(7-oxospiro[3.5]nonan-2-yl)-2-oxa-5,7-diazaspiro[3.4]octane-6,8-dione (310 mg, 1.11 mmol) in DCM (5 mL) was added SEM-Cl (371.4 mg, 2.23 mmol) and DIPEA (575.9 mg, 4.46 mmol). The mixture was stirred at 25 °C for 12 h. The residue was poured into H2O (20 mL) and extracted with DCM (20 mL x 2). The combined organic phase was washed with brine, dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiCL, petroleum ether: ethyl acetate = 20: 1 to 0: 1) to give the title compound (310 mg, 68%) as a white solid. MS (ESI): mass calcd. for CLoH^I^O Si: 408.21, found: 431.3 [M+Na]+.

[3960] 4-[(4-amino-l-methyl-cyclohexyl)methyl]-5-methyl-2-(2-trimethylsilylethoxymethyl)-l,2,4-triazol-3-one

[3961]

[3962] To a mixture of 5-methyl-4-[(l-methyl-4-oxo-cyclohexyl)methyl]-2-(2-trimethylsilylethoxymethyl)-l,2,4-triazol-3-one (2.17 g, 6.14 mmol), NH4OAC (9.46 g, 122.76 mmol) in MeOH (22 mL) was added NaBH(OAc)s (3.25 g, 15.35 mmol) under N2. After stirring at 25 °C for 16 h under N2, the reaction was concentrated under reduced pressure. The residue was poured into H2O (10 mL) and extracted with ethyl acetate (10 mL x 2). The combined organic phase was washed with brine, dried with anhydrous Na2SO4, filtered, and

[3963] -268- FoleyHoagUS13180487.1 GPX-02525

[3964] concentrated under reduced pressure to give the title compound (0.3 g, 99%) as a yellow oil. MS (ESI): mass calcd. for C2oH35N304Si: 409.24, found: 410.3 [M+H]+.

[3965] Intermediate 33.5-(7-hydroxyspiro[3.5]nonan-2-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-2-oxa-5,7-diazaspiro[3.4]octane-6, 8-dione was prepared from 5-(7-oxospiro[3.5]nonan-2-yl)-7-(2-trimethylsilylethoxymethyl)-2-oxa-5,7-diazaspiro[3.4]octane-6, 8-dione (see Intermediate 32) following analogous procedures to those described for Intermediate 18.

[3966]

[3967] Intermediate 34. l-(((lr,4r)-4-hydroxycyclohexyl)methyl)-5,5-dimethyl-3-((2- (trimethylsilyl)ethoxy)methyl)imidazolidine-2, 4-dione

[3968] o Synthetic scheme

[3969]

[3970] (lr,4r)-ethyl 4-hydroxycyclohexanecarboxylate

[3971] -269- FoleyHoagUS13180487.1 GPX-02525

[3972] HO,,.

[3973]

[3974] To a suspension of (lr,4r)-4-hydroxycyclohexane-l -carboxylic acid (2 g, 13.5 mmol) in EtOH (9.7 mL) was added H2SO4 (52.9 pL, 942 pmol). The mixture was stirred at 70 °C for 2.5 h. After cooling to rt, the resulting mixture was basified with 1 M aqueous Na2COs solution and concentrated to remove most of the solvent. The aqueous mixture was diluted with water and extracted with EtOAc (x3). The combined organic layer was washed with water (xl), dried over Na2SO4, filtered, and concentrated to provide the crude title compound (2.27 g, 98%) as a yellow oil. ’H NMR (400 MHz, CDCh) 8 ppm 4.11 (q, J = 7.1 Hz, 2H), 3.53 - 3.65 (m, 1H), 2.15 - 2.30 (m, 1H), 1.91 - 2.10 (m, 4H), 1.64 (br s, 1H), 1.41 - 1.59 (m, 2H), 1.18 - 1.36 (m, 5H).

[3975] (lr,4r)-ethyl 4-(benzyloxy)cyclohexanecarboxylate

[3976] Ph

[3977]

[3978] A mixture of (lr,4r)-ethyl 4-hydroxycyclohexanecarboxylate (2.27 g, 13.2 mmol), N, N-diisopropylethylamine (5.8 mL, 33 mmol), and benzyl bromide (1.7 mL, 13.8 mmol) was stirred at 150 °C for 2.5 h. The resulting mixture was poured into 1 M aqueous HC1 (46 mL) at 0 °C and vigorously stirred for 5 min. The reaction was extracted with EtOAc (x3). The combined organic layer was washed with brine (xl), dried over Na2SO4, filtered and concentrated. The crude residue was purified by column chromatography (silica, 5-10% EtOAc / heptanes to provide the title compound (1.82 g, 53%). ’H NMR (400 MHz, CDCh) 6 ppm 7.30 - 7.38 (m, 4H), 7.23 -7.30 (m, 1H), 4.56 (s, 2H), 4.11 (q, J = 7.1 Hz, 2H), 3.34 (m, 1H), 2.27 (m, 1H), 2.08 - 2.19 (m, 2H), 1.97 - 2.07 (m, 2H), 1.47 (ddd, 7= 24.7, 13.2, 3.1 Hz, 2H), 1.28 - 1.39 (m, 2H), 1.21 - 1.27 (m, 3H).

[3979] ((lr,4r)-4-(benzyloxy)cyclohexyl)methanol

[3980] Ph^O,,.

[3981]

[3982] To a solution of (lr,4r)-ethyl 4-(benzyloxy)cyclohexanecarboxylate (1.82 g, 6.94 mmol) in THF (17.3 mL) was added lithium aluminum hydride (624 mg, 15.6 mmol) at 0 °C.

[3983] -270- FoleyHoagUS13180487.1 GPX-02525

[3984] The mixture was stirred at 0 °C for 5 min then at 60 °C for 5 h. The resulting mixture was cooled to rt and quenched by a slow addition of sodium sulfate decahydrate. The mixture was filtered through a pad of Celite by aid of EtOAc and concentrated to provide the crude title compound (1.5 g, 98%) as a white solid which was used as such in the next step.1H NMR (400 MHz, CDCh) 8 ppm 7.30 - 7.39 (m, 4H), 7.26 (s, 1H), 4.57 (s, 2H), 3.45 (t, J = 6.0 Hz, 2H), 3.31 (tt, J = 10.9, 4.2 Hz, 1H), 2.09 - 2.19 (m, 2H), 1.80 - 1.91 (m, 2H), 1.41 - 1.59 (m, 1H), 1.23 - 1.40 (m, 3H), 0.98 (m, 2H).

[3985] l-(((lr,4r)-4-(benzyloxy)cyclohexyl)methyl)-5,5-dimethyl-3-((2-(trimethylsilyl)ethoxy)methyl)imidazolidme-2, 4-dione

[3986] V o

[3987]

[3988] o

[3989] To a solution of ((lr,4r)-4-(benzyloxy)cyclohexyl)methanol (1.2 g, 5.45 mmol) and triethylamine (835 pL, 5.99 mmol) in MeCN (27.2 mL) was added methanesulfonyl chloride (465 pL, 5.99 mmol) at 0 °C dropwise. The reaction was stirred at 0 °C for 15 min then was quenched with a saturated aqueous NaHCCh solution and a small amount of water and extracted with DCM (x4). The combined organic layer was dried over Na2SO4, filtered, and concentrated to give the crude mesylate as a colorless oil. To a solution of the crude mesylate and 5, 5-dimethyl-3-((2-(trimethylsilyl)ethoxy)methyl)imidazolidine-2, 4-dione (2.11 g, 8.17 mmol) in MeCN (27.2 mL) was added potassium iodide (913 mg, 5.45 mmol) followed by cesium carbonate (5.43 g, 16.3 mmol). The reaction was stirred at 90 °C for 15.5 h. After cooled to rt, the resulting mixture was quenched with water and extracted with EtOAc (x3). The combined organic layer was dried over Na2SO4, filtered, and concentrated. The crude mixture was purified by column chromatography (silica, 1-50% EtOAc / heptane) to afford the title compound (2.27 g, 90%) as a colorless oil. MS (ESI): mass calcd. for C2sH4oN204Si: 460.28 found: 483.5 [M+Na]+.

[3990] l-(((lr,4r)-4-hydroxycyclohexyl)methyl)-5,5-dimethyl-3-((2-(trimethylsilyl)ethoxy)methyl)imidazolidme-2, 4-dione

[3991] HOZ,

[3992]

[3993] O

[3994] -271- FoleyHoagUS13180487.1 GPX-02525

[3995] To a solution of l-(((lr,4r)-4-(benzyloxy)cyclohexyl)methyl)-5,5-dimethyl-3-((2-(trimethylsilyl)ethoxy)methyl)imidazolidine-2, 4-dione (2.55 g, 5.54 mmol) in THF (111 mL) was added 10% palladium on carbon (895 mg, 8.41 mmol) under N2. The reaction flask was submitted to 3 cycles of vacuum / hydrogen purges and stirred under hydrogen for 23 h. The mixture was filtered through a pad of Celite by aid of MeOH and concentrated. The crude residue was purified by column chromatography (silica, 1-80% EtOAc / heptane) to afford the title compound (1.47 g, 72%) as a yellow oil.1H NMR (400 MHz, CDCh) 5 ppm 4.92 (s, 2H), 3.50 - 3.66 (m, 3H), 3.11 (d, 7 = 7.5 Hz, 2H), 1.94 - 2.04 (m, 2H), 1.65 - 1.86 (m, 3H), 1.41 (s, 6H), 1.15 - 1.32 (m, 2H), 0.98 - 1.14 (m, 2H), 0.89 - 0.98 (m, 2H), -0.05 - 0.04 (m, 9H).

[3996] Intermediate 35. 5-(bis(ethylthio)methylene)-l-(cyclopentylmethyl)-3-((5S,7s,10S)-3-methyl-2,4-dioxo-l,3-diazadispiro[4.1.57.l5]tridecan-10-yl)pyrimidine-2,4,6(lH,3H,5H)-trione (1-35) and 5-(bis(ethylthio)methylene)-l-(cyclopentylmethyl)-3-((5R,7r,10R)-3-methyl-2,4-dioxo-l,3-diazadispiro[4.1.57.l5]tridecan-10-yl)pyrimidine-2,4,6(lH,3H,5H)-trione

[3997]

[3998] Synthetic scheme:

[3999] -272- FoleyHoagUS13180487.1 GPX-02525

[4000]

[4001] 4-nitrophenyl (cyclopentylmethyl)carbamate

[4002]

[4003] To a solution of cyclopentylmethanamine (4 g, 40.3 mmol) in DCM (80 mL) was added DMAP (4.93 g, 40.3 mmol), pyridine (80.7 mmol, 6.51 mL) and (4-nitrophenyl) chloroformate (8.13 g, 40.3 mmol). The mixture was stirred at 25 °C for 10 min. After completion, the title compound (10.7 g, crude) was used in the next step without further purification. MS (ESI): mass calcd. for C13H16N2O4: 264.11, found: 265.0 [M+H]+.

[4004] l-(cyclopentylmethyl)-3-(3-methyl-2,4-dioxo-l,3-diazadispiro[4.1.57.l5]tridecan-10-yl)urea

[4005]

[4006] 0

[4007] To a solution of Intermediate 17 (9.57 g, 40.3 mmol) in DCM (200 mL) was added TEA (8.16 g, 80.7 mmol) and 4-nitrophenyl (cyclopentylmethyl)carbamate (10.7 g, 40.3 mmol). The mixture was stirred at 25 °C for 16 h. After completion, the mixture was poured

[4008] -273- FoleyHoagUS13180487.1 GPX-02525

[4009] into water (200 mL) and extracted with DCM (200 mL x 3). The combined organic phase was washed with brine, dried with anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiCL, petroleum ether: ethyl acetate = 50: 1 to 0: 1) to give the title compound (9.6 g, 66%) as a white solid. MS (ESI): mass calcd. for C19H30N4O3: 362.23, found: 363.3 [M+H]+.

[4010] l-(cyclopentylmethyl)-3-(3-methyl-2,4-dioxo-l,3-diazadispiro[4.1.57.l5]tridecan-10- yl)pyrimidine-2,4,6(lH,3H,5H)-trione

[4011]

[4012] To a solution of l-(cyclopentylmethyl)-3-(2-methyl-l,3-dioxo-2,4- diazadispiro[4.1.57.l5]tridecan-10-yl)urea (9.6 g, 26.48 mmol) in AcOH (100 mL) was added malonic acid (5.51 g, 52.97 mmol) and AC2O (18.93 g, 185.4 mmol). The mixture was stirred at 80 °C for 3 h. After completion, the mixture was poured into water (200 mL) and extracted with ethyl acetate (150 mL x 3). The combined organic phase was washed with brine, dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiCL, petroleum ether: ethyl acetate = 80: 1 to 0: 1) to give the title compound (6.3 g, 55.3%) as a white solid. MS (ESI): mass calcd. for C22H30N4O5: 430.22, found: 431.2 [M+H]+.

[4013] 5-(bis(ethylthio)methylene)-l-(cyclopentylmethyl)-3-(3-methyl-2,4-dioxo-l,3- diazadispiro[4.1.57.l5]tridecan-10-yl)pyrimidine-2,4,6(lH,3H,5H)-trione

[4014]

[4015] To a solution of l-(cyclopentylmethyl)-3-(3-methyl-2,4-dioxo-l,3- diazadispiro[4.1.57.l5]tridecan-10-yl)pyrimidine-2,4,6(lH,3H,5H)-trione (6.3 g, 14.6 mmol) in DMSO (63 mL) was added TEA (45.9 g, 454 mmol) and CS2 (80.2 g, 1050 mmol). After addition, the mixture was stirred at 25 °C for 1 h. Bromoethane (75.9 g, 697 mmol) was added. The resulting mixture was stirred at 25 °C for 2 h. The mixture was poured into water (200

[4016] -274- FoleyHoagUS13180487.1 GPX-02525

[4017] mL) and extracted with ethyl acetate (150 mL x 3). The combined organic phase was washed with brine, dried with anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC to give the title compound (4.4 g, 63.5%) as a yellow solid. MS (ESI): mass calcd. for C27H38N4O5S2: 562.23, found: 563.3 [M+H]+.

[4018] 5-(bis(ethylthio)methylene)-l-(cyclopentylmethyl)-3-((5S,7s,10S)-3-methyl-2,4-dioxo-l,3-diazadispiro[4.1.57.l5]tridecan-10-yl)pyrimidine-2,4,6(lH,3H,5H)-trione (1-35) and 5-(bis(ethylthio)methylene)-l-(cyclopentylmethyl)-3-((5R,7r,10R)-3-methyl-2,4-dioxo-l,3-diazadispiro[4.1.57.l5]tridecan-10-yl)pyrimidine-2,4,6(lH,3H,5H)-trione

[4019]

[4020] 5-(bis(ethylthio)methylene)-l-(cyclopentylmethyl)-3-(3-methyl-2,4-dioxo-l,3-diazadispiro[4.1.57.l5]tridecan-10-yl)pyrimidine-2,4,6(lH,3H,5H)-trione (4.4 g) was separated by chiral SFC (column: DAICEL CHIRALPAK IG (250mmx30mm,10 um); mobile phase: CO2-EtOH; 50% B with isocratic elution) to give Intermediate 35 (1.1 g) from the first eluting peak as a yellow solid. MS (ESI): mass calcd. for C27H38N4O5S2: 562.23, found: 563.3 [M+H]+. 5-(bis(ethylthio)methylene)-l-(cyclopentylmethyl)-3-((5R,7r,10R)-3-methyl-2,4-dioxo- 1,3-diazadispiro[4.1,57. l5]tridecan- 10-yl)pyrimidine-2,4,6( lH,3H,5H)-trione (1.1 g) was obtained from the second eluting peak as a yellow solid. MS (ESI): mass calcd. for C27H38N4O5S2: 562.23, found: 563.3 [M+H]+.

[4021] Intermediate 36. 5-(bis(ethylthio)methylene)-l-(cyclobutylmethyl)-3-((5S,7s,10S)-3-methyl-2,4-dioxo-l,3-diazadispiro[4.1.57.l5]tridecan-10-yl)pyrimidine-2,4,6(lH,3H,5H)-trione was prepared following analogous procedures to those described for Intermediate 35.

[4022]

[4023] -275- FoleyHoagUS13180487.1 GPX-02525

[4024] Intermediate 37. 5-(bis(ethylthio)methylene)-l-((5R,7r,10R)-3-methyl-l-(oxetan-3-ylmethyl)-2,4-dioxo-l,3-diazadispiro[4.1.57.l5]tridecan-10-yl)pyrimidine-2,4,6(lH,3H,5H)-trione and 5-(bis(ethylthio)methylene)-l-((5S,7s,10S)-3-methyl-l-(oxetan-3-ylmethyl)-2,4-dioxo-l,3-diazadispiro[4.1.57.l5]tridecan-10-yl)pyrimidine-2,4,6(lH,3H,5H)-trione (1-37)

[4025] Synthetic scheme:

[4026]

[4027] l-(3-methyl-l-(oxetan-3-ylmethyl)-2,4-dioxo-l,3-diazadispiro[4.1.57.l5]tridecan-10-yl)urea

[4028] o

[4029]

[4030] To a solution of Intermediate 19 (41 g, 133 mmol) in DCM (440 mL) was added TEA

[4031] -276- FoleyHoagUS13180487.1 GPX-02525

[4032] (44.5 g, 440 mmol) and isocyanato(trimethyl)silane (33.8 g, 293 mmol). The mixture was stirred at 30 °C for 12 h under N2 and was concentrated under reduced pressure. The residue was purified by column chromatography (SiCL, ethyl acetate: methanol = 50: Ito 10: 1) to give the title compound (45 g, 96%) as a white solid. MS (ESI): mass calcd. for C17H26N4O4: 350.20, found: 351.1 [M+H]+.

[4033] l-(3-methyl-l-(oxetan-3-ylmethyl)-2,4-dioxo-l,3-diazadispiro[4.1.57.l5]tridecan-10-yl)pyrimidine-2,4,6(lH,3H,5H)-trione

[4034] , O Q

[4035] N

[4036]

[4037] To a solution of [2-methyl-4-(oxetan-3-ylmethyl)-l,3-dioxo-2,4-diazadispiro[4.1.57.l5]tridecan-10-yl]urea (30 g, 85.6 mmol) in EtOH (300 mL) was added diethyl propanedioate (17.8 g, 111 mmol) and EtONa (43.7 g, 128 mmol, 20% purity). The mixture was stirred at 85 °C for 12 h. After which it was cooled to rt, the poured into water (1 L), adjusted to pH = 4 using citric acid (1 M), and extracted with ethyl acetate (1 L x 2). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was triturated with petroleum ether (50 mL) to give the title compound (30 g) as a white solid, which was used without further purification. MS (ESI): mass calcd. for C20H26N4O6: 418.19, found: 419.2 [M+H]+.

[4038] 5-(bis(ethylthio)methylene)-l-(3-methyl-l-(oxetan-3-ylmethyl)-2,4-dioxo-l,3-diazadispiro[4.1.57.l5]tridecan-10-yl)pyrimidine-2,4,6(lH,3H,5H)-trione

[4039] \

[4040] S— / s

[4041]

[4042] To a solution of l-[2-methyl-4-(oxetan-3-ylmethyl)-l,3-dioxo-2,4-diazadispiro[4.1.57.l5]tridecan-10-yl]hexahydropyrimidine-2, 4, 6-trione (60 g, 0.14 mol) in DMSO (600 mL) was added TEA (84.5 g, 0.84 mol) and CS2 (31.9 g, 0.42 mol). After stirring at 25 °C for 1 h, bromoethane (90.68 g, 0.84 mol) was added. After stirring at 25 °C for 6 h, the reaction was poured into water (2 L) and extracted with ethyl acetate (2 L x 2). The organic

[4043] -277- FoleyHoagUS13180487.1 GPX-02525

[4044] layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiCh, petroleum ether: ethyl acetate = 5: 1 to 0: 1) to give the title compound (32 g, 41%) as a yellow solid. MS (ESI): mass calcd. for C25H34N4O6S2: 550.19, found: 551.3 [M+H]+.

[4045] 5-(bis(ethylthio)methylene)-l-((5R,7r,10R)-3-methyl-l-(oxetan-3-ylmethyl)-2,4-dioxo-l,3-diazadispiro[4.1.57.l5]tridecan-10-yl)pyrimidine-2,4,6(lH,3H,5H)-trione and 5-(bis(ethylthio)methylene)-l-((5S,7s,10S)-3-methyl-l-(oxetan-3-ylmethyl)-2,4-dioxo-l,3-diazadispiro[4.1.57.l5]tridecan-10-yl)pyrimidine-2,4,6(lH,3H,5H)-trione (1-37)

[4046]

[4047] 5-[bis(ethylsulfanyl)methylene]-l-[2-methyl-4-(oxetan-3-ylmethyl)-l,3-dioxo-2,4-diazadispiro[4.1.57.l5]tridecan-10-yl]hexahydropyrimidine-2, 4, 6-trione (32 g) was separated by chiral SFC (column: DAICEL CHIRALPAK AD (250mmx50mm,10 um); mobile phase: CO2-IPA; 40% B with isocratic elution) to give 5-(bis(ethylthio)methylene)-l-((5R,7r,10R)-3-methyl-l-(oxetan-3-ylmethyl)-2,4-dioxo-l,3-diazadispiro[4.1.57.l5]tridecan-10-yl)pyrimidine-2,4,6(lH,3H,5H)-trione (14.19 g) from the first eluting peak as a yellow solid. MS (ESI): mass calcd. for C25H34N4O6S2: 550.19, found: 551.2 [M+H]+. Intermediate 37 (16.71 g) was obtained from the second eluting peak as a yellow solid. MS (ESI): mass calcd. for C25H34N4O6S2: 550.19, found: 551.2 [M+H]+.

[4048] Intermediate 38. l-(cyclopentylmethyl)-3-((5S,7s,10S)-3-methyl-l-(oxetan-3-ylmethyl)- 2,4-dioxo-l,3-diazadispiro[4.1.57.l5]tridecan-10-yl)pyrimidine-2,4,6(lH,3H,5H)-trione

[4049]

[4050] Synthetic scheme:

[4051] -278- FoleyHoagUS13180487.1 GPX-02525

[4052] Py, DMAP, DCM

[4053] AcOH, AC2O, dioxane

[4054]

[4055] 4-nitrophenyl (cyclopentylmethyl)carbamate

[4056]

[4057] To a solution of cyclopentylmethanamine (0.51 g, 5.14 mmol) in DCM (10 mL) was added pyridine (814 mg, 10.3 mmol, 830 pL), DMAP (628 mg, 5.14 mmol) and (4-nitrophenyl) carbonochloridate (1.04 g, 5.14 mmol). The mixture was stirred at 20 °C for 0.5 h to give the title compound (1.36 g, crude) as a colorless liquid, which was used without further purification, l-(cyclopentylmethyl)-3-((5S,7s,10S)-3-methyl-l-(oxetan-3-ylmethyl)-2,4-dioxo-l,3-diazadispiro[4.1.57.l5]tridecan-10-yl)urea

[4058]

[4059] To a solution of (4-nitrophenyl) A-(cyclopentylmethyl)carbamate (1.34 g, 5.07 mmol) in DCM (15 mL) was added TEA (1.03 g, 10.1 mmol, 1.41 mL) and (5S,7s,10S)-10-amino-3-methyl-l-(oxetan-3-ylmethyl)-l,3-diazadispiro[4.1.57.l5]tridecane-2, 4-dione (from chiral SFC separation of Intermediate 19) (1.56 g, 5.07 mmol). The mixture was stirred at 20 °C for 4 h. After completion, the mixture was concentrated under reduced pressure. The residue was diluted with saturated aqueous NH4CI (100 mL) and HOAc (5 mL) and extracted with ethyl acetate (100 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate)

[4060] -279- FoleyHoagUS13180487.1 GPX-02525

[4061] to give the title compound (2 g, 91.2%) as a white solid. MS (ESI): mass calcd. for C23H36N4O4: 432.27, found: 433.2 [M+H]+.

[4062] l-(cyclopentylmethyl)-3-((5S,7s,10S)-3-methyl-l-(oxetan-3-ylmethyl)-2,4-dioxo-l,3-diazadispiro[4.1.57.l5]tridecan-10-yl)pyrimidine-2,4,6(lH,3H,5H)-trione

[4063]

[4064] A solution of malonic acid (106 mg, 1.02 mmol) in AcOH (4.4 mL) and AC2O (4.4 mL) was stirred for 0.5 h at 80 °C. The reaction was added l-(cyclopentylmethyl)-3-((5S,7s,10S)-3-methyl-l-(oxetan-3-ylmethyl)-2,4-dioxo-l,3-diazadispiro[4.1.57.l5]tridecan-10-yl)urea (440 mg, 1.02 mmol) in dioxane (8.8 mL) and stirred at 80 °C for 1 h. After completion, 3 parallel reactions were worked-up together. The reaction was quenched with H2O (60 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (2 g, crude) as a yellow solid. MS (ESI): mass calcd. for C26H36N4O6: 500.26, found: 501.2 [M+H]+.

[4065] Intermediate 39. l-(cyclopropylmethyl)-3-[2-methyl-l,3-dioxo-4-[[(3R)-tetrahydrofuran-3-yl]methyl]-2,4-diazadispiro[4.1.57.l5]tridecan-10-yl]hexahydropyrimidine-2, 4, 6-trione

[4066]

[4067] The title compound was prepared following analogous procedures to those described for Intermediate 38. MS (ESI): mass calcd. for C25H34N4O6: 486.25, found: 487.3 [M+H]+.

[4068] Intermediate 40. l-(3-methyl-2,4-dioxo-l-(((R)-tetrahydrofuran-3-yl)methyl)-l,3-diazadispiro[4.1.57.l5]tridecan-10-yl)-3-(4,4,4-trifluorobutyl)pyrimidine-2,4,6(lH,3H,5H)-trione

[4069] -280- FoleyHoagUS13180487.1 GPX-02525

[4070]

[4071] The title compound was prepared following analogous procedures to those described for Intermediate 38. MS (ESI): mass calcd. for C25H33F3N4O6: 542.24, found: 543.3 [M+H]+.

[4072] Intermediate 41. l-(2-methyl-4-(oxetan-3-ylmethyl)-3-oxo-l,4- diazadispiro[4.1.57. l5]tridec- 1-en- 10-yl)-3-((( ls,3S)-3- methylcyclobutyl)methyl)pyrimidine-2,4,6(lH,3H,5H)-trione

[4073]

[4074] The title compound was prepared following analogous procedures to those described for Intermediate 38 using Intermediate 21 and Intermediate 3.

[4075] Intermediate 42. l-((5S,7s,10S)-3-methyl-l-(oxetan-3-ylmethyl)-2,4-dioxo-l,3- diazadispiro[4.1.57.l5]tridecan-10-yl)-3-(((ls,3R)-3- methylcyclobutyl)methyl)pyrimidine-2,4,6(lH,3H,5H)-trione

[4076]

[4077] The title compound was prepared following analogous procedures to those described for Intermediate 38 using Intermediate 3. MS (ESI): mass calcd. for C26H36N4O6: 500.26, found: 501.2 [M+H]+.

[4078] Intermediate 43. l-((3,3-difluorocyclobutyl)methyl)-3-((5S,7s,10S)-3-methyl-l-(oxetan-3- ylmethyl)-2,4-dioxo-l,3-diazadispiro[4.1.57.l5]tridecan-10-yl)pyrimidine- 2,4,6(lH,3H,5H)-trione

[4079] -281- FoleyHoagUS13180487.1 GPX-02525

[4080]

[4081] The title compound was prepared following analogous procedures to those described for Intermediate 38. MS (ESI): mass calcd. for C25H32F2N4O6: 522.23, found: 523.3 [M+H]+.

[4082] Intermediate 44. l-(cyclobutylmethyl)-3-((5S,7s,10S)-3-methyl-l-(oxetan-3-ylmethyl)- 2,4-dioxo-l,3-diazadispiro[4.1.57.l5]tridecan-10-yl)pyrimidine-2,4,6(lH,3H,5H)-trione

[4083]

[4084] The title compound was prepared following analogous procedures to those described for Intermediate 38. MS (ESI): mass calcd. for C25H34N4O6: 486.25, found: 487.3 [M+H]+.

[4085] Intermediate 45. l-(3-methyl-l-(oxetan-3-ylmethyl)-2,4-dioxo-l,3-diazadispiro[4.1.57.l5]tridecan-10-yl)-3-(3,3,3-trifluoropropyl)pyrimidine- 2,4,6(lH,3H,5H)-trione

[4086]

[4087] The title compound was prepared following analogous procedures to those described for Intermediate 38.

[4088] Intermediate 46. l-(cyclobutylmethyl)-3-(2-methyl-4-(oxetan-3-ylmethyl)-3-oxo-l,4-diazadispiro[4.1.57.l5]tride...

Claims

GPX-02525CLAIMSWe claim:

1. A compound having the structure of Formula (XXIII):or a pharmaceutically acceptable salt thereof, wherein:Rais (C3-Cs)cycloalkyl, hydrogen, ORe, SRe, (Ci-Ce)alkyl, (C3-Cs)cycloalkyl(Ci-Ce)alkyl, (Ce-Cio)aryl, (C6-Cio)aryl(Ci-C6)alkyl, 4- to 7-membered heterocycloalkyl, 4- to 7-membered heterocycloalkyl(Ci-C6)alkyl, 5- to 10-membered heteroaryl, or 5- to 10-membered heteroaryl(Ci-C6)alkyl; wherein (Ci-Ce)alkyl, (C3-Cs)cycloalkyl, (C3-C8)cycloalkyl(Ci-C6)alkyl, (Ce-Cio)aryl, (C6-Cio)aryl(Ci-C6)alkyl, 4- to 7-membered heterocycloalkyl, 4- to 7-membered heterocycloalkyl(Ci-C6)alkyl, 5- to 10-membered heteroaryl, or 5- to 10-membered heteroaryl(Ci-C6)alkyl are optionally substituted with one or more substituents selected from halo, hydroxy, (Ci-Ce)alkyl, (Ci-C6)hydroxyalkyl, (Ci-C6)haloalkyl, (Ci-Ce)alkoxy, (Ci-C6)cycloalkoxy, (Ci-C6)haloalkoxy, cyano, N(Rf)2, and SO2N(Rf)2;R1and R2taken together with the carbon atom to which they are attached form:- 1296 - FH13180518.3GPX-02525Rbis:i) (Ci-Ce)alkyl optionally substituted with one or more substituents selected from (C3-C8)cycloalkyl, hydroxy, (Ci-Ce)alkoxy, halo, cyano, N(Rf)2, 4- to 10-membered heterocycloalkyl, and 5- to 10-membered heteroaryl; wherein (C3-Cs)cycloalkyl, 4- to 10-membered heterocycloalkyl, and 5- to 10-membered heteroaryl are each optionally substituted with one or more substituents selected from hydroxy, halo, (Ci-Ce)alkyl, (C3-Cs)cycloalkyl, (Ci-Ce)alkoxy, (Ci-Ce)hydroxy alkyl, (Ci-C6)alkoxy(Ci-C6)alkyl, (Ci-C6)haloalkyl, (Ci-C6)haloalkoxy, C(O)N(Rf)2, CO2Rf, CH2CO2Rf, 5- to 10-membered heteroaryl, cyano, oxo, =NRf, N(Rf)SO2Rf, SO2Rf, CH2N(Rf)C(O)N(Rf)2, N(Rf)C(O)Rf, and N(Rf)2;ii) hydrogen;iii) (C3-Cs)cycloalkyl optionally substituted with one or more substituents selected from (Ci-Ce)alkyl, halo, and hydroxy;iv) 4- to 7-membered heterocyclo alkyl optionally substituted with one or more substituents selected from (Ci-Ce)alkyl, halo, and hydroxy; orv) (C2-C6)alkynyl optionally substituted with 1 one or more substituents selected from (Ci-Ce)alkyl, halo, and hydroxy;Rcis (Ci-Ce)alkyl or hydrogen;Rdis hydrogen, (Ci-Ce)alkyl, or hydroxy, and — represents a single bond or a double bond; wherein: i) — represents a double bond when Rdis hydrogen or (Ci-Ce)alkyl; or ii) — represents a single bond when Rdis hydroxy;Reis hydrogen or (Ci-Ce)alkyl;Rfis independently for each occurrence hydrogen or (Ci-Ce)alkyl, wherein (Ci-Ce)alkyl is optionally substituted with phenyl, or two occurrences of Rftaken together with the nitrogen to which they are attached form a 4- to 7- membered heterocycloalkyl; and R3is:i) (Ci-Ce)alkyl optionally substituted with one or more substituents selected from (C3-Cs)cycloalkyl, halo, pentafluoro thio, 4- to 10-membered heterocycloalkyl, and 5- to 10-membered heteroaryl; wherein (C3-Cs)cycloalkyl is optionally substituted with one or more substituents selected from halo, (Ci-C6)haloalkyl, (C2-C6)alkynyl, (Ci-Ce)alkyl, (Ci-Ce)hydroxyalkyl, and (Ci-C6)alkoxy(Ci-C6)alkyl; orii) (C3-Cs)cycloalkyl optionally substituted with one or more substituents selected from halo, hydroxy, and (Ci-C6)alkyl.- 1297 - FH13180518.3GPX-025252. A compound having the structure of Formula (IV):or a pharmaceutically acceptable salt thereof, wherein:Rais (C3-Cs)cycloalkyl, hydrogen, ORe, SRe, (Ci-Ce)alkyl, (C3-Cs)cycloalkyl(Ci-Ce)alkyl, (Ce-Cio)aryl, or (C6-Cio)aryl(Ci-C6)alkyl, wherein (Ci-Ce)alkyl, (C3-Cs)cycloalkyl, (C3-C8)cycloalkyl(Ci-C6)alkyl, (Ce-Cio)aryl, or (C6-Cio)aryl(Ci-C6)alkyl, are optionally substituted with one or more substituents selected from halo, hydroxy, (Ci-Ce)alkoxy, (Ci-Ce)haloalkoxy and cyano;R1and R2taken together with the carbon atom to which they are attached form:Rbis (i) (Ci-Ce)alkyl optionally substituted with one or more substituents selected from (C3-Cs)cycloalkyl, hydroxy, (Ci-Ce)alkoxy, halo, cyano, and 4- to 7-membered heterocycloalkyl; wherein (C3-Cs)cycloalkyl, and 4- to 7-membered heterocycloalkyl are each optionally substituted with one or more substituents selected from hydroxy, halo, (Ci-Ce)alkyl, (Ci-Ce)alkoxy, (Ci-C6)hydroxyalkyl, (Ci-C6)alkoxy(Ci-C6)alkyl, (Ci-C6)haloalkyl, (Ci-C6)haloalkoxy, CO2Rf, 5- to 10-membered heteroaryl, cyano, N(Rf)SO2Rf, SO2Rf, N(Rf)C(O)Rf, and N(Rf)2 or (ii) hydrogen;Rcis (Ci-Ce)alkyl or hydrogen;- 1298 - FH13180518.3GPX-02525Rdis hydrogen, (Ci-Ce)alkyl, or hydroxy, and — represents a single bond or a double bond; wherein: i) — represents a double bond when Rdis hydrogen or (Ci-Ce)alkyl; or ii) — represents a single bond when Rdis hydroxy;Reis hydrogen or (Ci-Ce)alkyl;Rfis independently for each occurrence hydrogen or (Ci-Ce)alkyl, wherein (Ci-Ce)alkyl is optionally substituted with phenyl, or two occurrences of Rftaken together with the nitrogen to which they are attached form a 4- to 7- membered heterocycloalkyl; and R3is (Ci-Ce)alkyl optionally substituted with one or more substituents selected from (C3-Cs)cycloalkyl, halo, pentafluoro thio, and 4- to 10-membered heterocycloalkyl; wherein (C3-Cs)cycloalkyl is optionally substituted with one or more substituents selected from halo, (Ci-C6)haloalkyl, and (Ci-C6)alkyl.

3. The compound of claim 1 or 2, wherein:Rbis hydrogen or (Ci-Ce)alkyl optionally substituted with one or more substituents selected from hydroxy, (Ci-Ce)alkoxy, halo, cyano, (C3-Cs)cycloalkyl and 4- to 7-membered heterocycloalkyl; wherein (C3-Cs)cycloalkyl, and 4- to 7-membered heterocycloalkyl are each optionally substituted with one or more substituents selected from halo, (Ci-Ce)alkyl, hydroxy, (Ci-Ce)alkoxy, (Ci-C6)alkoxy(Ci-C6)alkyl, (Ci-C6)haloalkyl, (Ci-C6)haloalkoxy, cyano, and N(Rf)2.

4. The compound of any one of claims 1-3, wherein:R3is (Ci-Ce)alkyl optionally substituted with one or more substituents selected from halo, pentafluoro thio, and (C3-Cs)cycloalkyl, wherein (C3-Cs)cycloalkyl is optionally substituted with one or more substituents selected from halo, (Ci-C6)haloalkyl. and (Ci-C6)alkyl.

5. The compound of any one of claims 1-4 having the structure of any one of Formulae- 1299 - FH13180518.3GPX-02525(IVa-iii); (IVa-iv); (IVb-i); (IVb-ii); (IVb-iii); (IVb-iv);(IVc-ii);(IVc-iv);- 1300 - FH13180518.3GPX-02525or a pharmaceutically acceptable salt thereof:

6. The compound of any one of claims 1-5, wherein Rais hydrogen.

7. The compound of any one of claims 1-5, wherein Rais (Ci-Ce)alkyl optionally substituted with one or more substituents selected from fluoro, hydroxy and cyano.

8. The compound of claim 7, wherein Rais methyl, ethyl, isopropyl, or n-butyl, each of which is optionally substituted with one or more instances of fluoro.

9. The compound of any one of claims 1-5, wherein Rais (C3-Cs)cycloalkyl optionally substituted with one or more instances of fluoro.

10. The compound of claim 9, wherein Rais cyclopropyl optionally substituted with one or more instances of fluoro.

11. The compound of claim 10, wherein Rais cyclopropyl substituted with a fluoro.

12. The compound of any one of claimsl-5, wherein Rais (C3-C8)cycloalkyl(Ci-C6)alkyl.

13. The compound of any one of claims 1-5, wherein Rais phenyl, benzyl, or phenethyl.

14. The compound of any one of claims 1-5, wherein Rais:hydrogen, hydroxy, thiomethoxy, methyl, ethyl, isopropyl, n-butyl, difluoromethyl, cyclopropyl, cyclobutylmethyl, hydroxymethyl, 2-hydroxyethyl, cyanomethyl, phenyl,OHbenzyl, phenethyl,or15. The compound of any one of claims 1-5, wherein Rais:

16. The compound of any one of claims 1-5, wherein Rais- 1301 - FH13180518.3GPX-0252517. The compound of any one of claims 1-16, having the structure of any one of Formulae (IVa-i) to (IVa-iv):

18. The compound of any one of claims 1-16, having the structure of any one of Formulae(IVb-ii);(IVb-iv);19. The compound of any one of claims 1-16, having the structure of any one of Formulae (IVc-i) to (IVc-iv):- 1302 - FH13180518.3GPX-02525(IVc-ii);(IVc-iv).

20. The compound of any one of claims 1-19, wherein Rbis (Ci-Ce)alkyl optionally substituted with one or more substituents selected from hydroxy and fluoro.

21. The compound of any one of claimsl-19, wherein Rbis (Ci-Ce)alkyl optionally substituted with (C3-Cs)cycloalkyl, wherein (C3-Cs)cycloalkyl is substituted with one or more substituents selected from fluoro, hydroxy, (Ci-Ce)alkyl, (Ci-Ce)fluoroalkyl, cyano, and N(Rf)2.

22. The compound of any one of claims 1-19, wherein Rbis (Ci-Ce)alkyl substituted with (C3-Cs)cycloalkyl, wherein (C3-Cs)cycloalkyl is substituted with hydroxy.

23. The compound of any one of claims 1-22, wherein each Rfis hydrogen.

24. The compound of any one of claims 1-22, wherein each Rfis methyl.

25. The compound of any one of claims 1-19, wherein Rbis (Ci-Ce)alkyl substituted with 4- to 7-membered heterocycloalkyl, wherein 4- to 7-membered heterocycloalkyl is optionally substituted with one or more substituents selected from halo, hydroxy, (Ci-Ce)alkyl, and (Ci-Ce)alkoxy.

26. The compound of any one of claims 1-19, wherein Rbis:- 1303 - FH13180518.3GPX-0252528. The compound of any one of claims 1-27, wherein Rcis methyl.- 1304 - FH13180518.3GPX-0252529. The compound of any one of claims 1-28, wherein R3is (Ci-Ce)alkyl optionally substituted with one or more fluoro atoms.

30. The compound of any one of claims 1-28, wherein R3is (Ci-Ce)alkyl substituted with (C3-Cs)cycloalkyl, wherein (C3-Cs)cycloalkyl is optionally substituted with one or more substituents selected from halo and (Ci-C6)alkyl.

31. The compound of claim 30, wherein R3is methyl substituted with (C3-Cs)cycloalkyl, wherein (C3-Cs)cycloalkyl is optionally substituted with one or more substituents selected from halo and (Ci-C6)alkyl.

32. The compound of claim 30 or 31, wherein the (C3-Cs)cycloalkyl is cyclopropyl, cyclobutyl, or cyclopentyl, each of which is optionally substituted with one or more instances of a substituent selected from fluoro and (Ci-C6)alkyl.

33. The compound of any one of claims 30-32, wherein R3is methyl substituted with cyclobutyl, wherein the cyclobutyl is further substituted with one or more fluoro, and optionally the cyclobutyl is substituted with two fluoro.

34. The compound of any one of claims 1-28, wherein R3is:- 1305 - FH13180518.3GPX-0252536. The compound of any one of claims 1-28, wherein R3isF37. A compound having the structure of Formula (IVb-i):(IVb-i),or a pharmaceutically acceptable salt thereof, wherein:Rais cyclopropyl substituted with one or more instances of fluoro;Rbis methyl substituted with (C3-Cs)cycloalkyl, wherein (C3-Cs)cycloalkyl is further substituted with hydroxy;Rcis methyl; andR3is methyl substituted with cyclobutyl, wherein the cyclobutyl is further substituted with one or more fluoro.

38. The compound of claim 37, wherein:

39. The compound of claim 37 or 38, having the structure of compound no. 257:- 1306 - FH13180518.3GPX-02525(257).

40. A compound according to Formula (XXII):(XXII);or a pharmaceutically acceptable salt thereof;wherein:R1is hydrogen or (Ci-Ce)alkyl;R2is hydrogen or (Ci-Ce)alkyl optionally substituted with one or more substituents selected from hydroxy, (Ci-Ce)alkoxy, halo, cyano, (C3-Cs)cycloalkyl and 4- to 7-membered heterocycloalkyl; wherein (C3-Cs)cycloalkyl, 4- to 7-membered heterocycloalkyl are each optionally substituted with one or more substituents selected from halo, (Ci-Ce)alkyl, hydroxy, (Ci-Ce)alkoxy, (Ci-C6)alkoxy(Ci-C6)alkyl, (Ci-C6)haloalkyl, (Ci-C6)haloalkoxy, cyano, and N(RC)2;R3is (Ci-Ce)alkyl optionally substituted with halo, (C3-Cs)cycloalkyl or phenyl, each of which is optionally substituted with one or more substituents selected from halo, (Ci-C6)haloalkyl and (Ci-Ce)alkyl;R4aand R4bare independently hydrogen, phenyl, N(Rd)2, CON(Rd)2, ORe, (Ci-Ce)alkyl, or (C3-Cs)cycloalkyl; wherein the (Ci-C6)alkyl is optionally substituted with one or more instances of halo, hydroxy, heterocycloalkyl, phenyl, N(Rd)2, or CON(Rd)2; and- 1307 - FH13180518.3GPX-02525R5aand R5bare independently hydrogen, phenyl, N(Rd)2, C0N(Rd)2, ORe, or (Ci-Ce)alkyl, wherein the (Ci-Ce)alkyl is optionally substituted with one or more instances of halo, hydroxy, heterocycloalkyl, phenyl, N(Rd)2, or CON(Rd)2; wherein at least one of R4a, R4b, R5a, and R5bis phenyl, N(Rd)2, CON(Rd)2, ORe, or (Ci-C6)alkyl; wherein the (Ci-C6)alkyl is substituted with one or more instances of alkoxy, phenyl, N(Rd)2, or CON(Rd)2;Rcis independently for each occurrence hydrogen or (Ci-Ce)alkyl; or two occurrences of Rctaken together with the nitrogen to which they are attached form a 4- to 7-membered heterocycloalkyl;Rdis independently for each occurrence hydrogen or (Ci-Ce)alkyl; or two occurrences of Rdtaken together with the nitrogen to which they are attached form a 4- to 7-membered heterocycloalkyl; andReis hydrogen or (Ci-C6)alkyl.

41. A compound according to Formula (I):or a pharmaceutically acceptable salt thereof;wherein:R1is hydrogen or (Ci-Ce)alkyl;R2is hydrogen or (Ci-Ce)alkyl optionally substituted with one or more substituents selected from hydroxy, (Ci-Ce)alkoxy, halo, cyano, (C3-Cs)cycloalkyl and 4- to 7-membered heterocycloalkyl; wherein (C3-Cs)cycloalkyl, 4- to 7-membered heterocycloalkyl are each optionally substituted with one or more substituents selected from halo, (Ci-Ce)alkyl, hydroxy, (Ci-Ce)alkoxy, (Ci-C6)alkoxy(Ci-C6)alkyl, (Ci-C6)haloalkyl, (Ci-C6)haloalkoxy, cyano, and N(RC)2;R3is (Ci-Ce)alkyl optionally substituted with halo, (C3-Cs)cycloalkyl or phenyl, each of which is optionally substituted with one or more substituents selected from halo, (Ci-Ce)haloalkyl and (Ci-Ce)alkyl;- 1308 - FH13180518.3GPX-02525R4aand R4bare independently hydrogen, phenyl, N(Rd)2, C0N(Rd)2, ORe, or (Ci-Ce)alkyl; wherein the (Ci-Ce)alkyl is optionally substituted with one or more instances of halo, hydroxy, heterocycloalkyl, phenyl, N(Rd)2, or CON(Rd)2; andR5aand R5bare independently hydrogen, phenyl, N(Rd)2, CON(Rd)2, ORe, or (Ci-Ce)alkyl, wherein the (Ci-Ce)alkyl is optionally substituted with one or more instances of halo, hydroxy, heterocycloalkyl, phenyl, N(Rd)2, or CON(Rd)2; wherein at least one of R4a, R4b, R5a, and R5bis phenyl, N(Rd)2, CON(Rd)2, ORe, or (Ci-C6)alkyl; wherein the (Ci-C6)alkyl is substituted with one or more instances of alkoxy, phenyl, N(Rd)2, or CON(Rd)2;Rcis independently for each occurrence hydrogen or (Ci-Ce)alkyl; or two occurrences of Rctaken together with the nitrogen to which they are attached form a 4- to 7-membered heterocycloalkyl;Rdis independently for each occurrence hydrogen or (Ci-Ce)alkyl; or two occurrences of Rdtaken together with the nitrogen to which they are attached form a 4- to 7-membered heterocycloalkyl; andReis hydrogen or (Ci-C6)alkyl.

42. The compound of claim 40 or 41, having the structure of Formula (la) or (lb):or a pharmaceutically acceptable salt thereof.

43. The compound of any one of claims 40-42, wherein R1is methyl.

44. The compound of any one of claims 40-43, wherein R2is (Ci-Ce)alkyl substituted with 4- to 7- membered heterocycloalkyl.

45. The compound of any one of claims 40-43, wherein R2is methyl substituted with 4-to 7- membered heterocycloalkyl.- 1309 - FH13180518.3GPX-0252546. The compound of any one of claims 40-43, wherein R2is methyl substituted with 4-to 7- membered heterocycloalkyl and fluoro.

47. The compound of any one of claims 40-46, wherein R3is (Ci-Ce)alkyl optionally substituted with (C3-Cs)cycloalkyl.

48. The compound of any one of claims 40-46, wherein R3is methyl substituted with (C3-Cs)cycloalkyl.

49. The compound of any one of claims 40-46, wherein R3is methyl substituted with cyclopropyl, cyclobutyl, or cyclopentyl.

50. The compound of any one of claims 40-49, wherein three of R4a, R4b, R5aand R5bare hydrogen.

51. The compound of any one of claims 40-50, wherein one of R4a, R4b, R5aand R5bis (Ci-Ce)alkyl substituted with one or more instances of alkoxy, phenyl, N(Rd)2, or CON(Rd)2.

52. The compound of any one of claims 40-50, wherein one of R4a, R4b, R5aand R5bis phenyl.

53. The compound of any one of claims 40-50, wherein one of R4a, R4b, R5aand R5bis N(Rd)2, CON(Rd)2, or ORe.

54. The compound of any one of claims 40-50 and 53, wherein each Rdis hydrogen.

55. The compound of any one of claims 40-50 and 53, wherein each Rdis methyl.

56. The compound of any one of claims 40-50 and 53, wherein one Rdis methyl and one Rdis hydrogen.

57. The compound of any one of claims 40-50 and 53, wherein Reis hydrogen.

58. A compound having the structure of Formula (II):- 1310 - FH13180518.3GPX-02525R4b-N N-R5br2(II);or a pharmaceutically acceptable salt thereof, wherein:R1and R2taken together with the carbon atom to which they are attached form a heterocyclic ring having the structure:RaiNRais (Ci-Ce)alkyl optionally substituted with 4- to 7-membered heterocycloalkyl;; wherein:Rbis (Ci-Ce)alkyl substituted with:(i) 4- to 7-membered heterocycloalkyl and fluoro; or(ii) (C3-Cs)cycloalkyl optionally substituted with one or more of (Ci- Cs) alkyl and cyano; andRcis hydrogen or (Ci-Ce)alkyl; or(c); wherein:Reis hydrogen, (Ci-Ce)alkyl optionally substituted with 4- to 7-membered heterocycloalkyl; andRfis hydrogen or (Ci-Ce)alkyl;R3is (Ci-Ce)alkyl optionally substituted with (C3-Cs)cycloalkyl or phenyl, each of which is optionally substituted with one or more substituents selected from halo, (Ci-Ce)haloalkyl, and (Ci-Ce)alkyl;- 1311 - FH13180518.3GPX-02525R4aand R4bare independently hydrogen, phenyl, N(Rd)2, C0N(Rd)2, ORg, or (Ci-Ce)alkyl, wherein the (Ci-Ce)alkyl is optionally substituted with one or more instances of halo, hydroxy, heterocycloalkyl, phenyl, N(Rd)2, or CON(Rd)2;R5aand R5bare independently hydrogen, phenyl, N(Rd)2, CON(Rd)2, ORg, or (Ci-Ce)alkyl, wherein the (Ci-Ce)alkyl is optionally substituted with one or more instances of halo, hydroxy, heterocycloalkyl, phenyl, N(Rd)2, or CON(Rd)2;Rdis independently for each occurrence hydrogen or (Ci-Ce)alkyl, or two occurrences of Rdtaken together with the nitrogen to which they are attached form a 4- to 7-membered heterocycloalkyl; andRgis hydrogen or (Ci-C6)alkyl.

59. The compound of claim 58, wherein the compound has the structure of formula (Ila) or (lib):or a pharmaceutically acceptable salt thereof, wherein:if the compound is formula (Ila), then R1and R2taken together with the carbon atom to which they are attached form a heterocyclic ring having the structure of (Ila-i), (Ila-ii), or (Ila-iii):- 1312 - FH13180518.3GPX-02525R4aR5aO (Ila-ii), orif the compound is Formula (lib), then R1and R2taken together with the carbon atom to which they are attached form a heterocyclic ring having the structure (Ilb-i), (Ilb-ii), or (Ilb-iii):- 1313 - FH13180518.3GPX-0252560. The compound of claim 58 or 59, wherein R3is (Ci-Ce)alkyl optionally substituted with (C3-Cs)cycloalkyl.

61. The compound of claim 60, wherein R3is methyl substituted with (C3-Cs)cycloalkyl.

62. The compound of claim 61, wherein R3is methyl substituted with cyclopropyl, cyclobutyl, or cyclopentyl.

63. The compound of any one of claims 58-62, wherein three of R4a, R4b, R5aand R5bare hydrogen.

64. The compound of any one of claims 58-63, wherein one of R4a, R4b, R5aand R5bis (Ci-C6)alkyl.

65. The compound of claim 64, wherein one of R4a, R4b, R5aand R5bis methyl.

66. A compound according to Formula (III):R4b-N N-R5bNR2or a pharmaceutically acceptable salt thereof;wherein:R1is hydrogen or (Ci-Ce)alkyl;R2is hydrogen or (Ci-Ce)alkyl optionally substituted with one or more substituents selected from hydroxy, (Ci-Ce)alkoxy, halo, cyano, (C3-Cs)cycloalkyl and 4- to 7-membered heterocycloalkyl; wherein (C3-Cs)cycloalkyl, 4- to 7-membered heterocyclo alkyl are each optionally substituted with one or more substituents selected from halo, (Ci-Ce)alkyl, hydroxy, (Ci-Ce)alkoxy, (Ci-C6)alkoxy(Ci-C6)alkyl, halo, (Ci-C6)haloalkyl, (Ci-Ce)haloalkoxy, cyano, and N(RC)2;R3is (Ci-Ce)alkyl substituted with one or more substituents selected from halo and (C3-Cs)cycloalkyl, wherein (C3-Cs)cycloalkyl is substituted with one or more substituents selected from halo, halo(Ci-C6)alkyl and (Ci-Ce)alkyl;- 1314 - FH13180518.3GPX-02525R4aand R4bare independently hydrogen, phenyl, N(Rd)2, C0N(Rd)2, ORe, or (Ci-Ce)alkyl, wherein the (Ci-Ce)alkyl is optionally substituted with one or more instances of halo, hydroxy, heterocycloalkyl, phenyl, N(Rd)2, or CON(Rd)2; andR5aand R5bare independently hydrogen, phenyl, N(Rd)2, CON(Rd)2, ORe, or (Ci-Ce)alkyl, wherein the (Ci-Ce)alkyl is optionally substituted with one or more instances of halo, hydroxy, heterocycloalkyl, phenyl, N(Rd)2, or CON(Rd)2;Rcis independently for each occurrence hydrogen or (Ci-Ce)alkyl; or two occurrences of Rctaken together with the nitrogen to which they are attached form a 4- to 7-membered heterocycloalkyl;Rdis independently for each occurrence hydrogen or (Ci-Ce)alkyl; or two occurrences of Rdtaken together with the nitrogen to which they are attached form a 4- to 7-membered heterocycloalkyl; andReis hydrogen or (Ci-C6)alkyl.

67. The compound of claim 66, having the structure of Formula (Illa) or (Illb):or a pharmaceutically acceptable salt thereof.

68. The compound of claim 66 or 67, wherein R3is (Ci-Ce)alkyl substituted with one or more instances of fluoro.

69. The compound of claim 68, wherein R3is 4,4,4-trifluorobutyl.

70. The compound of claim 66 or 67, wherein R3is (Ci-Ce)alkyl substituted with cyclobutyl, wherein cyclobutyl is substituted with one or more instances of fluoro or (Ci-Ce)fluoroalkyl.

71. The compound of claim 66 or 67, wherein R3is 2,2-difluoromethyl, 3,3-difluoromethyl, or 3-(trifluoromethyl)cyclobutylmethyl.- 1315 - FH13180518.3GPX-0252572. The compound of any one of claims 66-71, wherein three of R4a, R4b, R5aand R5bare hydrogen.

73. The compound of any one of claims 66-72, wherein one of R4a, R4b, R5aand R5bis (Ci-C6)alkyl.

74. The compound of claim 73, wherein one of R4a, R4b, R5aand R5bis methyl.

75. A compound according to Formula (V):or a pharmaceutically acceptable salt thereof, wherein:X is N or CRX;Y is N(R4)2;R1is hydrogen or (Ci-Ce)alkyl optionally substituted with one or more substituents selected from hydroxy, (Ci-Ce)alkoxy, halo, cyano, (C3-Cs)cycloalkyl and 4- to 7-membered heterocycloalkyl; wherein (C3-Cs)cycloalkyl, 4- to 7-membered heterocycloalkyl are each optionally substituted with one or more substituents selected from halo, (Ci-Ce)alkyl, hydroxy, (Ci-Ce)alkoxy, (Ci-C6)alkoxy(Ci-C6)alkyl, (Ci-C6)haloalkyl, (Ci-C6)haloalkoxy, cyano, and N(RC)2;Rcis independently for each occurrence hydrogen or (Ci-Ce)alkyl; or two occurrences of Rctaken together with the nitrogen to which they are attached form a 4- to 7- membered heterocycloalkyl;R2is hydrogen or (Ci-Ce)alkyl;R3is (Ci-C6)haloalkyl or (Ci-Ce)alkyl substituted with (C3-Cs)cycloalkyl, wherein (C3-Cs)cycloalkyl is optionally substituted with one or more substituents selected from halo, (Ci-Ce)alkyl, and (Ci-C6)haloalkylR4is independently for each occurrence hydrogen or (Ci-Ce)alkyl; or two occurrences of R4taken together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycloalkyl; andRxis hydrogen or (Ci-C6)alkyl.- 1316 - FH13180518.3GPX-0252576. A compound according to claim 75, having the structure of Formula (Va) or (Vb):or a pharmaceutically acceptable salt thereof.

77. The compound of claim 75 or 76, wherein Y is NH2.

78. The compound of any one of claims 75-77, wherein R3is CH2CH2CH2CF3, or cyclopentylmethyl.

79. The compound of any one of claims 75-78, wherein X is CH.

80. The compound of any one of claims 75-78, wherein X is N.

81. The compound of any one of claims 75-80, wherein R1is (Ci-Ce)alkyl substituted with 4- to 7-membered heterocycloalkyl.

82. The compound of claim 81, wherein R1is methyl substituted with 4- to 7-membered heterocycloalkyl.

83. The compound of any one of claims 75-82, wherein R2is hydrogen.

84. The compound of any one of claims 75-82, wherein R2is (Ci-C6)alkyl.

85. The compound of claim 84, wherein R2is methyl.

86. A compound of Formula (XXIV):^X2N(R4)2xk J. QR2(XXIV);or a pharmaceutically acceptable salt thereof, wherein:- 1317 - FH13180518.3GPX-02525R1and R2taken together with the carbon atom to which they are attached form:R\,0Rais hydrogen or (Ci-Ce)alkyl optionally substituted with one or more substituents selected from hydroxy, (Ci-Ce)alkoxy, (Ci-C6)haloalkoxy, C(0)N(Rc)2, halo, cyano, (C3-Cs)cycloalkyl and 4- to 7-membered heterocycloalkyl; wherein (C3-Cs)cycloalkyl, 4- to 7-membered heterocycloalkyl are each optionally substituted with one or more substituents selected from halo, (Ci-Ce)alkyl, hydroxy, (Ci-Ce)hydroxy alkyl, CChR0, SChR0, SO2N(CO)RC, C(0)N(RC)2, =NH, C(0)N0H, (Ci-C6)alkoxy, (Ci-C6)alkoxy(Ci-C6)alkyl, (Ci-C6)haloalkyl, (Ci-C6)haloalkoxy, cyano, and N(RC)2;Rbis hydrogen or (Ci-Ce)alkyl;Rcis independently for each occurrence hydrogen or (Ci-Ce)alkyl; or two occurrences of Rctaken together with the nitrogen to which they are attached form a 4- to 7- membered heterocycloalkyl;R3is (Ci-Ce)alkyl optionally substituted with one or more substituents selected from halo and (C3-Cs)cycloalkyl, wherein (C3-Cs)cycloalkyl is optionally substituted with one or more substituents selected from (Ci-Ce)alkyl, (Ci-C6)haloalkyl, and halo;R4is independently for each occurrence hydrogen, (Ci-Ce)alkyl, or two occurrences of R4taken together with the nitrogen atom to which they are attached forms a 4- to 7-membered heterocycloalkyl;X1is CH or N;X2is CR5or N; provided that at least one of X1is X2is N;R5is hydrogen, hydroxy, (Ci-Ce)alkyl, (Ci-C6)haloalkyl, (Ci-C6)haloalkoxy, (Ci-Ce)hydroxyalkyl, (Ci-C6)alkoxy(Ci-C6)alkyl, (C3-Cs)cycloalkyl, CN, CO2R6, (Ci-C6)haloalkoxy(Ci-C6)alkyl, C(O)N(R7)2, or halo;R6is hydrogen or (Ci-Ce)alkyl;R7is independently for each occurrence selected from hydrogen and (Ci-Ce)alkyl,- 1318 - FH13180518.3GPX-02525provided the compound is not:

87. A compound of Formula (VI):r2(VI);or a pharmaceutically acceptable salt thereof, wherein:R1and R2taken together with the carbon atom to which they are attached form:(a) O; orRais hydrogen or (Ci-Ce)alkyl optionally substituted with one or more substituents selected from hydroxy, (Ci-Ce)alkoxy, (Ci-C6)haloalkoxy, C(O)N(RC)2, halo, cyano, (C3-Cs)cycloalkyl and 4- to 7-membered heterocycloalkyl; wherein (C3-Cs)cycloalkyl, 4- to 7-membered heterocycloalkyl are each optionally substituted with one or more substituents selected from halo, (Ci-C6)alkyl, hydroxy, CO2RC, SO2RC, SO2N(CO)RC, C(O)N(RC)2, C(O)NOH, (Ci-Ce)alkoxy, (Ci-C6)alkoxy(Ci-C6)alkyl, (Ci-C6)haloalkyl, (Ci-C6)haloalkoxy, cyano, and N(RC)2;Rbis hydrogen or (Ci-C6)alkyl;Rcis independently for each occurrence hydrogen or (Ci-Ce)alkyl; or two occurrences of Rctaken together with the nitrogen to which they are attached form a 4- to 7-membered heterocycloalkyl;- 1319 - FH13180518.3GPX-02525R3is (Ci-Ce)alkyl optionally substituted with one or more substituents selected from halo and (C3-Cs)cycloalkyl, wherein (C3-C8)cycloalkyl is optionally substituted with one or more substituents selected from (Ci-Ce)alkyl, (Ci-C6)haloalkyl, and halo;R4is independently for each occurrence hydrogen, (Ci-Ce)alkyl, or two occurrences of R4taken together with the nitrogen atom to which they are attached forms a 4- to 7-membered heterocycloalkyl;X1is CH or N;X2is CR5or N; provided that at least one of X1is X2is N;R5is hydrogen, hydroxy, (Ci-Ce)alkyl, (Ci-C6)haloalkyl, (Cl-C6)haloalkoxy, (Ci-Ce)hydroxyalkyl, (Ci-C6)alkoxy(Ci-C6)alkyl, (C3-Cs)cycloalkyl, CN, CO2R6, (Ci-C6)haloalkoxy(Ci-C6)alkyl, C(O)N(R7)2, or halo;R6is hydrogen or (Ci-Ce)alkyl;R7is independently for each occurrence selected from hydrogen and (Ci-Ce)alkyl,provided the compound is not:

88. The compound of claim 86 or 87, wherein the compound is represented by Formula (Via), (VIb), (Vic), or (Vid):- 1320 - FH13180518.3GPX-0252589. The compound of any one of claims 86-88, wherein Rais hydrogen or (Ci-Ce)alkyl optionally substituted with one or more substituents selected from hydroxy, (Ci-Ce)alkoxy, halo, cyano, (C3-Cs)cycloalkyl and 4- to 7-membered heterocycloalkyl; wherein (C3-Cs)cycloalkyl, 4- to 7-membered heterocycloalkyl are each optionally substituted with one or more substituents selected from halo, (Ci-Ce)alkyl, hydroxy, (Ci-Ce)alkoxy, (Ci-C6)alkoxy(Ci-C6)alkyl, (Ci-C6)haloalkyl, (Ci-C6)haloalkoxy, cyano, and N(RC)2.

90. The compound of any one of claims 86-89, wherein X1is N.

91. The compound of any one of claims 86-90, wherein X2is CR5.

92. The compound of any one of claims 86-91, wherein R5is cyano, chloro, fluoro, CO2H, (Ci-C6)alkyl, or (Ci-C6)fluoroalkyl.

93. The compound of any one of claims 86-91, wherein R5is hydrogen.

94. The compound of any one of claims 86-90, wherein X2is N.

95. The compound of any one of claims 86-89, wherein X1is CH.

96. The compound of any one of claims 86-95, wherein R1is (Ci-Ce)alkyl substituted with 4- to 7-membered heterocycloalkyl.

97. The compound of any one of claims 86-96, wherein R2is hydrogen or methyl.

98. The compound of any one of claims 86-97 wherein R3is methyl substituted with (C3-Cs)cycloalkyl.

99. The compound of any one of claims 86-97, wherein R3is -CH2CH2CH2CH3,orThe compound of any one of claims 86-99, wherein each R4is hydrogen.

101. A compound of Formula (VII):- 1321 - FH13180518.3GPX-02525or a pharmaceutically acceptable salt thereof, wherein:R1is (Ci-Ce)alkyl optionally substituted with halo or (C3-Cs)cycloalkyl, wherein (C3-Cs)cycloalkyl is optionally substituted with one or more substituents selected from halo and (Ci-C6)alkyl;X is N or CR2;R2is hydrogen, halo, N(Ra)2, or (Ci-Ce)alkyl;R3is hydrogen, N(Ra)2, (Ci-Ce)alkoxy, (C3-Cs)cycloalkyl, or (Ci-Ce)alkyl, wherein (C3-Cs)cycloalkyl and (Ci-Ce)alkyl are each optionally substituted with one or more halo;R4is hydrogen, (Ci-Ce)alkyl or N(Ra)2;Rais independently for each occurrence hydrogen or (Ci-Ce)alkyl, or two occurrences of Rataken together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycloalkyl;R6is hydrogen or (Ci-Ce)alkyl optionally substituted with one or more substituents selected from hydroxy, (Ci-Ce)alkoxy, halo, cyano, (C3-Cs)cycloalkyl and 4- to 7-membered heterocycloalkyl; wherein (C3-Cs)cycloalkyl, 4- to 7-membered heterocycloalkyl are each optionally substituted with one or more substituents selected from halo, (Ci-Ce)alkyl, hydroxy, (Ci-Ce)alkoxy, (Ci-C6)alkoxy(Ci-C6)alkyl, (Ci-C6)haloalkyl, (Ci-C6)haloalkoxy, cyano, and N(RC)2;Rcis independently for each occurrence hydrogen or (Ci-Ce)alkyl; or two occurrences of Rctaken together with the nitrogen to which they are attached form a 4- to 7- membered heterocycloalkyl; andR7is hydrogen or (Ci-C6)alkyl.

102. The compound of claim 101, having the structure of Formula (Vila) or (Vllb):- 1322 - FH13180518.3GPX-02525pharmaceutically acceptable salt thereof.

103. The compound of claim 101 or 102, wherein R4is hydrogen, (Ci-Ce)alkyl or N(Ra)2;104. The compound of any one of claims 101-103, wherein R1is (Ci-Ce)alkyl substituted with (C3-Cs)cycloalkyl.

105. The compound of any one of claims 101-104, wherein R6is (Ci-Ce)alkyl optionally substituted with 4- to 7-membered heterocycloalkyl.

106. The compound of claim 105, wherein R6is methyl substituted with 4- to 7-membered heterocycloalkyl.

107. The compound of any one of claims 101-106, wherein R7is methyl.

108. The compound of any one of claims 101-107, wherein X is CN(Ra)2; and R3and R4are each hydrogen.

109. The compound of any one of claims 101-107, wherein X is CR2, R3is N(Ra)2; and R4is hydrogen.

110. The compound of claim 109, wherein R2is hydrogen, fluoro, or (Ci-C6)alkyl.

111. The compound of any one of claims 101-107, wherein X is N; and R3and R4are each N(Ra)2.

112. The compound of any one of claims 101-111, wherein each Rais hydrogen.

113. A compound according to Formula (VIII):- 1323 - FH13180518.3GPX-02525or a pharmaceutically acceptable salt thereof, wherein:X and Y are defined such that:a) X is hydrogen and Y is halo;b) X is N(R4)2and Y is hydrogen; orc) X is halo and Y is N(R4)2;R1is hydrogen or (Ci-Ce)alkyl optionally substituted with one or more substituents selected from hydroxy, (Ci-Ce)alkoxy, halo, cyano, (C3-Cs)cycloalkyl and 4- to 7-membered heterocycloalkyl; wherein (C3-Cs)cycloalkyl, 4- to 7-membered heterocycloalkyl are each optionally substituted with one or more substituents selected from halo, (Ci-Ce)alkyl, hydroxy, (Ci-Ce)alkoxy, (Ci-C6)alkoxy(Ci-C6)alkyl, (Ci-C6)haloalkyl, (Ci-C6)haloalkoxy, cyano, and N(RC)2;Rcis independently for each occurrence hydrogen or (Ci-Ce)alkyl; or two occurrences of Rctaken together with the nitrogen to which they are attached form a 4- to 7- membered heterocycloalkyl;R2is hydrogen or (Ci-Ce)alkyl;R3is (Ci-Ce)alkyl optionally substituted with halo or (C3-Cs)cycloalkyl, wherein (C3-Cs)cycloalkyl is optionally substituted with one or more substituents selected from halo, (Ci-Ce)alkyl, and (Ci-C6)haloalkyl; andR4is independently for each occurrence hydrogen or (Ci-Ce)alkyl; or two occurrences of R4taken together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycloalkyl.

114. A compound according to claim 113, having the structure of Formula (Villa) or (Vlllb)- 1324 - FH13180518.3GPX-02525or a pharmaceutically acceptable salt thereof.

115. The compound of claim 113 or 114, wherein Y is chloro.

116. The compound of any one of claims 113-115, wherein X is NH2.

117. The compound of any one of claims 113-115, wherein X is hydrogen.

118. The compound of claim 113 or 114, wherein Y is NH2; and X is chloro.

119. A compound having the structure of Formula (IX):or a pharmaceutically acceptable salt thereof, wherein:R1is (Ci-Ce)alkyl optionally substituted with halo or (C3-Cs)cycloalkyl, wherein (C3-Cs)cycloalkyl is optionally substituted with one or more substituents selected from halo, (Ci-Ce)alkyl, and (Ci-C6)haloalkyl; andR2is hydrogen or (Ci-Ce)alkyl;R3is hydrogen or (Ci-Ce)alkyl optionally substituted with one or more substituents selected from hydroxy, (Ci-Ce)alkoxy, halo, cyano, (C3-Cs)cycloalkyl and 4- to 7-membered heterocycloalkyl; wherein (C3-Cs)cycloalkyl, 4- to 7-membered heterocycloalkyl are each optionally substituted with one or more substituents selected from halo, (Ci-Ce)alkyl, hydroxy, (Ci-Ce)alkoxy, (Ci-C6)alkoxy(Ci-C6)alkyl, (Ci-C6)haloalkyl, (Ci-C6)haloalkoxy, cyano, and N(RC)2; and- 1325 - FH13180518.3GPX-02525Rcis independently for each occurrence hydrogen or (Ci-Ce)alkyl; or two occurrences of Rctaken together with the nitrogen to which they are attached form a 4- to 7- membered heterocycloalkyl.

120. The compound of claim 119, having the structure of Formula (IXa) or (IXb):or a pharmaceuically acceptable salt thereof.

121. A compound of Formula (Xi) or (Xii):or a pharmaceutically acceptable salt thereof, wherein:R1is hydrogen or (Ci-Ce)alkyl optionally substituted with one or more halo or (C3-Cs)cycloalkyl, wherein (C3-Cs)cycloalkyl is optionally substituted with one or more substituents selected from halo, (Ci-Ce)alkyl, and (Ci-C6)haloalkyl;R2is hydrogen or (Ci-Ce)alkyl;R3is hydrogen or (Ci-Ce)alkyl;R4is hydrogen or (Ci-Ce)alkyl optionally substituted with one or more substituents selected from hydroxy, (Ci-Ce)alkoxy, halo, cyano, (C3-Cs)cycloalkyl and 4- to 7-membered heterocycloalkyl; wherein (C3-Cs)cycloalkyl, 4- to 7-membered heterocycloalkyl are each optionally substituted with one or more substituents selected from halo, (Ci-Ce)alkyl, hydroxy, (Ci-Ce)alkoxy, (Ci-C6)alkoxy(Ci-C6)alkyl, (Ci-C6)haloalkyl, (Ci-C6)haloalkoxy, cyano, and N(RC)2; and- 1326 - FH13180518.3GPX-02525Rcis independently for each occurrence hydrogen or (Ci-Ce)alkyl; or two occurrences of Rctaken together with the nitrogen to which they are attached form a 4- to 7- membered heterocycloalkyl.

122. The compound of claim 121, having the structure of Formula (Xi):or a pharmaceutically acceptable salt thereof.

123. The compound of claim 121, having the structure of Formula (Xi-a) (Xi-b), (Xii-a), or (Xii-b):or a pharmaceutically acceptable salt thereof.

124. The compound of claim 123, having the structure of Formula (Xi-a) or (Xi-b):- 1327 - FH13180518.3GPX-02525or a pharmaceutically acceptable salt thereof.

125. The compound of claim any one of claims 121-124,, wherein R2is methyl.

126. The compound of claim any one of claims 121-124, wherein R2is hydrogen.

127. The compound of any one of claims 121-126, wherein R1is methyl substituted with C3-Cs)cycloalkyl.

128. The compound of any one of claims 121-127, wherein R3is methyl.

129. The compound of claim any one of claims 121-128, wherein R4is 4- to 7-membered heterocycloalkyl optionally substituted with one or more substituents selected from halo, (Ci-Ce)alkyl, hydroxy, (Ci-Ce)alkoxy, (Ci-C6)alkoxy(Ci-C6)alkyl, (Ci-C6)haloalkyl, (Ci-Ce)haloalkoxy, cyano, and N(RC)2.

130. A compound according to Formula (XI):or a pharmaceutically acceptable salt thereof, wherein:X is N or CRX;Y is N(R4)2;R1is hydrogen or (Ci-Ce)alkyl optionally substituted with one or more substituents selected from hydroxy, (Ci-Ce)alkoxy, halo, cyano, (C3-Cs)cycloalkyl and 4- to 7-membered heterocycloalkyl; wherein (C3-Cs)cycloalkyl, 4- to 7-membered heterocycloalkyl are each- 1328 - FH13180518.3GPX-02525optionally substituted with one or more substituents selected from halo, (Ci-Ce)alkyl, hydroxy, (Ci-Ce)alkoxy, (Ci-C6)alkoxy(Ci-C6)alkyl, (Ci-C6)haloalkyl, (Ci-C6)haloalkoxy, cyano, and N(RC)2;Rcis independently for each occurrence hydrogen or (Ci-Ce)alkyl; or two occurrences of Rctaken together with the nitrogen to which they are attached form a 4- to 7- membered heterocycloalkyl;R2is hydrogen or (Ci-Ce)alkyl;R3is (Ci-C6)haloalkyl or (Ci-Ce)alkyl substituted with (C3-Cs)cycloalkyl, wherein (C3-Cs)cycloalkyl is optionally substituted with one or more substituents selected from halo, (Ci-Ce)alkyl, and (Ci-C6)haloalkylR4is independently for each occurrence hydrogen or (Ci-Ce)alkyl; or two occurrences of R4taken together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycloalkyl; andRxis hydrogen or (Ci-C6)alkyl.

131. A compound according to claim 130, having the structure of Formula (Xia) or (Xlb):or a pharmaceutically acceptable salt thereof.

132. The compound of claim 130 or 131, wherein Y is NH2.

133. The compound of any one of claims 130-132, wherein R3is n-butyl.

134. The compound of any one of claims 130-133, wherein X is CH.

135. The compound of any one of claims 130-133, wherein X is N.

136. The compound of any one of claims 130-135, wherein R1is (Ci-Ce)alkyl optionally substituted with 4- to 7-membered heterocycloalkyl.- 1329 - FH13180518.3GPX-02525137. The compound of claim 136, wherein R1is methyl optionally substituted with 4- to 7-membered heterocycloalkyl.

138. The compound of any one of claims 130-137, wherein R2is methyl.

139. A compound according to Formula (XII):or a pharmaceutically acceptable salt thereof, wherein:X is N or CRX;Y is N(R4)2;Rlaand Rlbare each independently hydrogen or (Ci-Ce)alkyl, or Rlaand Rlbtaken together with the carbon atom to which they are attached form a 4- to 7-membered heterocycloalkyl or (C3-Cs)cycloalkyl.R2is hydrogen or (Ci-Ce)alkyl;R3is (Ci-C6)haloalkyl or (Ci-Ce)alkyl substituted with (C3-Cs)cycloalkyl, wherein (C3-Cs)cycloalkyl is optionally substituted with one or more substituents selected from halo, (Ci-Ce)alkyl, and (Ci-C6)haloalkyl;R4is independently for each occurrence hydrogen or (Ci-Ce)alkyl; or two occurrences of R4taken together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycloalkyl; andRxis hydrogen or (Ci-C6)alkyl.

140. A compound according to claim 139, having the structure of Formula (Xlla) or (Xllb):- 1330 - FH13180518.3GPX-02525or a pharmaceutically acceptable salt thereof.

141. The compound of claim 139 or 140, wherein Y is NH2.

142. The compound of any one of claims 139-141, wherein R3is CH2CH2CH2CF3, or cyclopentylmethyl.

143. The compound of any one of claims 139-142, wherein X is CH.

144. The compound of any one of claims 139-142, wherein X is N.

145. The compound of any one of claims 139-144, wherein R1is (Ci-Ce)alkyl substituted with 4- to 7-membered heterocycloalkyl.

146. The compound of claim 145, wherein R1is methyl substituted with 4- to 7-membered heterocycloalkyl.

147. The compound of any one of claims 139-146, wherein R2is hydrogen.

148. The compound of any one of claims 139-146, wherein R2is (Ci-C6)alkyl.

149. The compound of any one of claims 139-146, wherein R2is methyl.

150. A compound according to Formula (XIII)- 1331 - FH13180518.3GPX-02525or a pharmaceutically acceptable salt thereof, wherein:R1and R2taken together with the carbon atom to which they are attached form:R\,0Rais hydrogen or (Ci-Ce)alkyl optionally substituted with one or more substituents selected from hydroxy, (Ci-Ce)alkoxy, (Ci-C6)haloalkoxy, halo, cyano, (C3-Cs)cycloalkyl and 4- to 7-membered heterocycloalkyl; wherein (C3-Cs)cycloalkyl, 4- to 7-membered heterocycloalkyl are each optionally substituted with one or more substituents selected from halo, (Ci-C6)alkyl, hydroxy, CO2RC, SO2RC, (Ci-C6)alkoxy, (Ci-C6)alkoxy(Ci-C6)alkyl, (Ci-Ce)haloalkyl, (Ci-C6)haloalkoxy, cyano, and N(RC)2;Rbis hydrogen or (Ci-Ce)alkyl;Rcis independently for each occurrence hydrogen or (Ci-Ce)alkyl; or two occurrences of Rctaken together with the nitrogen to which they are attached form a 4- to 7- membered heterocycloalkyl;R3is (Ci-Ce)alkyl optionally substituted with one or more substituents selected from halo and (C3-Cs)cycloalkyl, wherein (C3-Cs)cycloalkyl is optionally substituted with one or more substituents selected from (Ci-Ce) alkyl and halo;R4is independently for each occurrence hydrogen, (Ci-Ce)alkyl, or two occurrences of R4taken together with the nitrogen atom to which they are attached forms a 4- to 7-membered heterocycloalkyl; andR5is hydrogen, (Ci-Ce)alkyl, (Ci-C6)haloalkyl, (Ci-C6)hydroxyalkyl, (Ci-Ce)alkoxyalkyl, (C3-Cs)cycloalkyl, (Ci-Ce)alkoxy alkyl, or (Ci-C6)haloalkoxy(Ci-C6)alkyl.

151. The compound of claim 150, wherein R1and R2taken together with the carbon atom to which they are attached form:- 1332 - FH13180518.3GPX-02525152. The compound of claim 150 or 151, wherein Rais (Ci-Ce)alkyl optionally substituted with one or more substituents selected from hydroxy, (Ci-Ce)alkoxy, (Ci-C6)haloalkoxy, halo, cyano, (C3-Cs)cycloalkyl and 4- to 7-membered heterocycloalkyl; wherein (C3-Cs)cycloalkyl, 4- to 7-membered heterocycloalkyl are each optionally substituted with one or more substituents selected from halo, (Ci-Ce)alkyl, hydroxy, CChR0, SChR0, (Ci-Ce)alkoxy, (Ci-C6)alkoxy(Ci-C6)alkyl, (Ci-C6)haloalkyl, (Ci-C6)haloalkoxy, cyano, and N(RC)2.

153. The compound of any one of claims 150-152, wherein Rbis hydrogen or (Ci-C6)alkyl.

154. The compound of any one of claims 150-153, wherein R3is (Ci-Ce)alkyl optionally substituted with (C3-Cs)cycloalkyl, wherein (C3-Cs)cycloalkyl is optionally substituted with one or more substituents selected from (Ci-Ce)alkyl and halo.

155. The compound of any one of claims 150-154, wherein each R4is hydrogen.

156. The compound of any one of claims 150-155, wherein R5is (Ci-C6)alkyl.

157. A compound having the structure of Formula (XIV):0(XIV),or a pharmaceutically acceptable salt thereof, wherein:Rais hydrogen (Ci-Ce)alkyl, (C3-Cs)cycloalkyl, (C3-C8)cycloalkyl(Ci-C6)alkyl, wherein (Ci-Ce)alkyl, (C3-Cs)cycloalkyl, (C3-C8)cycloalkyl(Ci-C6)alkyl are optionally substituted with one or more substituents selected from halo, hydroxy, (Ci-Ce)alkoxy, (Ci-C6)haloalkoxy and cyano;R1and R2taken together with the carbon atom to which they are attached form:- 1333 - FH13180518.3GPX-02525Rbis hydrogen or (Ci-Ce)alkyl optionally substituted with one or more substituents selected from hydroxy, (Ci-Ce)alkoxy, halo, cyano, (C3-Cs)cycloalkyl and 4- to 7-membered heterocycloalkyl; wherein (C3-Cs)cycloalkyl, and 4- to 7-membered heterocycloalkyl are each optionally substituted with one or more substituents selected from halo, (Ci-Ce)alkyl, hydroxy, (Ci-Ce)alkoxy, (Ci-Ce)hydroxy alkyl (Ci-C6)alkoxy(Ci-C6)alkyl, (Ci-C6)haloalkyl, (Ci-C6)haloalkoxy, CO2Rf, 5- to 10-membered heteroaryl, cyano, N(Rf)SO2Rf, SO2Rf, NRf(CO)Rf, and N(Rf)2;Rcis hydrogen or (Ci-Ce)alkyl;Rfis independently for each occurrence hydrogen or (Ci-Ce)alkyl, wherein (Ci-Ce)alkyl is optionally substituted with phenyl, or two occurrences of Rftaken together with the nitrogen to which they are attached form a 4- to 7- membered heterocycloalkyl;R3is (Ci-Ce)alkyl optionally substituted with one or more substituents selected from halo, pentafluoro thio, (C3-Cs)cycloalkyl, and 4- to 10-membered heterocycloalkyl wherein (C3-Cs)cycloalkyl is optionally substituted with one or more substituents selected from halo, (Ci-C6)haloalkyl. and (Ci-Ce)alkyl; andn is an integer from 1 to 6.

158. A compound of Formula (XXV), (XXVI), (XXVII), (XXVIII) (XXIX), (XXX), or (XXXI):- 1334 - FH13180518.3GPX-02525R2(XXIX), R2(XXX),or a pharmaceutically acceptable salt thereof, wherein:R1and R2taken together with the carbon atom to which they are attached form:Rais hydrogen or (Ci-Ce)alkyl optionally substituted with one or more substituents selected from hydroxy, (Ci-Ce)alkoxy, (Ci-C6)haloalkoxy, halo, cyano, (C3-Cs)cycloalkyl, and 4- to 7-membered heterocycloalkyl; wherein (C3-Cs)cycloalkyl and 4- to 7-membered heterocycloalkyl are each optionally substituted with one or more substituents selected from halo, (Ci-C6)alkyl, hydroxy, CO2RC, SO2RC, (Ci-C6)alkoxy, (Ci-C6)alkoxy(Ci-C6)alkyl, (Ci-Ce)haloalkyl, (Ci-C6)haloalkoxy, cyano, and N(RC)2;- 1335 - FH13180518.3GPX-02525Rbis hydrogen or (Ci-Ce)alkyl;Rcis independently for each occurrence hydrogen or (Ci-Ce)alkyl; or two occurrences of Rctaken together with the nitrogen to which they are attached form a 4- to 7- membered heterocycloalkyl;R3is (Ci-Ce)alkyl optionally substituted with one or more substituents selected from halo and (C3-Cs)cycloalkyl, wherein (C3-Cs)cycloalkyl is optionally substituted with one or more substituents selected from (Ci-Ce)alkyl and halo;R4is independently for each occurrence hydrogen, (Ci-Ce)alkyl, or two occurrences of R4taken together with the nitrogen atom to which they are attached forms a 4- to 7-membered heterocycloalkyl;R5is hydrogen, (Ci-Ce)alkyl, (Ci-C6)haloalkyl, (Ci-C6)hydroxyalkyl, (Ci-Ce)alkoxyalkyl, (C3-Cs)cycloalkyl, (C3-C8)cycloalkyl(Ci-C6)alkyl, CN, CO2R6, (Ci-Ce)alkoxyalkyl, (Ci-C6)haloalkoxy(Ci-C6)alkyl, C(O)N(R7)2, or halo; wherein (C3-C8)cycloalkyl(Ci-C6)alkyl is optionally substituted with hydroxy;R6is hydrogen or (Ci-Ce)alkyl;R7is independently for each occurrence selected from hydrogen and (Ci-Ce)alkyl; and X is CH or N.

159. A compound of Formula (XV), (XVI), (XVII), (XVIII) (XIX), (XX), or (XXI):- 1336 - FH13180518.3GPX-02525or a pharmaceutically acceptable salt thereof, wherein:R1and R2taken together with the carbon atom to which they are attached form:R\,0s< YhHRb(a) O; orRais hydrogen or (Ci-Ce)alkyl optionally substituted with one or more substituents selected from hydroxy, (Ci-Ce)alkoxy, (Ci-C6)haloalkoxy, halo, cyano, (C3-Cs)cycloalkyl and 4- to 7-membered heterocycloalkyl; wherein (C3-Cs)cycloalkyl, 4- to 7-membered heterocycloalkyl are each optionally substituted with one or more substituents selected from- 1337 - FH13180518.3GPX-02525halo, (Ci-C6)alkyl, hydroxy, CO2RC, SO2RC, (Ci-C6)alkoxy, (Ci-C6)alkoxy(Ci-C6)alkyl, (Ci-Ce)haloalkyl, (Ci-C6)haloalkoxy, cyano, and N(RC)2;Rbis hydrogen or (Ci-Ce)alkyl;Rcis independently for each occurrence hydrogen or (Ci-Ce)alkyl; or two occurrences of Rctaken together with the nitrogen to which they are attached form a 4- to 7- membered heterocycloalkyl; P P.R3is (Ci-Ce)alkyl optionally substituted with one or more substituents selected from GM / - \halo and (C3-Cs)cycloalkyl, wherein (C3-Cs)cycloalkyl is optionally substituted with one or more substituents selected from (Ci-Ce)alkyl and halo;R4is independently for each occ 1urrence hydrogen, (Ci-Ce)alkyl, or two occurrences of R4taken together with the nitrogen atom to which they are attached forms a 4- to 7-membered heterocycloalkyl;R5is hydrogen, (Ci-Ce)alkyl, (Ci-C6)haloalkyl, (Ci-C6)hydroxyalkyl, (Ci-Ce)alkoxyalkyl, (C3-Cs)cycloalkyl, CN, CO2R6, (Ci-Ce)alkoxyalkyl, (Ci-C6)haloalkoxy(Ci-C6)alkyl, C(O)N(R7)2, or halo;R6is hydrogen or (Ci-Ce)alkyl;R7is independently for each occurrence selected from hydrogen, (Ci-Ce)alkyl; and X is CH or N.

160. A compound selected from the following table:Compound Structure Compound Structure1 364\ 00 NH O. S- 1338 - FH13180518.3GPX-02525 2 H\, N., NH2365 < / NH2° 0A TA.0A? 0 AHc / X p’?Q L VoM / - \3 366 < / NH2^A0o1A A HQA04 1 367HN NH2°^PP^0rNYN'-n-< A0zM A~~N H0^ _0o \xy 5 368 A^ NH;,HN^NH2O^Al z0 PX.-N Nz,A n [ oF 0AA '" V"l A^ N — < \3Z CM fl " 1 N—“ bp3 °- 1339 - FH13180518.3GPX-02525- 1340 - FH13180518.3GPX-02525- 1341 - FH13180518.3GPX-02525 15 1 378 OHHN NH2Y / NH2F3CY [ | o A ' c^0P Y OH17 NH2379H2N^ _NH°yL°C-<, N., N,_ / V0HV\ZYN2, / \ Ao FO Y r 3Y i Y Y / 0U1, N'" Y >° '" T >°< YN\18 NH2380H2N NH k / NH20V V0°V Y° IY YY / \F / A Y Y Y. YYOHVYNVN„.^0YKJ Y 1 1^. p° Ji '" Y >0oYN-—p19 OH 381 OHH2N NH YNH20 JyO °V V°Y -'Y O Y r c w.o„FV- 1342 - FH13180518.3GPX-02525 20 OH 382 OHH2N_, NH Y-NH2°VV°OYY° / " OY I L.< -r ov. '""j )=OYNo \ YFC21 383 A ^NH2H0Y°v v°L z 1*Ccjr / > o22 1 384HN NH2 / \ / NHHO y2Y |. N=\0zNY\0VQ23 1H2N NH 385z— A / NH2O^YL zO Ox^Zx^O r\Q0LANA Y°V24 IH2N^NH 386 ^Y, NH2oYL ^o N / „ / \FAL / NXZN'-YZ'X O n 1 A I 9IF 1'"'T ' N—zNY Y '. oFCCo- 1343 - FH13180518.3GPX-0252525 387Z:XX^NH2O^Jk^0x\, N,,1iFV26 1HN^NH2388Fs_N., N,,0'Cu N::^p z27 NH2O )N < - 389HN NH2FsCx^^NyN,,.028 H 390^^YN"'O ^C°o Lzr'^~ / \c-r >o ^Y'Qvt < A A \ 0HN~^ 0Z- 1344 - FH13180518.3GPX-02525- 1345 - FH13180518.3GPX-02525- 1346 - FH13180518.3GPX-0252538 400 L. NH2o^-X^oo,, / NX,N / , r^9 F'' ' FL \ U r ^1\=O N= / 39 \ NH2401' - / O °i°=\ ' M" / . <>.. M ’'""\ N— <NAH0 / ^>0p OH 40 \ NH2z402p o°=\ ' iR / \ ZN^4 ' - / ' / NX)FX>- CXO.1 xN <± o. ZzA *-o '"'T N— k J oo ' HOJ0LL?6 OH41 NH2403[> —zp o ^\ / NH2° \ ' 'j" ( jiK / X / N^VV~ / OFX>- oLo / M k00A°H42 NH2404[> —zp oo^^JL ^o°=\ ' M" / y^\ i. <>.. M ’■" r •FV< M / -< \0\ / o o k- 1347 - FH13180518.3GPX-02525 43 NH2405 / \0=\ N" / A A 1x—z'',NX)0- 0*-o AYA,.P OH44 r° 406NH2) — '>-Y,9 \ °Y V°o=( N'"< / f A A7\ N — ' - N \\z — / ° < AN,A n°°45 ' — \ NH2407zp 0 O^yL^O o=( ' 'J" / V^A ' J*FP YA r1 / H* ' / P C / " ' o (NN <01Qk 1 o / \ oLL?L 49 OH 46 408 ^-V X-NHS°Y V°O>^N N,, PAOHF" T Y [ A A0M^LN -> A >° N / 47 \ NH2409 t- < / NH2' —zp 0C^YL Y}0\ ' 'J" / j*X ” A,- 1348 - FH13180518.3GPX-0252548 \ NH2410 AHO y, NH22O^Jk^OF FA49 NH24 h"[> — p 11 A / NH 02H0H1 I SOH0\ ' 'j" / j*T ” A,50 NH[> —2p 4120 ^-NH,HO Y20°<^YX°\ ' 'jY" / j*Z\, M "yNY xPx / N^N'.. / \F< ¥ \ V, ¥0¥0F F51 r° 413 / ¥ / NH2\ NH2¥ —1H0H'Y Y ^, P \oHW GA A ON¥=< N'"< Z Y T F' U'" \ \=0 Z \ \> ’| / / N^n o ' 0 "XN^ / F F52 r° 414\ NH2¥ —1A _, NH,HO Y / P \ o^ J¥>oo=( N" ( / Y T C^ / N Nz / .F' ¥ \ K, A2H >N- o ^-¥VNXF F / N^ f 0HO *- 1349 - FH13180518.3GPX-0252553 \ NH2415 AHO Y. NH22 / — \ / — \ Xo=( N" < A A 1 / \ ~ / NAA10 / 'OH 54 416°XAA°h '- 0Q. / / Xn 00F 55 r° 417NH2F-J — 1o, ^■-z, AH / P \2x1 INA° O^J JL ^O°=\, ZZ, XN'"< A A IA XWXN- < / / °—10 0F FA0 5 F6 418 r°NH2F-J — 1AH2 / P \NA° °vA° O=< N" < X X IO,„ / N N,„" Vx f" I CX1, VN\>=0F F0 \ F 57 419 r°\ NH2J —1Z-X>. NH2 / P \N^Z°0=\N" \ A A TN — ' — NX / ^0F FA">3- 1350 - FH13180518.3GPX-02525 58 r° 420 F\ NH2J —1 / P \N^°0=\N" \ X A TN'F F.rA t QSo zN~L: 0 ^^ OOZ'^OH 59 SMe 421 FH2NS- / ^-X^NHs0=\ 'N"<( / N~4X',N^oo- ° ^X oLo1 'OH 60 422 FX NH2oXL ^o61 HO NH2423 Fzp 0X NH2o=\ ^ '*" / y^Ck' / N^O0- 0 X-Q, N., N,, Ay-0HY r A / Lo0QTIN -O'T ^=0 0 \ 62 HO^. NH2OH424zp O / L XNH2QX-L,0°=\ 'j" / y^Qi N,, ^< Z\^OH +F' Q [ L rX / O- 00M-y'T >°Lo- 1351 - FH13180518.3GPX-02525- 1352 - FH13180518.3GPX-0252568 FX NH2430]>—zp Ov V °=\ ' M" / W ",NAO- ofoy z z —.I o o \69 F, NH2431 A. NH, / — C / ? °\H0iT°=\ ' 7~,NA O-. / N N„.F' A 1 U° Vj0A-XVL0zN-^ kx°OH70 F NH2432p—zp o ^NH,H0HO= / 'N / °Xv°\ "'\ X X 1 5r-V^ / ~N\ / N,, / ^^ Z\ W,NA)0HF4 Y \0-AIN ° v> -'" r ^=0L-o0 \71 F,NH2433 / \ ^NH2H0H0= / ' / \N" \ X X I7\ N^oT •\ 0OH72 NH2434 YX^NH2^""'L z'0O^XL ^O o=( ^ M" / j!'''',NA> +- Y CMXFU AL °V- 1353 - FH13180518.3GPX-02525- 1354 - FH13180518.3GPX-02525- 1355 - FH13180518.3GPX-0252582 * NH2444 / / °0L / N H2HOAA / A / SA0=\N'"\ A A I,NA)° Vj ^ r-QvLoP.NA r° 83 H2N HA 445O N> / — < k / N H2^A0oi / M o NC''84 446 FX NH2oXY>oNz,F" A n [ A° XYLNA85 P-A ^NH2447 ^Y. NH2O^JU^OF\F1 1F'^X^N N„.Pp-Y^rvF^yQpvANZNY* oF- 1356 - FH13180518.3GPX-02525- 1357 - FH13180518.3GPX-02525 90 452 ^k / NH2JPs^Nx / N„.^^0 / N^ HO / ,y__ ° / )o P > \ / K Z Z % Y—— / - C^ )((< ) ° °==== X X z z z z——91 > ZE V ■L, NH O °2, — y / - \ 453 X / NH2NYYP-, / N N _0>^'NXx'N'-H<\Z''> F< T |F^A p° c x O-v A° ° JI \^o '""f ^ N i 1— N^= / r°92 454J\ / NH2p ( J0zN^ HO*J _0\ / °93 455 A^NH2Nyk^o O^N N„.^xT \ pF° \ JI'"'1 ^ N—J- 1358 - FH13180518.3GPX-02525- 1359 - FH13180518.3GPX-02525 98 A, NH2460 J\, NH2 / X X. AIA V O ° °° °vYoo \ / \ °^ o k YA 11 O? N < - 7z'—v ) A= Ak A k k 'sr° AN 'o99 A, NH2461V Oyl^OA yn. oo k YA 11k100 L, NH2462 XAXNH2°YV°NIl'sk I\P^° nAvNA / T \ k. p FAFY, k o k< A JI 0LXVk ''"’X N— / A Y^ H(k f? k 0 $101 L, NH2463\Nrkk ° V ANkH°iY ° \ 1 1 OH oW o knA\ J oi G-TC^''"’X N— / s$- 1360 - FH13180518.3GPX-02525 102 Y.NH2464 1 o ^ J>° / \ -O ~ 1 / ^Y z - °z° C'V'Y1Y 3 H— O \ Q O^N N„. / \ T rX O-1''F7 n \ oF° Y< VX O OJ O O.? Nq < e - ' - 'y z z— y y z z 2 z — — zNY ccC > > > > Y°=°==k °3 OH Y Yi.103 Y.NH2465°<iY^°O-.^N Nz„F7 T | oF° Y< Vx'""1 ^ N—zNY1 °3 OH104 Y.NH2466YX<NH2 O^, N N„.F< Y 1 1 ^. °F° YYYVXF^“rOV.zNY Y *Y0k ° / ''OH / 'OH105 Y NHJ 467o^YL ^oV-,z / N N„.F1 Y | OF° YYYVA'"'l ^ N—ZNYk ° / 'OH- 1361 - FH13180518.3GPX-02525 106 4680V v° UFF IT ^Y \ U 9N—0107 469 [X / NH2N Y^yoFXT V [ 3,0Y-KY ZO.x< V Y °= °°^^, Z zx A— 0££ } _ oi — 'y z z z—)\C > > >°°==108 NH2470d [> — 03<< °==O _=y( \ N" ( / \ K^X. / 1 NX / \ / NY ' / NYD0L- 0 f.o 109 471^x / NH2NV x°F-T T r xF0 Y< VNX / yNY o>QYOH- 1362 - FH13180518.3GPX-02525- 1363 - FH13180518.3GPX-02525 114Z-K. NH2476 1 1 ^y o>° °dZV°\ / / \ I A\ ° ° —"" z. O O d )JN C <' - ' - y y y z z z z — — —vvv ) ) )===00% 1115 477V^y ov ox°°x°zz°££ } J\ T _ O _ Oll ' - - ° ' - y y zz zz y—— zz—\\z> > > >v°°== >= / I / / o116 o 478d LL? d %>- J=\ z z—f OM- / 4^o I117 479- 1364 - FH13180518.3GPX-02525 118 ^ 480 \ NH2A, NH2H / 1 / N=\ Ni ' < X X T I I,o. N^< N-% \ o 4 ° X-HJ-"• r y=o F F / / ""V^On n119Z?? Z Z——, - / - -XX / NH2481Xx M M / = / = \ NH2\ \'' I IT O O K c c w / — / — O- / C N=< N" < M KAAM X^N N,„ 1 ( ) ( ) 2 \ / W - VNXn I \ / \ / O o, _ ° x / ° X<7VJ / -7 0 0V ^?*z- F F^^AA°° ( (HO40120 482 Y~~o \ NH2X^ / "" / F~C / P \N^° N=< N" - < X X 1 \ / W - yNxy>— 0 0 F F121 483 \ NH2H-XN=\ N" < X X 1. N^o\Z ^0F F / < *V^o- 1365 - FH13180518.3GPX-02525- 1366 - FH13180518.3GPX-02525 126 / \<NH2488 J\, NH2i Y / ^ o°z0-X r? Z-2YA'"” ^TQ AvtF 0VTLN y z z—\ f ° — '"'L >° < A \ > >°=HO 6' "127 / -X^NH2489zo.Y / £ J _ ©l - ' HOy zz—v > >°=128 490f^NH2A?FP-NYN'-r>F 0M" VNF'"'£ >° o \129 / '\<NH2491Ar Ny^yNHoi■ Y Y,»'""\ N— AN> ° 0 HOPx O- 1367 - FH13180518.3GPX-02525130 \ ' — NH2 z492p oN XjryNH!o=\ ' 'J" / W,NA JP^N N„.\z — ° \ F4 j r p o OF°HxX'>" V"1 ^( N — zNX K Z V <— o ((pp ) J ° °==X X Z z z z——? O r - / 131 \ NH2f f O —,7493' — p / I \ O ^k^NH2\yo_" >o=N<;^A^O\ 'O,NP ^C / TZ,NA\z — ' ° \ FWF-'NY0 N''P XY- Y1LN / "'^HHO ° \ p=OF< ZNX132 494NyX^O0rC-F 0M^LNP '"'I >° o \133 495 YN"2NyXyOF4 O^, N N„.Y \ 1 ^. oF°xX'>" V'T ^( N —Z?NX O PoH134 4960=\N" \ A 1z\ / N—4 ' — / ' / N” <) Y YP-N' YXN'-A [ A Y <x / ° ° \, FF 0-'" r yo \ / ^Fop- 1368 - FH13180518.3GPX-02525 135 497 1N / Ni o / ^ ' — / 33\z — ' °y z z—\ T ° '" F \ > >°=<■136 \ NH2498 ^k^NH2N; - ')NrQ>, XF 0VTVN \Z —0'' '"1 >°137 499r^xY'NH2Noz) \AT >° 6 °138 500Ary n<N. NT _f N,,° Ay"s\ F< T I ].F 0VTVN N '" X >° (3 ) \\ — T~7 / " AA( >°y- NHOx- 1369 - FH13180518.3GPX-02525- 1370 - FH13180518.3GPX-02525 x / O Y O' 143 H2N CI 505X\ I ° 'X zz ' fX,c x >°=l A / / '^0Z'S Y 0144 H2N CI 506N,„F< Y.F°L"-XVNX - CL / 4 O 0 W145 507c O. N / \ A< UY<^0XF< Y I L. / XX F oUL XYLN '-v" Y >=° N= / 146 NH2508 / y zp / X^N„\Z « I 1 O° \ JI'""1 ^ N—Y147 Cl NH2509ArNH2■Y -OM '""\ N— X xYO=, S^ Y 0- 1371 - FH13180518.3GPX-02525- 1372 - FH13180518.3GPX-02525 153 NH2515N^ °CF3 ZN^ 0154 NH2516 xik^NH2r\ T T,o ^ v-' c^CF3O \155 ^£\ _NH2517rX^Y'N H2 XY'x -N. _, N„ AOY | F< Y [ A.-»IT y=o0YN0 \41 ^X, H " A o' °56 N2518N^J-k^oN AyYN^HO2kkNN„,Y i p0^YYA ' ■ I ' CX, AN\ 0OHA- 1373 - FH13180518.3GPX-02525- 1374 - FH13180518.3GPX-02525 161 523Y^ --O N YYoFp. JYInVyF 0< YVN yz.z.— -\ X ° - '"'L >°162 524 Y ^k^NH2< / = N JY)z z \—° / — \N=y ~ o> / O / L / <zo 4 oW163£y oy 525y z z y— z z— JvNH2v > >v N YY>°= > >°= o h t O..,^N Nz„FF v \ Y.F° YYLNXY164 526N< SJL^ON / / X.Y | |. oo''"" I N'y- 1375 - FH13180518.3GPX-02525165 ^\. NH2527JY VXN N,„T [ ]. o0YYrVA / NY0Y166 < Y J °=Azz- 528 ^Y°” “ / — \o Y Y QA / Y<O / L o o 4W167 ^\ _NH2vr p529NyJ-l_L A x; o — 'zD ^VYN y z z— YYN,„V > >o= Y i o 4Y YY0YYVY YY''""1 N- '"'t >° % / M3 0Co168 530 ^YYFP-"YInz / „„Y'"'t >°169 NH2531Cy^F3C^^^ / N N,,. / \Z T QVJA, n / M0 1- 1376 - FH13180518.3GPX-02525 170 NH2532 X4'XTXNH2N<xX^0^ ''Nrw° XV LN'"'L >°o \171 533J\^NH2^X / NH2 N^JL^O T \.,o T Q 'o W. N^. N,, / ^CY [ i^.F 0M^N' '"'I >°0MfT, N 0 \ '»’< \=ox- <o \V X^rZ--'172 534J\. NH2^X / NH2NXJL \\y z z—^ _L. * Q V )> —° 5-^-,, / N N,,.^ X?SC F< Y ( V < Y / 'O O^vN ) >°= N,„ / xF 0M^N'?x- Y i o '"'L >° 0 \0'"’3 N- 4 °173 535N AyXr^O 3X QVY»- 1377 - FH13180518.3GPX-02525 174 536J\ xNH2„ p■ P -Y CH? Y0^ ^ VN\ p 5.Y ° V175 ’ ° p, 537 / rNH2J z.YT OVP176 538J\^NH2% ^Jx<^= / N X z zH —2N^Ul ^XD° / — \N YL.0Fp. JYInAoF 0<^VN ^Y'O-vP '"'L -Vf \=O n ' N=V177 539J^NH2NJLO'^ Y'C^ Y- 1378 - FH13180518.3GPX-02525- 1379 - FH13180518.3GPX-02525- 1380 - FH13180518.3GPX-02525- 1381 - FH13180518.3GPX-02525- 1382 - FH13180518.3GPX-02525195 XXX. NH2557N Aylkr.0 FSC^^N^N,,. V-^, N N„.F'lp Y \ 3 00F 0\XT VA LAtN '""l ' N— '"'LfNS >°o \oHO6°196 L?v 558J\<< °= y= YH2AXY-NH2NX z z—, V TO- \ / O^N N„.^FT0[ L- / <^VN X^~ o s- '"'L >° '-Y'' ChvorO _ _■Y197 559N AykrN^HO2T | | _ pF 0XY '" V' 1 A^ N—ZNS0198 560J\ / NH2,, -Y-'‘-r oyY5f199 561N< Uk^>o,, Y-3n 1 1^.0 L'x'^CVN\5fFz>0- 1383 - FH13180518.3GPX-02525 200 Cl 562 Jx^-N^Jx / NH2■?-T Cw A°T i0'"'T ^=0 5fo \201 Cl 563JX / NH2,, ‘t1’ Nx OoN,„ / K '5s' CW, Y | L. 9 1 A \ 0N0'""(^r o° N- / X rT^°oy°H <NzYX\ / ° - pZ. Z-- ■' 4 ”y\ )°= u.=202 564 JXXNH2o^Y'O^A \ 0NOY°H203 565^kx-NH2 AX'NH2 NyYo Ox^ TN^Y N,,° / x, Ox, N^N,, / XNC\ACFT0[ A / ATVN n i '"'t >°0< Z '»"j y=oNXO \- 1384 - FH13180518.3GPX-02525- 1385 - FH13180518.3GPX-02525209 0 0 571^X / N H2H2Nw 1 A N'"< Y XT Y°1 0 H F< Y I L. / Fo LY^V N F3C NY \=O210 0 H 572Y\ / N H2T F N" / x X TNyAy \ _ / \<Nx CjJCjY\ 0 ozFp-vr>,Fo VY '»■L■[N \=o F3Y NY2112 X / A 573 HO.H N / ^ 1 1 ^k / NH2\Y / — \ >< < N^ 0°1 N" < A A 1^YYY100 zYk0oXoH212H N574 OH 2 x JrY^' pN?\NH2N F Y-TY-N Y N„. / Y* nFrY w -NAOF 0YYVN -> Y Y° N=y F h213 NH2575. OHHN- / O 0ArNy^yO<\ / N^ ' — / / N^o T \ Y.Q- ■0^YVNS1-0 \ 0F- 1386 - FH13180518.3GPX-02525214 r° 576. OHNH2) —1HN— / O ( Ar Ny^yO 0=k yu MX=\,N'"\ A A I T I 1^, 0FoN— Ly — ' °0zNX 0 < p I F z z X —215 H \N— C / / N O 577 JDH / ' / / 2= / — \ rAXV'NH2 O=( N'"< X, A IO- o^ ^^-rz ■ Av c^ L-O^A° o■P OH216 578 OH jxyNH2 H2N—XN (>=( / — \ yk Ny°O=< N'"( K N JFr T | |. p AJHWrN-F 0N— [ ) — ' 0 0n217 579 yOHH2N— vXN 0 AX / NH2 ^ ■■ ■orx PvNvI — \ / N^( ' — / / NX) FTLN'-y>T 1 1^. PF 0N— A^0218 580 X.-'OHN^JL ^O ^ "rcyoOH- 1387 - FH13180518.3GPX-02525- 1388 - FH13180518.3GPX-02525 224 586 \,sOHrYNH2Ny^yOO^, N N,,^.Y | 1^. oF 0N— T"' coZ o o v\ / \ / ZE ZE _ _) ( f 2 N> - 225 XNH20 0 587 yOHAN^LyNH2NNyX<V / 'O^3w" " A.'5w.P;oX - zz—\ Q)^Zx o226 588 HO^ / ^k / NH2N< JL^OFY N„.^^ / xFY0\ << / / 'OH XK ->"’fN \=O N= / 227H0 589 HO^ / N 2 HN^z>° r^VNH2N"N< JX; O1 || ’< A A 1N< Jky \ / VNX] Q> FY Y0\ ] _ M^NV<NY F3CT / 'OH 228 590 HO,, / FY Y01 1 ^, < Y / 'OH XX '>"•[N \=O N= / - 1389 - FH13180518.3GPX-02525229 591 HO,, / r^VNH2F< T I L.0AXN <NX 'z— n~ \Vz / 'OH \ / i _) (M—230 HOOC NH2592 HO^ / r^VNH2W Ao F'lp I [ 3 0 0- 0F 0N— L-O / ''OH231 HOH2C NH2593 HO,, / r^VNH2 tAkA xz\ W Ao F'lp I [ 3 p 0-.S;jF 0N— / ''OH232 594 HO^ / ^X^NH2 -E-oA / \ / A ' — ' A°0- 0*— o ■F-I-CM 5r233 595 HO,, / ,< A / NH2nAL ^o Eft oA t / \ / A ' — / ,NX)*-o(-HV- 1390 - FH13180518.3GPX-02525- 1391 - FH13180518.3GPX-02525 239 601NATNH2 / N-',NX)O- 0FP-NYN''f>°Lo / N^ 0 240 H, N— fXN 0 60241-o^x / \ / M / 00- 0 Y [ L- / M V-""f \=oLo N= / 241 H2N^, N^, NH2603\ H ri^<NH2T | ] p. P-V-y-V,0V N— \=0N= / / sV242 604,N=<fH2N— \ N 0NyJL ^°P V V°. N— / sN^oPY o- ■> 0L0243 H 605H2NV»N°NyJL ^°Jr^N N,F< Y I I.o=\ ° / \ / H,Nx)PY0- « y, 0Lo- 1392 - FH13180518.3GPX-02525 244 606CX^N N„.A -OO-’X Y0[ L-.MX" 0- <■ xI— 0?OH245 607N^X^OH2NX^'N <FP-NYN''f> 0=( N" ( A A I00246 608H2N— x (' N 0OX° < X>oXxZ\ / NX / 0rP -NYN- ru 0- 0L0 0247 E NH2609 ^k_<NH2NXX° tX^NFn [ ] _ o A W,N00N'' o- " X ZN^ 0 *-o HO A 3i 0248 610 ^k_<NH2H2N^N J* o NXXOL N"" / yAs / A / O „, / N N„.Fn f o Tl "0'"'X ^ N"Fs^ zN^ F'JFH°X 0- 1393 - FH13180518.3GPX-02525- 1394 - FH13180518.3GPX-02525- 1395 - FH13180518.3GPX-02525258 F 620Y^Y^ -oo Y, NH2o^YL ^oY<- y\\ T I } y z z z z—— ° ° / — / P rcw \ Y\ > Y°= / v\zwY1o rOH259 621^Y_, NH2Y0- e O" oYYo zY) P-NYN._ HO^ 0% / N., N.„ / xOw o=^O -0YY -"■VfN y=o • I CM N=Z4"""\rOH260 622L, NH2°VV°O^N N,„Y 1 o0YY^A Jl''"' T N-Q00261 623rY'NH2nYY^o0.,, / N N„.F' 1 L o YYLNHY °- 1396 - FH13180518.3GPX-02525 262 624,, -7z\ W,NA)\z -0- 'TCh??11 o0263 6252— < ^NH2A“n 1 1 r0H-p'i ' cn6 / Mo264 < / NH2626CK JL^°NV >^°P -, / N t.F 11 \ \^°Ak0zN^ f 0 %zH0' \ OH265 < / NH2627CK JL^° ArO r°" F J f P. / "' \> H ' ^ V Qy ° VTVN ->■■■[ \=o N= / A266Z-PX^NH2628rPv'NH2o^ JL ^oNpP>°O.„ / N N,„F 1 1^.o'-. o'- 0 HO^T OH- 1397 - FH13180518.3GPX-02525 267 L -NH2629 1 oUlyO N< JY> O xV - °° N,„rA’"' v0n \ pJi\ i ° —y z—z)\ Y° r° )r^ ~=268 630AY / NH2YNH2A °YY P.„ / N N„.F' Y \oAN< / NY>kx° 4 °OH269 Y-NH2631 ^Jx^NH2NpY0CAF' Y 1 1^.~VQV0VTVN -" Y >=o op270 632L ^NH2°pP°N„.Y T [ i. pCF30'"'TP271 633 ^X^NH2Y. NH2NyPo0oV v° P-Y^ rCA" Y n [ ]. pCF3° YYVA'■■" I N-- 1398 - FH13180518.3GPX-02525- 1399 - FH13180518.3GPX-02525 277 639c?>2,.. rev?278 64011 1^y o^y- o°z^^^3 z / — J r \ r \ / '0^ Xz° J* —r fz°“ / \ o“" / \ zO. N C - 'y z z } — O O O.. NMM C C C - - / - 'y y y z z z z z z — — —v >=279 vvv _j _j _j / I #z> —>*=== 6413> / NH23 3 3 <= / ° / - \z^ 0NY~ ' o 280 642N Ay^yNHO2P-NYNr. y4« o MrU)^O N=V- 1400 - FH13180518.3GPX-02525 281 643Y> / NH2O,„ / N N,„F' Y0\ Y.\Yl^ / MV' 282 ^Y, NH2644YY-NH2 oYY>onYL ^o O,. / N N„ P -, / N t.FT n | |. F Y.0ZNY>0 r Y - °d / OH283 HO / , / Z-ks. NH2645O. N < - oY^O YX / y z z—NH2nYL ^o Pv\_ ^) >N°=F< v YN'^ \ Y* O / / / / N N„.Fo YVN^ F Y | Y d0PYN Y °F / OHOH284ZYVNH2646 HO* / oYY° Y^-NnzNYL ^OO / / , / N N„.N== / F Y | Y0PYNF OH285 Y, NH2647 HO,, / O^^ JL ^O JX.NH2rY 1 I i — r0HNYY>0Y'T' ^Y " N^ / ^°- 1401 - FH13180518.3GPX-02525- 1402 - FH13180518.3GPX-02525291 653 HO.Jx, NH2] [ I — r-OHNv^<°rO., / N N„.N^ / ^° F n \ ]. p0\^T '" V'Y^A N— / M k0O^OH292 HOL, NH2654.N^UL^OO-., / N N„. O,„ / N N,,. / ^.FF 0N L F'0 i ^fVN ( 0N^ F4F° F / ''OH293 ^\ N2655 HO., H^k / NH2 O^. Jt.0M^j Jt^ON / zF j T flF0 ^CVNx •° '■*” o=| - Vfr294 HO.^x, NH2656JX.NH2 o^ JL ^oFp-V-n,0P-Y-'Qy^”°o- 1403 - FH13180518.3GPX-02525295 <XNH2657 HO.X. NH2NPL ^O0P., / N N„.'"" I )=o F 1 1^. N=s / 0 LX-PVNXkx° OH296 <XNH2658 CF3PV'NH2 MPL ^OFp k \c? CP / N N„.n i |. p '"" I )=oN=s / 0'"'l ^ N—4 ° } O O. MN C < F ' - - ' ‘297 y yz z z^— 659 OHv_ >< > > P°°== rA / NH2MPL ^O Ck^N N„.n i |. p0'"'l ^ N—4 °298 660 FFPOrPv'NH2NPP>0CP / N N,„I 1^. p0'"' 1 ^ N—X- 1404 - FH13180518.3GPX-02525 299 66 HO.^\, NH21ZX / NH2 NZL ^O CV / N N,„n \ |. o. - w0'"'1 ^ <N^\ 0Y;. V 3 M<’ZK ~Z—.- 300 V Io / - \ 662\X O —z \VOZZo oz^^Y^Y ° °°°A Vi -S'o / V —x" / \ T °\\ X O. M C - ' - 7 Z 2 > — zZ^301 v > > 663 ^0v > Zy X z —o ZC)lp. NZZOCk Q^pyN N,„( Y ° O )==\ | |. o0xYYYY °■ “ / — \ZCZ* oz AZ>°< o 1 302 664 XYA01 Y YYLN'"'t >° oZ- 1405 - FH13180518.3GPX-02525- 1406 - FH13180518.3GPX-02525307 669 ^k / NH2F\F N<53 F° C\^N N,,.F7 n 1 L. 9vF 00N—0Vo' NH308 ^\ NH2670 ^k / NH2o^ JL ^oF\F N<53 F° C\^N N,,. V '"' / NYN / '-<>F7 n 1 L. 9F 00N—ZE \ / M 0 5^yo° 0z\O A'_.r ZE Vo' NHO. N C - 309 y z. z — 671r#=^'V'NH2 v >=Y -v-rvFF0MA-N.z1^ 0310 L- 672r#=^'V'NH2C\^, N N„FF n \ ]. o 5r^V'' ruF F 0 k''' i '"" I N— -yN / M z1^0 V HO / '^OH- 1407 - FH13180518.3GPX-02525- 1408 - FH13180518.3GPX-02525 315 ^Y.NH2677 o Y^o o J ovQ Y _ z Ly\_ xYY O —Z^ JP^N YF o F< Y n |Y'0y. zz.——\ X\ x\ X ° ° ° - —y yzz - } — y z z—\ T ) zi— ° - \\ > Y > Y°°=1 o _JT > M\° > Y°=="yyrPtP - - J ( o o o^03 LL? l_L?316 678 ^\ / NH2F‘c^N'CYy iY^?°\ i ruO. N C - 317Z-X^NfH y zz. o—2' (I 679y z z —o,vX_ ><2 >< >°=2ocy 1 n >z. >—'°=y Y r—, ''0HOl \ nz.—'Yv O]Y *Nv YN"^ Y-7i Y° YYN'" Y ^0N=Z318 ^X^NH2680o^YL ^o319 681- 1409 - FH13180518.3GPX-02525- 1410 - FH13180518.3GPX-02525- 1411 - FH13180518.3GPX-02525330 692 ^k,N H2 i k / NH2\ I / G\ 1 \,oV- <, N, / "'o'''CL. \ T °y z z—'"" F ^=0A-N \ > >°=0 \ yr^- ~331 VA, NH2693 o ^\.NH2LL?F Y F Y Ch- _ AZN~A 0 G332 AA ^NH2694AV °°P^N N, ~ A-F7 n [ oF 0v^NvN''Cu AA JO. N < - ' '""1 ^ N — F F0M^N y z z —ZNAr0 ^v_J>=V333 695334 696^k xNH2L / NHJN^ J-L X)■ * '.-? ' T C / jr OH- 1412 - FH13180518.3GPX-02525335 AAF-A 697A-T^N^N,^ ATA? ° M-LN '"'£ >° 6^\336 ^A. NH2698A O J A NXSN^HA O2LF3C\ / -\^ N N,,.^-X AJ n \ |. o / M O4 °337 A, NH2699O N A^ JL ^ yXN^HQ O2F3CxT^N^, N,,.yx / - / NVN''Z\,. G^ Y Q o0k / Hj N=V A° / AV338 700Z^A / NH2ANyXNyH2>F3C^ / -\^N^N„.y^° ^CVNX ^ T'C^VO AH2N^3 0<<>F339 ^A_NH2701Ar0^ / V° A VAr -NYN*rT, ^ T Q^0zA ->" [ i \=O N= / zXH2N^^ oF- 1413 - FH13180518.3GPX-02525340z— K, NH2702 1Y^s--O ArNHaNyk^O YT °°ZYY v FV^H^N,,. r YFF Y I 1^. / 7 n | |. p0£ Y J _ ©F(TJ - - YV N ° YzY y Y y zz~ y\ z z / I— ° - ' '"• \ )=ON= / c > >°=F^ / ^M C ) >°=0OH341 Y NH2703Nz / Fr n \ V. pF°'"' 'l ' / MF^y>°OH342 Y. NH2704 ZY / NH2O^ JL ^O N^YL^O■ ^T Ch t0^tVNx 0FVF343Z-^X<NH2705O^ JL ^O■ Z-T O^zNS? oF^F- 1414 - FH13180518.3GPX-02525344 706 1 1 xV^T^r ° ° °°°°zZrCrv^ v)XV°^Z0 Z£ J _ ©J - y\ i z z— ° c > > y° zz= y zz^~\ i ° — — ' '\\ > > > >°=°=> n■345 ^A, NH2707^ vCbr t,uA / / A o ° °°0346 A zNH O?2708N < - 'o^ JL^ y z z — ov >=<s •347 A zNH2709 CNo^ JL^oNv^<-0VA^J^NZ,[ L-»0zM '"'V N— '- orNA " C-oV- 1415 - FH13180518.3GPX-02525348 X / NHJ 710 1 y oX° rCx^°zo > ' — o1XUY349 X / NHJ 711H2N Y / O^ JL ^O kN>XX / N^N,,. z-.X \ L- p N— HOJ A00350 X N2712 CF3z H \ NH2,NXNv\^°Y \ p '5.rQvl0XY vXHOX00 4 ° 351 X zNH; 713O^XL ^Ol T X-A ° \zfNS X352 X zNH; 714oXX-01 il T L 9 < ^nxxxx r HpN'ZN~<'- 0o- 1416 - FH13180518.3GPX-02525353 X. NH2715 \ NH20<xJAx>° AYN, X, ON y' ■ ' ^ ' C3v r. x.b' x354 X. NH27160<xJAx>°zNS00355 717 \ NHX. NH2 2'NY0<xJAx>°Nvx*°CV / N N„. / Xn 1 L< 90p / sHO*L0o 4 °^0^OXz 356 X 718 \ NH2. NH2A>o< ozXN^JX° 0<xJAx>°t-Vx / N Nz, / x Ao ii I L.0< YIN '"'T ^>=0 0 \ / sH° / A00357 H2X. NH2719 N°Yv°X ^?NYO o '"' IsN— n■A 4 °- 1417 - FH13180518.3GPX-02525358 720 H2N / yN1^T °°ZCK / N N„. Y)4V^°'ZY0\ 1^.O )M C Y - -YA J 9 yz.i— ~ '""|KN— A FNH4 ° r0 A359 NH2721 H2N / yN'°V VY\, N,, N,. Ao n 1 L< '""j ^=00\ S oPH0360 7220 b:361 A MH;723 H2NX^?\ / T H°< V^V'NVV / N N„.n 1 L. f?0PPf vP zNS A S o4 PNX0362 ^\> NH2724 NH2o^ JL ^o1Qh '° " W. zNA^ o '- oHN'F0- 1418 - FH13180518.3GPX-02525161. A compound selected from the following table:Compound Structure Compound StructureF NH2Y.NH20. JL.0PvNN„.726 904 FA T r i o °. V QvvF° YYA Ji A0 \ OA OH F F^FZ-\y / NH2■■^NHZ O^J JL^O Px / N N,,727 905 F^ n 1 1 ^. o °. r o u -fo YYr\Y Y\ O k °c OH OH- 1419 - FH13180518.3GPX-02525F y / NH2Y NH2o^yL ^o o^yy ^oPv'Nx YzN'. / ^Xy v. o 728 906°. r o-ytF 0Yz< v\NYz Mk °OHX° c OHFY,, NH2O^ JL ^O O^N N„ PKZN\ZN'. / ^ 729 Y Y | 1^. o 907FY y u o o YYr\ YF 0YXYAYN— / \M / M 0 '■ oS^OH OH FY- NH2o^yy^o °V^Z°F I73 -TYN Y N„. \ b.0 ^ Y'-QVL 9080^Y3r\YY^ Y 1 o k0; OH 6'o F yZ-XX / NH2■-,, Z-NH2o^yy^o YvO O^, N Nz„ O^, N N„.731 F< Y r 909 FY Y \ Y ° yyyNx0Ny* '- o f 0Cg^ •- / / X / -x c OH 00- 1420 - FH13180518.3GPX-02525Z-\^NH2o^ JL ^o OP N,,.^F< Y n732 9100( O _ _ '• o / / ''z-x o / - \ 00P VY>< O / HNH2°PP>°^>XOOz1 CP / N Nc,F< Y \ Y, 733 9110'• o Cg^ "' Q QMM C C X - / X - / 00HO.VpNH2o^PP^o O^N N„.734 912F7 n i Y pF 0YYY JI -v-f ^ N— \ 0OHF \^OH H2NXJP NH2O< PpO °PPz°P -, / N N„.^ PvNvN'- zYF4 Y \ Y p 735 F' n \ ]. p 9130Y YF 0\zYYX Y Y ''"• N— '"’ '' ' N— / M / NY \ 0 1 oS^OH OH- 1421 - FH13180518.3GPX-02525F \..'OH H2N^ JJP^N N„.PP N„. FY Y \ O 736 FY Y r i p 914FFo o \ Y1 Ji YYYA JI '"' I ' N— '"" I ' N—zNYk03 OH OH F OH— Y / NH2NH2o oPP>oYI.0N„. / \FY Y | YFO OYVN^ 737 915FF T I 1 ^.0F 0YYYVY,NP Cx° / Mk0OH3 OHNH2FYNH2Z^ -,,<NH2OPPYoYL ^OPvN N„.^738 916 F^ Y \ 0 ^ ■T':2hJF° YYYVX\ N— / Mk0OH / 'OHF FFAY. NH2\----*^SS^NH2 OpP>°F-Y Y \ \^ 917 739F° \-Y vY ^ Y'- QvtNY^\ OOH OH- 1422 - FH13180518.3GPX-02525F y■■,,^NH20^,°PvN N,,.^740 FY Y [ ]. 918 Fp^NYN"-r>00Y zN^ kX° k °OH w ° OM / - \; OHF / \ I° \ / <YZNH?o^yy^o^Y° O1O^N N,„741 F< Y n 919 Fp^NYN"-r>0°k''~< VNx kX° kx°OH; OHY-, / NH2742 920 P^YOYv M \ °F / — \ OH OHF yY ^■■-, / NH2NH2o^yy>o O^NNN„.743 „.F921 py Y 7 ri i Y p rF 0'”■ (,Ny* / NY FJ o 1 0H°Yx^ OH0H- 1423 - FH13180518.3GPX-02525- 1424 - FH13180518.3GPX-025250YNHY" Y / NH2O^^ JL^O748 926Y J \ A\ 0 YY °O! - \ OH / \ IO \ / HO^ / FL / NH2Y NH2> Aoozo^YL ^o °Yv° O^, N N„749 927FF Y \ 1 ^. pFYNrcbYF° YYA Jl '"■Y^ N— / M rNY \ 0 „ s ■ OH F^OY NH2k / NH2 O< YY;>Oo< YY^oN„,750 Y / 'Y ~N928 F< Y \ pF 0Y-T VX YNAY\ 0 i "OH OH F VY^NH2Y NH2o^YL ^o o^YY^0Nz, O^, N N,,. / ^ F< Y | p 751 F<FY0[ u 929F0 JI YTY '"■ IsN— rNY \ o F^ 0OHOH- 1425 - FH13180518.3GPX-02525- 1426 - FH13180518.3GPX-02525- 1427 - FH13180518.3GPX-02525- 1428 - FH13180518.3GPX-02525- 1429 - FH13180518.3GPX-02525- 1430 - FH13180518.3GPX-025251 FyPj / ppYo.-’ oPP.0PPP x < ° - '768 F4 Y \ 3 p 946F 0Y< '"'VYY' ' N—Y|::d Vs H=o0L / NH2F Y NH20pP>0769 947a. r cb, L p Y ° < X / Yi bN r< Y'"’L Y° o •" p.( o O. 00Fx / < Y ° / =1'XY..;NH2®M / — \ °PP>°O^, N N„.7^OX^ Y' ^z 770 F^ Y | P OF948o k / YA Jl'"■y\ ' N— / NY'• 0p° 8- 1431 - FH13180518.3GPX-02525- 1432 - FH13180518.3GPX-02525- 1433 - FH13180518.3GPX-02525- 1434 - FH13180518.3GPX-02525- 1435 - FH13180518.3GPX-02525F NC? SHsN' J^■•„ zzNH2oUUo °V' >^o783 961^N'' CHv zN^ '. 0o' NH Q.6X° FOz JL ^O L^NHHN^ °<yZ\^02Y ¥ r i p784Fo Y / Y5 JI 962'"' l ' N— (^ Y-Q^ / M zY 0 '- 0 Q Q- O 'N 00FL, NHOv^Y °V V°2O^N N„.F< T 1 Y0V^^NZZN'- Z^Z 785F0 \ Y1 JI 963vn \ p l ' N— ° / Ny 1 o A Cj3 •" O 'N 00NH2O^z lL zOo<y Ly, NH>o2F^ PL vNv Y^' ZX[ A7860M>x964 o ° YY^A A / N^ '"’ l ' N— 1 o zN-<1 o Q.6 '06 '0- 1436 - FH13180518.3GPX-02525<¥^.o- \ ^¥,0 r Oy r-^'^-5<XNH2i; O — ' pj\p? z. - 787 965 \ > >°=FT Y plN= / ¥F¥ NH2o¥,c - 1788 rp i i ^^ / oc°z / °JpS^Nxz' \ rX '-' 966N / , / ?=0IuCu C &j- '"■ v\NxopiZ=ON=ZK >oF¥, NH2n.¥ °O^ JL p) ¥NH2> I V ° / — \ ¥vNVN'' r\ °T Y° A F< ¥ \ \^ lA^N N„. / S~° 967 7890O^"^ ¥’rc ° UTVN'-"• ( \=o zN^ N= / 1 oQ ”"o 'o¥ / NH20^ X,0790 9680zN¥\* > o'S'n 00- 1437 - FH13180518.3GPX-02525- 1438 - FH13180518.3GPX-02525Fk. NH2Y NH2°v v°NZz, PvNvN'-Z\794 n [ A. 972 1 1 ^. °F 0AALN0Jl '"■3sN— H / ’M 0 CgZ* "' 006xoL / NH2FY._, NH2795 973zY 1 0 Q '" / / x' / *\ 00FY-NH2Y._, NH2°-\Zv° °VY^°PvN N„. zx974 796FF Y \ pF 0Y / Y\ JI ^ Y'CYt '"'Y^ N— ZMN-. 0QY V 6 0 o 'oFL / NH2A NH2°v v°O^N Nz„FJ Y \ p 797 975F 0YAVA'"'Y' / M '■ 0 / M1 oQY 6 0 00- 1439 - FH13180518.3GPX-02525< x,ro °° Fjvnj-^0"5O<;Jk. O £ _ ©! \ - / N„798 Y 1 1^. 9 976 rF° or L / / ^ —\1 / NY o;x / / ^pZ*X *00FZ^ -,,<NH2L, NH21 A^ YY0799FOYV:°p T \ oZ977Fo k / YrxA MA" / M '- 0 O > < N - 'k °%>xo s( Q / / ''z-x.o ° 00L / NH2y oy^J^o800 978A^N,'Q^N_A OCg^ •" o ° F^■. NH2L / NH2FyFOXL.0801 979Y ZY\ o '• o 'C-NH ■" o0- 1440 - FH13180518.3GPX-02525- 1441 - FH13180518.3GPX-02525- 1442 - FH13180518.3GPX-02525 o 1 Fy.ov^ o°zr Oz JL zOO^NN„, \ X °808 Y Y i i. p 986Fo k YX JI'"'A ' N— zf X \ ^Yz>°rNH°dd?>0NzF< Y [ X 0 809 987F 0YYrVX 1 zNY rz°rxAV\ jy o x- ' — Zzz"V ' >^0H F f ViY- NH2OY\ / Y o -NH2Ndd;>OX Y >°. rM°'VZZcyt 810 988AN\ o d1°... zM '■ o O HIM Sy-° oH110^NH2FZY -,,^NH2°V x°811 O^N N„. 989F< Y [ 1 ^. pFo VM IIH2N >-Y V°F- 1443 - FH13180518.3GPX-02525F X9 / NH2H T, NH2812 N„ 990F< Y [ Y ° ';' "' "rQ v vFo YY5 JI'"' I ' N— zM 1 0 \ F OH2NZ / " FF0?r0H0 F NH2°V^° YX / NH2813 F4 Y \ pF 0Y-Y5 Ji 991N— / M4^0F \,xOHZ-Y<NH2 9X / NH2 o9y. OPvN N,,.^ YY. N^N,,.^814FJ Y | pFo YY^A Jl 992F0 V H N '"'l ' N— / NY', o Y9"oFZ9, / NH2o<99^09XV'NH2 YK / N N,_.815 F4 Y \ Y pFo Y-YVY 993N—zN96H0- 1444 - FH13180518.3GPX-025251 F AY * °°H'Y. NH2} ON < - 'F< Y | k 0 816 V oo VJ^F 0JI 994Y-< \I ' N—1 oPH0FOYL AN„, / xF7 Y 1 Y 0817Fo AH JI 995PM4,NAOYF'Y. NH2°V V° YY ’ <k< > o O=PvN MkT 1z z zF7 n i i. o818F 0Y-YA JI 996 ° ° Ak kA'"' I ' N— / z \P7- ZNY'• okZ ' ^>1OOZ 1 p°F HO,, / Y NH2 / Y / NH2O^ A.0 H TM^SA^O819 A l l >0H Pv^ N,„ 997FYk-N-k- / A YY'” F n \ |. o FA Y [ Y YF 0\Y^ AF° YYN— -■•-Lf N \=0 N= / k0FAF- 1445 - FH13180518.3GPX-02525Fk NH2°V V° £ } O1 - '820 998 / \ / O O=F^N°N" QV°N_pJ > \- k 4 ^4F 0w °F o / — \k NH2HO^ / / \ _o^XL.0 X>oozxk-NH2NH T JP^ / N N„. 'AX^ 821 199 <\ T \ °, OH FJ T \ ]. o 9F 0\kr\x'"’T N— ■5• ■Zh d ZNX N=A0^822 1000 i0<k JJxFN< Mk NH2H2XJk^o °PX^.oN„. zx P -VrA, 823 F^ n \ o 1001 ° MI, NXF° \zXVA'"’ N—kX° A X OHHO- 1446 - FH13180518.3GPX-02525F / NH2Xv'NH2oXX.0NXX>°N„.^824 H [ Y o 1002F° YYY J.v N— ^■rovt F^\ O p OH0HHO FX / NH2XY'NH2°vX° NXXY YXY> XN„825 Y Y 1 Y P 0 -Y Y 1 Y.10 3 FF 0YYY JIF° YYT yY N— / NX>\ 0 F J ° Ao6HOHH2NF^-.,^^2 XY'NH2NXXY°Xv°o F-Y > YrN" Y | Y Y.826 FX^ Y T U 1004Fo YY\ YF° YY ^Y / NX ( o>OHY0H0F X NH2Y\ / NH2rlXX^o o XXo8 F4 PvNv YN" / \ \27 X oF1005o YYA Y / M Y -- " v OH0HH0 / \- 1447 - FH13180518.3GPX-02525cwV *° / X r I°^ °Z\ _ < T y.„ Ko-- J> o < — 'Y zz828 1006( > >=°AFA,, NH2J\ / NH2Oz Jh zOO^N N,,.n \ o829 1007 ^■ "N.,N^ 'NF° YY '" V■ iXN—z Y \ o \ o° ANH2H(JF^■. NH2XUV / NH2v t HN\Y TA>° PvNN„.F^ Y r i 0830F° MAA 1008■A T CY.. \ O AM \ 0 o^NO HO-M0F JA / NH2^■- NH2°MM>0 O^N N,„831 LY N.. N, 1009 Y Y \ o FA Y.Fo <! Y / F° AZZYVJ ”’ Y I Ao0^NH- 1448 - FH13180518.3GPX-02525 FY i z NH2px / NHsPvNYN'-NPP \ I < °y zz>~° —H832 T | L. 1010F° M yv3 NpQ >- f o ■w -cfcY 3°W o - \ / \ N\FJ z3. NH2oppo833 1011Niap0P^ / NH2NpP>o PvNF3 Y O.834 1012 %F'r3 °= °^ 3F^Y0s3 VNH F A'Y / o ZIF P4 VNY YN'- / r \835 4 p 1013F 0J / '”’ 1 ' N—\ 0F- 1449 - FH13180518.3GPX-02525FJ^ / N H2NH2N^Jk^O °V^°O^, N N„.836F 01014 / H '. o \ 0H0OH z°F / NH2U\ / N H2(V'V°837F F1015' / H TH \ 0 OH^OHFY F F J\ / N H2. NH20. JL.0p-'- 38 1 16Fo j? 8 0 '"••y N"^ V' C^0zN^\-. 0iS^ / <crHO F J\ / N H2. NH2NYP^0O^ JL ^O839 O^NN„.F10171 n i i. pFlx'^^vr- ° \x^i '”V• XZN^ \ N— '. oX‘ HO / HO- 1450 - FH13180518.3GPX-02525F NH2XU^NH2 a-lH To<xJk^oN-XYY° Y O^N N,, Pv n N,„840 i i. o F^ Y\ x °F1018 y z z— \° \ JI ° ^YV\ ^Y-> OY kOH ° ff- F ° 8F NH2O^x JL ^O / •L / NH2N / ;NiiXY TX Z2841 F^FY0l o 1019k< YY F^ Y [ Y Y^FF 0VH NN'"' 1 >o z Y NY Y OY N''0 / NAF2xk / NH NH2M HXY TXX^O o^pk.0Y^N N, - PvNN„ / -x F<842 F4 Y r i p 1020 Y [ Y.F 0Y< ° MI-N '" V■ x N— / M-1 / ;■ " OH ° YY0F Y FZ-^ -, / ^NH2843 1021u / / 0- 1451 - FH13180518.3GPX-02525F X NH2844 1022F X NH2NXX^OO^ Jk -O PvN N,,.^845 1023F P< Y Y Y Y I Y 0F 0YH Jl, r!Y - YM HO^ ° HOY CoH° P<, OH^k^NH2F'. NH, / >N^l^OH0846 >-u 1024F< Y I Y. / " \0Hx wF 0Y -<-Iy N v=No O— ✓ o o N= / F FF %> Y< °= / X Z zX NH2O / — < -j- < > oY°V'v^vNH2°HQ847 1025FYV‘Q^, Y„\ 0OH F X NH2r^^YNH2F\ °vY°FxX / N N,N848 1026° X t ■Y OI -3YN\ 0OH- 1452 - FH13180518.3GPX-02525FYv NH2. Ox Jt ^oHO''Y" A ] [849 1027'■ ’ T ' CK?P OH F HNT XYX^° Ox Jx Z)o"^v'\ ] i N„ / X N„.^XFY Y \ 1 ^. o 850 Y \ Y o 10280Y-YVYF 0N— ''” 1 ^ N — zMx'- 0 O / x. p o-s J HN^ OHF / 4X / N H2NH2H 1NX Y\^0X / x. °V v>0P^N>rN'' YYFY Y \ p 851 1029F 0YYYA JIr'Q^N'"■'I ' N—rM K M^Y - Yo 4 ° o% HY OH FYF^?k / ’NH°Y2, NH2>N^xJ-U^O C^, N N„.^xFY Y [ 1.852 0 10300YYYVY0 L^YXNXzNY\^ ZN~< O \ 0. OH OYOH- 1453 - FH13180518.3GPX-02525F^?k / NH2O 'Y.,, NHH <2Nv^Y3\ o^^Y3O^N N„N„. F4 Y \ ].853 Y | p 103100'"'l ' N—<NY\ o? AS'NH” °Y OHF^Y^NH2 N^Jk^O Oyl^O O^N N„.FY Y \ FxYYYN"- / k i.854FT Y | Y, 1032 °F 0YY^ 1 o kx°H(Y °Y FY\ / NH2'Y NH2NV'YY Ov^o O^N N„ / -.F4 Y \ ].855 Y Y | 10330^Vk\F 0^xV\k ° A ”? S'N. °Y H(YFY\ / Y., NH2NH2NO. JL > O > V / N NA.F^ -, / NVN„. F< Y [ Y* 856 F Y | Y. 1034F 0VZYN o YYYyN" / nF 0OH- 1454 - FH13180518.3GPX-02525 F NH2o^AL^oF~Y.857 F Y T u o 1035o JI'"•yJ OH HO^ / A\r / NH2N< AA?. O858 1036ryw i. J < V° Y jYj Y \YYrYz x°0\ o£ J O _l OH Y > z zz^\ T < ° - ' - 'HO,„ / 2\ Y Y >< >°°=) o o y YzA\r / NH2IN< AA?. O InYo859 1037 \\ > “T°. r °c / - \ ov Y\ o YY 1 ' o1OziOHOH 1 o FZ-k'-, / / NH2O^Ax^O860 1038OH- 1455 - FH13180518.3GPX-02525F HO / , / ^?k / NH2°v v°861FT ■[ u o 1039 °. r c^.\ N"Xk °OH; OH F HO^ / NH2^U / NH2 O^ Jb x)N„.862 n i p 1040 °. r ca t'"■ IsN— / X k0pOH / 'OH F HO,,. / Z-^ -, / / NH2N^Uk^O0V^V-0N„.863 n i o 10410X / r A JI °. rctw ''"’ ’I N—\ 0OH XF^■■,Z^NH2\.-'OHO^^ JL ^O J\ / NH2N^Jk^O864 1042 O..,z / N N„r A^ * cw.. FF' o [ U\ 0 ' / ■M0OH- 1456 - FH13180518.3GPX-02525- 1457 - FH13180518.3GPX-02525F Y^o Y NH2oYL > Oo869 F Y | Y 10470YYYN^ )\ >°= / NYJ> T£x°< OHF Y NH2870 FAF / M'Yn i Y p 1048° YYYYl ' N—k0c OHOH F YOH Y NH2J\ / NH2YY NYYJOY °871FAFYY"Y | |. p 1049° YYYYl ' N—zNY Y k0k0’ ■oUIZ c OH OH KJ OH F Y. SOH / NH2Y'Y1'12N YL,o °< V''Y^°PvN N„. / K872 1050 F4 Y \ Y o,?a. -J' Ckk.F° YYYX IsN— Yk0V ° / fc)H OH- 1458 - FH13180518.3GPX-02525F HO.k NH2 / k / NH2NH. A T\A3 O^N N„ / \F< Y ( >873FY \ o 1051F° A / H N0xk / YA k<ZNA>kx° k °< OH OH F HO.k. NH2XA-NH2 okL.0 H TN-Av0FYk-A^874 F Y f u? 10520YY \Y'"■ y N— A V- Q^ - Ak ° p FAFOH FN^Yk. NH2NH2NY / k A) 0^^.°F-AVNYN-. / X875Fn I I^. 10530M^LNP"'^NWN- krrV OH OH HO.F NV >k..,, NH2O^ JL ^O876 1054F7A-NYN'- n.° kN\ 0 A °F^FOH- 1459 - FH13180518.3GPX-02525NJy FNH2kJkjsO'k--, AH2O^N N„.FP n i o 877 1055F 0r / '. \ 0OHFNJyNH2, NH2°VA°878 1056■A--C1A, SVo ° F'k NH2879 N,_ 1057Fn kvM<= / °F^ kF°FT^■VNH2N^YNH21PJkx>0 Y°Y^Y°880 1058Y ° / '■'OHOH- 1460 - FH13180518.3GPX-02525F NV2Y.,;NH2YYO oYL.0 O^N N,,. / \Y Y \ Y O YY, N^, N,,Fo YY\ JI 881 Y f Y o 1059Fo YY \ YrNz;i 6xo OH FNJYNH2Y NH2oYYj.0 P^N N„Y Y \ Y p 882 t 1060F 0YY\YFo YY \ Y N — / Ni zNY 1 o (x°Q “" 6 'o OH HO^ / k / NH2NXYH2pPy0o y^yoY^N N„.PvNVN'^ F4 Y \ Y P 883 Y Y f Y 1061F 0YY\YF 0M yYNY <NY \ 0OH OH Y HO,,. / YNH2NX^2pPy0oY-YoPvN N„884 YvNN„. Y Y \ Y P Y Y | Y 1062F 0YY\YF 0M yV N —NY YY\ 0V OHOH- 1461 - FH13180518.3GPX-02525F F HO. / L / NH2H T ANH2N-YA-0O. JI. X) PvNvN''Z\F^p Y | A o 885 1063Fo YA\ Jn Y\ oN OH HO.F4^NH2 / A-NH2N H^Y T ^O O^l^OAAXNYN„, PvNYNZ„ 1FF T I A 0 886 F4 Y r i yY o o° 1064F0F 0A< 5 \ T / JI^V° / M \ 0 k0\ I < ° — / y zz^FA\ >° OHHO.A A-AY YAN^N'. r^X A Y [ A 887 1065°YA* kx° OH HO.Y. NH2 rAv'NH2N AA. O oA,oPvN N, - YVNVN''. / k A Y \ A 888 F-1 Y | A p 1066Fo AH NF 0XAAA o \ 06?"NHOH- 1462 - FH13180518.3GPX-02525HO.<>PXV'NH2 M^PL ^O °PPYYY, N N„. F^ Y \ Y.889 T i Y o 1067F° J / 0<NY\ 0OH 6'NHHO.HN-,N'JYNH2N-V^pPy>°Y-P-YYY / NN,„F< Y n890 10680PYV\4k"J"< Kv YN\ OOH OH N HO,,. / A{ N-VH2Y NH2pPy>°O-YL ^OYY-N N, - 891 F4 Y \ Y F\L Y [ Y ° 1069 0Fo YY5 JlF0 Y-YA JI -V’Y' N—'”'1 ' N—\ 0OH OH N HI HO^Y^ Y zNH2NXYH2pP^0YY^N N / ?892 PvM-^F4 1070F1 n i Y p Y \ Y oFo YYA JIF 0''"•’I ' N — '"'Y^ N—\ 0OHOH- 1463 - FH13180518.3GPX-02525H22N. s A=oY, NH2HO.oY, O Y-Y"NH2FN YY PVNoV Y^''.893 1 Y O 1071Fo YY j'"' l ' N—YY N=Y \ oOH HO.Y NH2PXV'NH2 oYY^O N YL.°YY / N'V-'N,,.894 1072F7 Y [ Y.0^YfVN\ ^ Vn yYYN\ oF OH HO.Y. NH2 / -Y-NH2 o^PP^o Il 1NxY^° O^N N„. / \ YYXN N„895 F< L Y \ 0 1073 F< Y | YF 0Y-YVY0t ^YV\ <NY\ 0 '• o POH OH OH HO.Y. NH2 / Y-NH2H Io< PP^o rj^Y^o896 1074 FY Y \ Y.°zNP>\ 0 Y '°( OH OHOH- 1464 - FH13180518.3GPX-02525HO.NJYNH2O. P.. OJp^N N'_.F4 Y \ Y 897 1075 ° ^^rVN\,NP \ o vx°F OHF"v-FZ-XV, NH2HO.NJyNH2N,,.^898 Y Y \ o 1076Fo YYA j / '"'y\ N—\ oOHF^F NH2Z-k-,, / NH2O^j JL ^OJP^N N„.899 F4 Y f 1 p 1077F° JI ■ ';l ' N—\ oV OHF\^FZ-X> / NH2Y20 0 °PP> OPvN N„. zx900 F4 Y p 1 p 1078 J H °F° \ JI'"’ I ' N— Fx JYrOH- 1465 - FH13180518.3GPX-02525 T JP^N N„.901 F4 Y f j p 1079F° JI\ oOHJ\. NH2nd-L ^o Fx A^N N„.FT V \902 1 1080F 0V / \. I / =Or \ T ° ' OH Z\ u. ) >°= m TILJ •, NH2L903FFFO 11 1 L 9 d1°\ 0 ^Y OOHor a pharmaceutically acceptable salt thereof.

162. A pharmaceutical composition, comprising a compound according to any one of claims 1-161; and at least one pharmaceutically acceptable excipient.

163. A method for treating or preventing osteoporosis, fracture, osteomalacia, arthritis, thrombocytopenia, hypoparathyroidism, hyperphosphatemia or tumoral calcinosis, comprising administering to a subject in need thereof a therapeutically amount of a compound of any one of claims 1-161, or a pharmaceutically acceptable salt thereof.

164. A method of:a) reducing of HbA1c;- 1466 - FH13180518.3GPX-02525b) treating or preventing type 2 diabetes, hyperglycemia, impaired glucose tolerance, or non-insulin dependent diabetes, and / or obesity;c) reducing body weight and / or food intake, and / or inducing satiety; and / or d) treating or preventing Alzheimer's disease, nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), and / or cardiovascular diseases;comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1-161, or a pharmaceutically acceptable salt thereof.- 1467 - FH13180518.3

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