GLYCOLATE OXIDASE INHIBITORS FOR THE TREATMENT OF DISEASE

FIELD

Described herein are compounds, methods of making such compounds, pharmaceutical compositions and medicaments containing such compounds, and methods to treat or prevent diseases or disorders associated with the enzyme glycolate oxidase (GO) or alterations in oxalate metabolism. Also described herein is that such compounds are for use in said methods for treating or preventing diseases or disorders. Such diseases or disorders include, for example, disorders of glyoxylate metabolism, including primary hyperoxaluria, that are associated with production of excessive amounts of oxalate.

BACKGROUND

Primary hyperoxaluria (“PH”) is an autosomal-recessive disorder of glyoxylate metabolism. PH type I (PH1) is caused by inherited mutations in the AGXT gene encoding liver peroxisomal alanine: glyoxylate aminotransferase (AGT) which is deficient or mistargeted to mitochondria (Danpure et al., FEBS Lett. 201(1):20-24 (1986)). AGT detoxifies glyoxylate to glycine. When AGT activity is deficient or mistargeted, excessive glyoxylate cannot be detoxified and is oxidized by intracellular lactate dehydrogenase (“LDH”) to oxalate. Excessive amounts of oxalate lead to urolithiasis and nephrocalcinosis, and can result in renal failure, end stage renal disease and systemic oxalosis.

Glycolate oxidase (GO) is a key enzyme involved in the oxalate metabolic pathway. Glycolate from internal metabolism and from diet will be oxidized by GO to glyoxylate. This oxidation only occurs in the liver peroxisome (Holmes et al., J. Urol. 160(5):1617-1624 (1998 November)). Under normal conditions, the glyoxylate generated by GO will be detoxified by AGT to glycine. However, in PH1 patients, where the glyoxylate to glycine pathway is blocked, the glyoxylate generated by GO is oxidized by LDH to produce excessive amounts of oxalate.

An approach to treatment of PH1 is to inhibit the GO enzyme to reduce the production of glyoxylate and ultimately reduce the production of excessive amounts of oxalate. It has been shown in HAO1 (GO)^−/−/AGXT^−/−double knockout mouse that GO deficiency can correct overproduction of urine oxalate over production in AGXT^−/−mouse (Martin-Higueras et al., Mol Ther. 24(4): 719-725 (2016)). In both humans and mice, the HAO1^−/−deficiency appears clinically/phenotypically normal except for the increased urine glycolate secretion (Martin-Higueras et al., Mol Ther. 24(4): 719-725 (2016)). Inhibition of GO with Dicer-substrate siRNA has also been shown to reduce urine oxalate secretion and reduce kidney calcium oxylate deposition in the PH1 mouse model (Dutta et al., Mol Ther. 24(4): 770-778 (2016 April)).

The most commonly observed effect of high levels of oxalate is the formation of crystals in various tissues. Crystal oxalate formation in the kidney results in nephrolithiasis, or kidney stones. Similarly, increased urinary oxalates can also lead to nephrocalcinosis.

Accumulation of oxalate is implicated in primary hyperoxaluria type II (“PH2) and primary hyperoxaluria type III (“PH3”). Similar to PH1, mutations in a gene results in decreased production or activity of the corresponding enzymes that are produced. Such disruptions to the enzymes adversely affects the normal breakdown of glyoxylate. In healthy subjects, glyoxylate is converted to glycine, which is readily secreted. In diseased subjects, there is a build-up of glyoxylate, which gets converted to oxalate. When the buildup of oxalate exceeds the capacity of the kidney to excrete it, the oxalate starts to deposit in various organ systems in a process called systemic oxalosis. In PH2 patients, a decrease in the breakdown of glyoxylate is caused by mutations in the GRHPR gene, which normally reduces glyoxylate to glycolate. PH3 is a third type of PH, and is identified in patients with previously unclassified forms of PH. PH3 is caused by mutations in the HOGA gene (formerly known as the DHDPSL gene). This enzyme functions in the final step of 4-hydroxyproline (Hyp) catabolic pathway. Overactivity of the enzyme leads to excess conversion of hydroxyproline to glyoxylate, which yields high levels of oxalate. The genetic mutations that cause PH are inherited as autosomal recessive traits.

Build-up of oxalate and deficiencies in processes involving urinary excretion of oxalate is further implicated in a variety of diseases and disorders, such as progressive kidney failure, recurrent kidney stones, nephrocalcinosis, urinary tract infections, chronic kidney disease, and end stage renal disease. Reducing urinary oxalate levels and plasma oxalate levels can helpful in treating or ameliorating these diseases and conditions.

Hyperoxaluria is characterized by an increased urinary excretion of oxalate. Excess urinary oxalate, whether from primary or enteric hyperoxaluria, can lead to oxalate deposits in the kidney. Primary and secondary hyperoxaluria are two distinct clinical expressions of hyperoxaluria. Primary hyperoxaluria, as discussed above, is caused by genetic mutations which increases oxalate production. Secondary hyperoxaluria includes dietary hyperoxaluria, enteric hyperoxaluria and idiopathic hyperoxaluria. In addition to these types of hyperoxaluria, there are pharmacologically induced hyperoxalurias that are caused by the ingestion of compounds that can be metabolized to oxalate, such as ethylene glycol or other precursors such as hydroxyproline.

Dietary hyperoxaluria is caused by increased dietary ingestion of oxalate, precursors of oxalate or alteration in intestinal microflora. A high intake of oxalate-rich foods (eg, chocolate, nuts, spinach) and a diet rich in animal protein can result in hyperoxaluria. Low dietary calcium intake can also result in hyperoxaluria via decreased intestinal binding of oxalate and the resulting increased absorption. Ascorbic acid can be converted into oxalate, resulting in increased urinary oxalate levels. Patients with abnormal or altered cellular membrane oxalate transport mechanism have abnormally high absorption of dietary oxalate. Patients with a deficiency of Oxalobacter formigenes, an intestinal oxalate degrading bacterial, will also have the increased oxalate absorption. Diets that are high in any metabolic precursor of oxalate can lead to elevated oxalate levels that could be reduced by inhibition of GO.

Enteric hyperoxaluria results from a chronic underlying gastrointestinal disorder associated with malabsorption of fat, bile acids, decreased enteric secretion of oxalate by the membrane protein anion transporter (slc26a6) due to the abnormal glycosylation of brush border, or triggered by obesity which influenced paracellular and transcellular transporting. Related diseases include steatorrhea, inflammatory bowel disease (“IBD”), biliary cirrhosis, short-bowel syndrome, celiac disease, pancreatic insufficiency, Crohn's disease, ulcerative colitis, bariatric surgery, jejunoileal bypass, ileal dysfunction, absence of gastrointestinal tract-dwelling bacterium Oxalobacter formigenes, and Roux-en-Y gastric bypass (“RYGB”). In addition, cystic fibrosis, high blood pressure, and diabetes can lead to metabolic changes which can result in increased oxalate (see Nazzal, L., et al., Nephrology Dialysis Transplantation, 31(3):375-382 (2016 March).

There is an increased risk of urolithiasis and loss of kidney function from oxalate nephropathy. With idiopathic hyperoxaluria, the causes are unknown.

Formation of oxalate crystals are associated with renal inflammation, fibrosis and progressive renal failure. Studies also show high oxalate levels can be an activator of inflammatory pathways, and in particular, with inflammasome activation and the progression of kidney disease, and NALP3-mediated inflammation (see Ermer, T; et al., Curr Opin Nephrol Hypertens, 25(4):363-371 (2016 July); and Knauf, F., et al., Kidney Int., 84(5):895-901 (2013 November)).

There is a known association of high urinary oxalate with acute kidney injury and chronic kidney disease (“CKD”). Studies show a correlation of higher urinary oxalate concentrations with a higher risk of CKD (Waikar, Sushru S., et al., JAMA Intern Med., 179(4):542-551 (2019)). These studies have shown that patients with chronic kidney disease that also have high normal urine oxalate levels have a more rapid disease progression rate than those similar patients with low normal urine oxalate levels. Therapeutic approaches to reduce the oxalate burden in these patients has the potential to slow the progression of disease. If any of the multiple sources of oxalate can be reduced, there could be benefits to these patients. For example, inhibition of GO or LDH (or any other metabolic step that contributes to the generation or absorption of oxalate) could reduce oxalate levels and slow the progression of disease. It has long been known that as glomerular filtration rate (GFR) becomes reduced in CKD, there is an elevation of plasma oxalate. Elevation of plasma oxalate in CKD may promote renal inflammation and more rapid progression of CKD independent of primary etiology. Higher urinary oxalate excretion among CKD patients is also associated with an elevated risk of end-stage renal disease (ESRD; also known as end-stage kidney disease, “ESKD”).

Hyperoxaluria has been implicated as a complication or undesired side effect of various diseases, such as Hirschsprung's disease, cystic fibrosis, chronic biliary pathology, pancreatic pathology, high blood pressure, diabetes, and obesity. Hyperoxaluria can also be related to genetic or environmental vitamin B6 deficiency, genetic or environmental abnormal calcium metabolism such as, hypercalciuria and hyperparathyroidism and abnormal collagen metabolism, abnormal oxalate or oxalate precursor transporters. Reduction of oxalate levels would also have therapeutic benefit in the management of the complications from these diseases and conditions.

Accordingly, molecules that inhibit the activity of GO may be used to treat disorders of glyoxylate metabolism, including PH1, that are associated with production of excessive amounts of oxalate. Other diseases and conditions impacted by excessive oxalate formation may benefit from treatment with a GO inhibitor, such as PH2, PH3, enteric hyperoxaluria, dietary hyperoxaluria, idiopathic hyperoxaluria, urolithiasis, nephrolithiasis, nephrocalcinosis, chronic kidney disease, end stage renal disease, or systemic oxalosis.

SUMMARY

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

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wherein:

ring C is selected from:

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wherein the wavy lines () indicate the points of attachment of the C₁carbon to the carbonyl of C(O)—OR¹, and the C₂carbon to L;

L is a bond, CH₂, CF₂, O, NR^L, S, S(═O), C(═O), CH₂-Q, or Q-CH₂; wherein Q is O, NR^L, or S;

R^Lis hydrogen, C_1-4alkyl, C_3-6cycloalkyl, phenyl, or benzyl; wherein the C_1-4alkyl is optionally substituted with hydroxycarbonyl, alkoxycarbonyl, hydroxycarbonylalkyl, or alkylcarbonyloxy; and the phenyl group alone or as a part of the benzyl group is optionally substituted with one or two groups selected from halo and haloalkoxy;

Ring A is C_3-8cycloalkyl, C_8-11spirocycloalkyl, 5-8 membered heterocycloalkyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, thienyl, phenyl, naphthyl, indanyl, tetrahydronaphthyl, dihydronaphthyl, pyridyl, indolyl, benzothiazolyl, quinolinyl, isoquinolinyl, indolinyl, isoindolinyl, tetrahydroquinolinyl, dihydroisoquinolinyl, tetrahydroisoquinolinyl, 2,3-dihydrobenzo[b][1,4]dioxinyl, or tetrahydro-methanonaphthalenyl;

Ring B is present or not present; wherein:

when Ring B is present, then Ring A is optionally substituted with one or two groups independently selected from halo, alkyl, alkoxy, cyano, hydroxy, haloalkoxy, (cycloalkyl)alkoxy, and cycloalkyl;

when Ring B is not present and Ring A is phenyl, then Ring A is substituted with:
- (i) one or two R^AAgroups;
- (ii) 2 halo groups when L is other than O;
- (iii) 2 halo groups when L is O, and R²and R³are not hydrogen or alkyl;
- (iv) one halo group when L is CH₂NR^L;
- (v) one halo group and one group selected from the group consisting of haloalkoxy, cycloalkyloxy, (cycloalkyl)alkoxy, and (phenyl)alkoxy, when L is bond, O, S, or S(═O), wherein the phenyl is optionally substituted with halo, cyano, haloalkyl, or haloalkoxy; or
- (vi) one cyano group and one (phenyl)alkoxy group, when L is bond or O, wherein the phenyl as part of the (phenyl)alkoxy group is optionally substituted with halo or haloalkoxy;

when Ring B is not present and Ring A is other than phenyl, then
- (i) Ring A is substituted with one or two R^ABgroups or
- (ii) Ring A is unsubstituted, wherein:
  - 1) when Ring A is unsubstituted tetrahydroquinolinyl, then L is a bond;
  - 2) when Ring A is unsubstituted 2,3-dihydrobenzo[b][1,4]dioxinyl, then L is O;
  - 3) when Ring A is unsubstituted tetrahydronaphthyl, then L is O, and R¹is not hydrogen or ethyl; or
  - 4) when Ring A is unsubstituted spirocycloalkyl, then L is O, S, or CH₂S;

each R^AAis independently alkyl; haloalkyl; haloalkoxy; cycloalkyloxy; (cycloalkyl)alkoxy; phenoxy optionally substituted with one or two halo groups; or alkylcarbonylaminoalkoxy;

each R^ABis independently halo; alkyl; hydroxy; alkoxy; haloalkyl; haloalkoxy; cycloalkyloxy; (cycloalkyl)alkoxy; or phenoxy optionally substituted with one or two halo groups;

Ring B, when present, is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each is optionally substituted with 1, 2, or 3 R^Bgroups;

each R^Bis independently halo; cyano; alkyl; hydroxyalkyl; alkylsulfonyl; aminosulfonyl; alkylaminosulfonyl; dialkylaminosulfonyl; haloalkyl; alkoxy; aminoalkoxy; alkylaminoalkoxy; dialkylaminoalkoxy; hydroxyalkoxy; haloalkoxy; alkylcarbonyl; alkoxyalkoxy; aminocarbonyl; alkylaminocarbonyl; dialkylaminocarbonyl; alkylcarbonylaminoalkoxy; cycloalkyl; (cycloalkyl)alkyl; cycloalkyloxy; (cycloalkyl)alkoxy wherein the cycloalkyl group is optionally substituted with hydroxyalkyl; cycloalkylcarbonyl; cycloalkylcarbonyloxy; heterocycloalkyl optionally substituted with one or two groups independently selected from halo, alkyl, and alkylcarbonyl; (5-6-membered heterocycloalkyl-one)alkyl; 5-6-membered heterocycloalkyl-one; (heterocycloalkyl)alkyl; heterocycloalkylcarbonyl; or 5-6 membered heteroaryl optionally substituted with one group selected from alkyl, hydroxyalkyl, (hydroxycycloalkyl)alkyl, alkoxyalkyl, and hydroxycycloalkyl;

R¹is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, or W; wherein W is alkyl substituted with amino, alkylamino, dialkylamino, alkylcarbonyloxy, alkoxycarbonyl, phenylcarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkoxycarbonyloxy, cycloalkylcarbonyloxy, —N(R^1A)C(O)R^1B, —N(R^1A)C(O)OR^1B, or —N(R^1A)C(O)NR^1BR^1C; wherein R^1A, R^1B, and R^1Care each independently hydrogen or C_1-6alkyl;

R²and R³are independently hydrogen, alkyl, phenyl, benzyl, or alkoxy-substituted benzyl; wherein the alkyl is optionally substituted with halo, alkoxy, haloalkoxy, alkylcarbonyloxy, cycloalkylcarbonyloxy, or heterocycloalkylcarbonyloxy optionally substituted with alkoxycarbonyl;

provided:
- i. when L is S or CH₂, and Ring A is phenyl other than phenyl substituted with (cycloalkyl)alkoxy, then Ring B cannot be halo-substituted phenyl;
- ii. when L is O, Ring A is phenyl, and Ring B is not present, then R^AAcannot be alkyl;
- iii. when L is O, Ring A is phenyl substituted with 1 R^AA, and Ring B is not present, then R^AAcannot be meta-substituted trifluoromethyl;
- iv. when L is O, Ring A is phenyl, Ring B is not present, and R¹is ethyl, then R^AAcannot be trifluoromethoxy;
- v. when L is bond, Ring A is other than phenyl, Ring B is not present, and R¹is H, then R^ABcannot be methyl, and
- vi. when L is NH, Ring A is pyridyl, indolyl, or indolinyl, and Ring B is not present, then R^ABcannot be alkyl; and
  
  optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.

In another aspect, provided herein is a compound of Formula (XII):

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wherein:

ring C is selected from:

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wherein the wavy lines () indicate the points of attachment of the C₁carbon to Z, and the C₂carbon to L;

L is a CH₂, CF₂, O, NR^L, S, S(═O), C(═O), CH₂-Q, or Q-CH₂; wherein Q is O, NR^L, or S;

Z is —C(═O)H or —CH₂OY;

Y is hydrogen or W;

W is methylene substituted with R⁴; —C(═O)R⁵; —C(═O)OR⁵; —C(═O)NR⁵R⁶; —C(═O)SR⁵; —S(O)R⁵; —S(O)₂R⁵; —S(O)(OR⁵); —S(O)₂(OR⁵); —SO₂NR⁵R⁶; —P(═O)(OR⁷)₂; —P(═O)(O⁻)₂; —P(═O)(OR⁷)(O⁻); or —P(═O)(X) wherein X is —O(C(R⁸)₂)_mO—;

R^Lis hydrogen, C_1-4alkyl, C_3-6cycloalkyl, phenyl, or benzyl; wherein the C_1-4alkyl is optionally substituted with hydroxycarbonyl, alkoxycarbonyl, hydroxycarbonylalkyl, or alkylcarbonyloxy; and the phenyl group alone or as a part of the benzyl group is optionally substituted with one or two groups selected from halo and haloalkoxy;

Ring A is cycloalkyl, C_8-11spirocycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

Ring B is present or not present; wherein:
- when Ring B is present, then Ring A is optionally substituted with 1 or 2 R^A1groups;
- each R^A1is independently selected from halo, alkyl, alkoxy, cyano, nitro, hydroxy, hydroxyalkyl, haloalkyl, haloalkoxy, (cycloalkyl)alkyl, (cycloalkyl)alkoxy, and cycloalkyl;
- when Ring B is not present, then Ring A is optionally substituted with 1, 2, or 3 R^A2groups;

Ring B, when present, is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each is optionally substituted with 1, 2, or 3 R^Bgroups;

each R^A2and R^Bis independently halo; cyano; alkyl; hydroxyalkyl; alkylsulfonyl; aminosulfonyl; alkylaminosulfonyl; dialkylaminosulfonyl; haloalkyl; alkoxy; aminoalkoxy; alkylaminoalkoxy; dialkylaminoalkoxy; hydroxyalkoxy; haloalkoxy; alkylcarbonyl; alkoxyalkoxy; aminocarbonyl; alkylaminocarbonyl; dialkylaminocarbonyl; alkylcarbonylaminoalkoxy; cycloalkyl; (cycloalkyl)alkyl; cycloalkyloxy; (cycloalkyl)alkoxy wherein the cycloalkyl group is optionally substituted with hydroxyalkyl; cycloalkylcarbonyl; cycloalkylcarbonyloxy; heterocycloalkyl optionally substituted with one or two groups independently selected from halo, alkyl, and alkylcarbonyl; (5-6-membered heterocycloalkyl-one)alkyl; 5-6-membered heterocycloalkyl-one; (heterocycloalkyl)alkyl; heterocycloalkylcarbonyl; or 5-6-membered heteroaryl optionally substituted with one group selected from alkyl, hydroxyalkyl, (hydroxycycloalkyl)alkyl, alkoxyalkyl, and hydroxycycloalkyl;

each R²and R³is independently hydrogen, alkyl, phenyl, benzyl, or alkoxy-substituted benzyl; wherein the alkyl is optionally substituted with halo, alkoxy, haloalkoxy, alkylcarbonyloxy, cycloalkylcarbonyloxy, or heterocycloalkylcarbonyloxy optionally substituted with alkoxycarbonyl;

R⁴is alkylcarbonyloxy, phenylcarbonyloxy, cycloalkylcarbonyloxy, heterocycloalkylcarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkoxycarbonyloxy, —N(R¹⁰)C(O)R¹¹, —N(R¹⁰)C(O)OR¹¹, —N(R¹⁰)C(O)NR¹²R¹³, —O—P(═O)(O⁻)₂, —O—P(═O)(OR⁷)(O⁻), or —O—P(═O)(X) wherein X is —O(C(R⁸)₂)_mO—;

each R⁸is independently hydrogen, halo, —CN, —OR⁹, —C(═O)R⁹, —C(═O)OR⁹, —C(═O)N(R⁹)₂, —N(R⁹)₂, —SR⁹, —S(O)R⁹, —S(O)₂R⁹, —OC(═O)R⁹, —OC(═O)OR⁹, —OC(═O)(N(R⁹)₂), —N(R⁹)C(═O)R¹⁴, —N(R⁹)C(═O)OR¹⁴, —SO₂N(R⁹)₂, alkyl, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl;

each R⁵, R⁶, R⁷, R⁹, R¹⁰, R¹¹, R¹², R¹³, and R¹⁴is independently hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, heterocycloalkyl, or heteroaryl; and

m is 1, 2, or 3; and

provided:
- i. the compound represented by Formula (XII) is exclusive of:
  - a. 4-(phenylamino)-1H-1,2,3-triazole-5-carbaldehyde;
  - b. 4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazole-5-carbaldehyde;
  - c. ethyl hydrogen (((5-((5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)-1H-1,2,3-triazol-4-yl)methoxy)methyl)phosphonate;
  - d. diethyl (((5-((5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)-1H-1,2,3-triazol-4-yl)methoxy)methyl)phosphonate; and
  - e. 1-((4-(hydroxymethyl)-1H-1,2,3-triazol-5-yl)methyl)-5-methylpyrimidine-2,4(1H,3H)-dione;
- ii. when Z is —C(═O)H, L is L, R^Lis hydrogen, and Ring A is phenyl, then Ring B is present and/or the phenyl Ring A is substituted with 1, 2, or 3 R^A2groups;
- iii. when Z is —C(═O)H, L is CH₂, and Ring A is cyclopropyl, phenyl, indole, or thiophene, then Ring B is present;
- iv. when Z is —C(═O)H, L is CH₂—O, and Ring A is phenyl, then Ring B is present;
- v. when Z is —CH₂OY, Y is W, W is —P(═O)(OR⁷)₂or —P(═O)(OR⁷)(O⁻), R⁷is ethyl, L is CH₂, and Ring A is pyrimidine-2,4-dione, then Ring B is present and/or the pyrimidine-2,4-dione Ring A is unsubstituted or substituted with 2 R^A2; and
- vi. when Z is —CH₂OY, Y is hydrogen, L is CH₂, and Ring A is pyrimidine-2,4-dione, then Ring B is present and/or the pyrimidine-2,4-dione Ring A is unsubstituted or substituted with 2 R^A2; and
  
  optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.

In another aspect, provided herein is a pharmaceutical composition comprising a compound disclosed herein, for example, a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), or (XII), as disclosed herein, and a pharmaceutically acceptable excipient.

In a further aspect, provided herein is a method of treating a disease or disorder associated with a defect in glyoxylate metabolism with a compound disclosed herein. Thus, a compound disclosed herein is for use in a method of treating a disease or disorder associated with a defect in glyoxylate metabolism, such as diseases or disorders associated with the enzyme glycolate oxidase (GO) or alterations in oxalate metabolism. Such a compound is, for example, a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), or (XII), as disclosed herein, or a pharmaceutical composition comprising the compound disclosed herein, and a pharmaceutically acceptable excipient, as disclosed herein.

In certain embodiments, the disease or disorder is a primary hyperoxaluria. In certain embodiments, the disease or disorder is primary hyperoxaluria type I. In certain embodiments, the disease or disorder is PH2. In certain embodiments, the disease or disorder is PH3. In certain embodiments, the disease or disorder is an enteric hyperoxaluria. In certain embodiments, the disease or disorder is a dietary hyperoxaluria, In certain embodiments, the disease or disorder is an idiopathic hyperoxaluria. In certain embodiments, the disease or disorder is urolithiasis. In certain embodiments, the disease or disorder is nephrolithiasis. In certain embodiments, the disease or disorder is nephrocalcinosis. In certain embodiments, the disease or disorder is chronic kidney disease. In certain embodiments, the disease or disorder is end stage renal disease. In certain embodiments, the disease or disorder is systemic oxalosis.

DETAILED DESCRIPTION
Abbreviations

Abbreviation
Meaning

DME
Dimethoxyethane

DMF
Dimethylformamide

NBS
N-Bromosuccinimide

NIS
N-Iodosuccinimide

PMB
p-Methoxybenzyl

THF
Tetrahydrofuran

TFA
Trifluoroacetic acid

Trt
Trityl

Definitions

To facilitate understanding of the disclosure set forth herein, a number of terms are defined below. Generally, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, and pharmacology described herein are those well-known and commonly employed in the art.

“About” preceding a numerical value refers to a range of values ±10% of the value specified.

“Acceptable” with respect to a formulation, composition or ingredient, means having no persistent detrimental effect on the general health of the subject being treated.

Whenever a group is described as being “optionally substituted,” it is meant that the referenced group can be “unsubstituted or substituted.”

“Alkoxy” means a group of the formula —OR, wherein R is alkyl. In certain embodiments, alkoxy includes methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, or hexyloxy.

“Alkoxyalkoxy” means a group of the formula —OR—OR′, wherein R is alkylene as defined herein, and R′ is alkyl as defined herein.

“Alkoxycarbonyl” means a group of the formula —C(O)R, wherein R is alkoxy, as defined herein.

“Alkoxycarbonyloxy” means a group of the formula —OC(O)R, wherein R is alkoxy, as defined herein.

“Alkylcarbonylaminoalkoxy” means a group of the formula —OR—NH—C(O)R′, wherein R is alkylene, as defined herein, and R′ is alkyl, as defined herein.

“Alkyl” means a straight or branched saturated hydrocarbon group containing from 1-10 carbon atoms, and in certain embodiments includes 1-6 carbon atoms. In certain embodiments, alkyl includes 1-4 carbon atoms (“C_1-4alkyl”). In certain embodiments alkyl includes 1-3 carbon atoms (“C_1-3alkyl”). In certain embodiments, alkyl includes methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylhexyl, n-heptyl, n-octyl, n-nonyl, or n-decyl.

“Alkylene” means a straight or branched saturated divalent hydrocarbon group containing from 1-10 carbon atoms, and in certain embodiments includes 1-6 carbon atoms.

“Alkylcarbonylamino” means a group of the formula —NHC(O)R, wherein R is alkyl, as defined herein.

“Amino” means an —NH₂group.

“Aminoalkoxy” means a group of the formula —O—R—NH₂, wherein R is alkyl as defined herein. In one embodiment, (amino)alkoxy includes (amino)propyloxy.

“Alkylaminoalkoxy” means an —O—R—NHR′ group, wherein R and R′ are independently alkyl as defined herein. In one embodiment (dialkylamino)alkoxy includes (methylamino)propyloxy.

“Aminocarbonyl” means an —C(O)NH₂group.

“Aminocarbonyloxy” means a group of the formula —OC(O)R, wherein R is amino, as defined herein.

“Alkylaminocarbonyloxy” means a group of the formula —OC(O)R, wherein R is alkylamino, as defined herein.

“Alkylamino” means a group of the formula —NHR, wherein R is alkyl as defined herein. In certain embodiments, alkylamino includes methylamino, ethylamino, n-propylamino, iso-propylamino, n-butylamino, iso-butylamino, or tert-butylamino.

“Alkylcarbonyl” means a group of the formula —C(O)R, wherein R is alkyl, as defined herein.

“Alkylcarbonyloxy” means a group of the formula —OC(O)R, wherein R is alkyl, as defined herein.

“Alkylsulfonyl” means a group of the formula —SO₂R, wherein R is alkyl, as defined herein.

“Aminosulfonyl” means a group of the formula —SO₂NH₂.

“Alkylaminosulfonyl” means a group of the formula —SO₂NHR, wherein R is alkyl, as defined herein.

“Dialkylaminoalkoxy” means an —O—R—NR′R″ group, wherein R, R′, and R″ are independently alkyl as defined herein. In one embodiment (dialkylamino)alkoxy includes (dimethylamino)propyloxy.

“Dialkylaminosulfonyl” means a group of the formula —SO₂NRR′, wherein R and R′ are independently alkyl, as defined herein.

“Aryl” means a monovalent six- to fourteen-membered, mono-, bi-, or tri-carbocyclic ring, wherein the monocyclic ring is aromatic and at least one of the rings in the bicyclic or tricyclic ring is aromatic. In certain embodiments, aryl includes phenyl, naphthyl, tetrahydronaphthyl, dihydronaphthyl, indanyl, or anthracenyl.

“Carbonyl” means an —C═(O) group.

“Carboxyl” means an —C(O)OH group.

“Cyano” means an —CN group.

“Cycloalkyl” means a monocyclic or bicyclic, saturated or partially unsaturated (but not aromatic), hydrocarbon ring of three to ten carbon ring atoms. Cycloalkyl groups include fused and bridged bicyclic rings. For example, when fused, the cycloalkyl group may comprise two rings that share adjacent atoms (e.g., one covalent bond). When bridged, the cycloalkyl group may comprise two rings that share three or more atoms, separating the two bridgehead atoms by a bridge containing at least one atom. When a cycloalkyl group contains from x-y ring carbon atoms, it may be referred to herein as C_x-ycycloalkyl. In certain embodiments, cycloalkyl is C_3-10cycloalkyl, or is C_5-7cycloalkyl, or is C_5-6cycloalkyl, or is C_3-6cycloalkyl, or is C_3-7cycloalkyl. In certain embodiments, cycloalkyl is C_3-8cycloalkyl. In certain embodiments, cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In certain embodiments, the cycloalkyl group is

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“(Cycloalkyl)alkyl” means an alkyl group, as defined herein, substituted with at least one cycloalkyl groups as defined herein. In certain embodiments, alkyl is substituted with 1 cycloalkyl group. In certain embodiments, alkyl is substituted with 1 or 2 cycloalkyl groups. In certain embodiments, (cycloalkyl)alkyl includes cyclobutylmethyl, cyclopentylmethyl, and cyclohexylmethyl.

“(Cycloalkyl)alkoxy” means a group of the formula —OR, wherein R is a (cycloalkyl)alkyl group as defined herein. In certain embodiments, (cycloalkyl)alkoxy includes cyclobutylmethoxy, cyclopentylmethoxy, and cyclohexylmethoxy.

“Cycloalkyloxy” means a group of the formula —OR, wherein R is cycloalkyl, as defined herein. In certain embodiments, cycloalkyloxy includes cyclobutyloxy, cyclopentyloxy, and cyclohexyloxy.

“Cycloalkylcarbonyl” means a group of the formula —C(O)R, wherein R is cycloalkyl, as defined herein.

“Cycloalkylcarbonyloxy” means a group of the formula —OC(O)R, wherein R is cycloalkyl, as defined herein.

“Dialkylamino” means a group of the formula —NRR′, wherein R and R′ are independently alkyl as defined herein. In certain embodiments, dialkylamino includes dimethylamino, diethylamino, N,N-methylpropylamino or N,N-methylethylamino.

“Dialkylaminocarbonyl” means a group of the formula —C(O)R, wherein R is dialkylamino, as defined herein.

“Dialkylaminocarbonyloxy” means a group of the formula —OC(O)R, wherein R is dialkylamino, as defined herein.

“Halo” means a fluoro, chloro, bromo, or iodo group.

“Haloalkoxy” means an alkoxy group, substituted with one or more halo atoms. In certain embodiments, all hydrogen atoms of the alkoxy group are replaced with halo atoms. In certain embodiments, the alkoxy is substituted with 1, 2, 3, 4, 5, or 6 halo atoms. In certain embodiments, the alkoxy is substituted with 1, 2, or 3 halo atoms. In certain other embodiments, the alkoxy is substituted with 2 halo atoms. In certain embodiments, the alkoxy is substituted with 1 halo atom. Certain embodiments of haloalkoxy include difluoromethoxy, trifluoromethoxy, or 1,1,1-trifluoroethoxy.

“Haloalkyl” means an alkyl group substituted with one or more halo atoms. In certain embodiments, all hydrogen atoms of the alkyl group are substituted with halo atoms. In certain embodiments, the alkyl group is substituted by 1, 2, 3, 4, 5, or 6 halo atoms. In certain embodiments, the alkyl group is substituted by 1, 2, or 3 halo atoms. In certain other embodiments, the alkyl group is substituted with 2 halo atoms. In certain embodiments, the alkyl group is substituted with 1 halo atom. In certain embodiments, haloalkyl includes trifluoromethyl, fluoromethyl, perfluoroethyl, or chloromethyl. Certain other embodiments of haloalkyl include chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, or 1,1,1-trifluoroethanyl.

“Heteroaryl” means a monocyclic, bicyclic, or tricyclic ring of 5 to 14 ring atoms containing one or more ring heteroatoms independently selected from —O—, —S—, —N═ (trivalent nitrogen), and —N(H)—, and the remaining ring atoms being carbon atoms, wherein the monocyclic ring is aromatic and wherein at least one of the rings in the bicyclic or tricyclic rings is aromatic (but does not have to be a ring which contains a heteroatom, e.g.; tetrahydroquinolinyl, dihydroisoquinolinyl, dihydrobenzodioxinyl, 2,3-dihydrobenzo[b][1,4]dioxinyl, and the like). In certain embodiments, heteroaryl is a monocyclic ring of 5 to 6 rings atoms. Unless stated otherwise, the valency may be located on any atom of any ring of the heteroaryl group, valency rules permitting.

In certain embodiments, heteroaryl includes, but is not limited to, triazolyl, tetrazolyl, pyrrolyl, imidazolyl, thienyl, furanyl, pyrazolyl, thiazolyl, oxazolyl, isooxazolyl, oxadiazolyl, thiadiazolyl, indolyl, indolinyl, isoindolinyl, indazolyl, benzimidazolyl, benzoxazolyl, benzofuranyl, benzothienyl, benzopyranyl, benzothiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, dihydroisoquinolinyl, pyrrolo[3,2-c]pyridinyl, pyrrolo[1,2-b]pyridazinyl, imidazo[1,2-a]pyridinyl, benzo[d][1,3]dioxolyl, 2,3-dihydrobenzo[b][1,4]dioxinyl, furo[2,3-d]thiazolyl, thieno[2,3-d]oxazolyl, thieno[3,2-b]furanyl, furo[2,3-d]pyrimidinyl, furo[3,2-b]pyridinyl, furo[3,2-c]pyridinyl, 6,7-dihydro-5H-cyclopenta[b]pyridinyl, 7,8-dihydro-6H-cyclopenta[g]quinoxalinyl, dihydrobenzodioxinyl, or 2,3-dihydrobenzo[b][1,4]dioxinyl.

“Heterocycloalkyl” means a saturated or partially unsaturated (but not aromatic) monocyclic ring of 3 to 9 ring atoms, or a saturated or partially unsaturated (but not aromatic) bicyclic ring of 5 to 12 ring atoms in which one or more ring atoms is a heteroatom independently selected from —O—, —S—, —N═ (trivalent nitrogen), or —NH—, and the remaining ring atoms are carbon. In certain embodiments, heterocycloalkyl is a saturated or partially unsaturated monocyclic group of 4 to 7 rings atoms, or a saturated or partially unsaturated bicyclic group of 7 to 9 ring atoms. In certain embodiments, heterocycloalkyl is a saturated or partially unsaturated monocyclic group of 5 to 6 rings atoms or a saturated or partially unsaturated bicyclic group of 6 to 8 ring atoms.

In certain embodiments, the heterocycloalkyl group comprises one, two, three, or four ring heteroatoms, independently selected from —O—, —S—, —N═ (trivalent nitrogen), or —NH—, and the remaining ring atoms are carbon. In certain embodiments, the heterocycloalkyl group contains only one or two nitrogen atoms, and the remaining ring atoms are carbon. When a heterocycloalkyl group contains from x to y ring atoms, it may be referred to herein as “a x-y membered heterocycloalkyl”. In certain embodiments, the heterocycloalkyl is a 4-7 membered heterocycloalkyl, or is a 5-6 membered heterocycloalkyl, or is a 7-9 membered heterocycloalkyl. In certain embodiments, the heterocycloalkyl is a 5-8 membered heterocycloalkyl.

Heterocycloalkyl groups include fused or bridged heterocycloalkyl bicyclic rings. For example, a fused heterocycloalkyl group may comprise two rings that share adjacent atoms (e.g., one covalent bond). When bridged, the heterocycloalkyl group may comprise two rings that share three or more atoms, separating the two bridgehead atoms by a bridge containing at least one atom. In certain embodiments, the heterocycloalkyl group is

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In certain embodiments, heterocycloalkyl includes, but is not limited to, azetidinyl, pyrrolidinyl, 2,5-dihydro-1H-pyrrolinyl, 2,5-dihydro-1H-pyrrolyl, piperidinyl, morpholinyl, piperazinyl, pyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1,3-dioxinyl, 1,3-dioxanyl, 1,4-dioxinyl, 1,4-dioxanyl, thiomorpholinyl, thiamorpholinyl, perhydroazepinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, dihydropyridinyl, tetrahydropyridinyl, oxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolinyl, thiazolidinyl, quinuclidinyl, isothiazolidinyl, octahydroindolyl, octahydroisoindolyl, octahydropyrrolo[3,4-c]pyrrolinyl, decahydroisoquinolyl, tetrahydrofuryl, 2-azaspiro[3.3]heptanyl, 4,7-diazaspiro[2.5]octanyl, 1,6-diazaspiro[3.3]heptanyl, 7-azabicyclo[2.2.1]heptanyl, 3-azabicyclo[3.2.1]octanyl, and 8-azabicyclo[3.2.1]octanyl.

“(Heterocycloalkyl)alkyl” means an alkyl group, as defined herein, substituted with at least one, in another example 1 or 2, heterocycloalkyl groups as defined herein. In certain embodiments, the alkyl is substituted with one heterocycloalkyl group.

“Heterocycloalkylcarbonyl” means a group of the formula —C(O)R, wherein R is heterocycloalkyl, as defined herein.

“Heterocycloalkylcarbonyloxy” means a group of the formula —OC(O)R, wherein R is heterocycloalkyl, as defined herein.

“Heterocycloalkyl-one” means a heterocycloalkyl group as defined herein and wherein one ring carbon atom of the heterocycloalkyl group forms a double bond with oxygen atom. In certain embodiments heterocycloalkyl-one group is

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“Hydroxy” means an —OH group. The terms “hydroxy” and “hydroxyl” are used interchangeably and mean an —OH group.

“Hydroxyalkyl” means a group of formula —R—(OH)_z, where R is an alkyl as defined herein and z is 1 or 2. In one embodiment, hydroxyalkyl is —ROH. In one embodiment, hydroxyalkyl includes —CH₂OH. In one embodiment, hydroxyalkyl is —R(OH)₂.

“Hydroxyalkoxy” means a group of formula —O—R—(OH)_z, where R is an alkyl as defined herein and z is 1 or 2. In one embodiment, hydroxyalkoxy is —OR—(OH). In one embodiment, hydroxyalkoxy is —OR—(OH)₂. In one embodiment (hydroxy)alkoxy includes (hydroxy)propyloxy.

“Hydroxycarbonyl” means an —C(O)OH group. As used herein, the terms “hydroxycarbonyl” and “carboxyl” are used interchangeably and refer to the same group.

“Hydroxycarbonylalkyl” means a group of the formula —RC(O)OH, wherein R is alkylene as defined herein.

“Hydroxycycloalkyl” means a group of the formula —ROH, wherein R is cycloalkyl as defined herein. In certain embodiments, hydroxycycloalkyl is

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“(Hydroxycycloalkyl)alkyl” means a group of formula —RR′ wherein R is alkyl and R′ is hydroxycycloalkyl as defined herein. In certain embodiments (hydroxycycloalkyl)alkyl is

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“(Phenyl)alkyl” means an alkyl group, as defined herein, substituted with at least one phenyl group. In certain embodiments, the alkyl is substituted with one phenyl group. In certain embodiments, (phenyl)alkyl is benzyl.

“(Phenyl)alkoxy” means a group of the formula —OR, wherein R is (phenyl)alkyl as defined herein.

“Phenylcarbonyloxy” means a group of the formula —OC(O)R, wherein R is phenyl.

“Spirocycloalkyl” means a bicyclic cycloalkyl ring of 5 to 12 carbon ring atoms having one quaternary carbon ring atom common to both rings. In certain embodiments, the spirocycloalkyl is a C_5-12spirocycloalkyl, or is a C_8-11spirocycloalkyl.

In certain embodiments, spirocycloalkyl groups include spiro[2.5]octane, spiro[3.4]octane, spiro[3.5]nonane, spiro[4.4]nonane, spiro[4.5]decane, or spiro[5.5]undecane. In certain embodiments, the spirocycloalkyl group is

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or is

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In some embodiments, compounds of the described herein exist as stereoisomers, wherein asymmetric or chiral centers are present. The term (R) and (S) used herein are configurations as defined in IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem., (1976), 45:13-30, hereby incorporated by reference. The embodiments described herein specifically includes the various stereoisomers and mixtures thereof.

“Stereoisomers” include (but are not limited to) geometric isomers, enantiomers, diastereomers, and mixtures of geometric isomers, enantiomers or diastereomers. In some embodiments, individual stereoisomers of compounds are prepared synthetically from commercially available starting materials which contain asymmetric or chiral centers or by preparation of racemic mixtures followed by resolution. These methods of resolution are exemplified by (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and liberation of the optically pure product from the auxiliary or (2) direct separation of the mixture of optical enantiomers on chiral chromatographic column.

“Amelioration” of the symptoms of a particular disorder by administration of a particular compound or pharmaceutical composition refers to any lessening of severity, delay in onset, slowing of progression, or shortening of duration, whether permanent or temporary, lasting or transient that can be attributed to or associated with administration of the compound or composition.

The terms “effective amount” or “therapeutically effective amount,” refer to a sufficient amount of an agent or a compound being administered which will relieve to some extent one or more of the symptoms of the disease or disorder being treated. The result includes reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an “effective amount” for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms. An appropriate “effective” amount in any individual case is determined using any suitable technique, such as a dose escalation study.

“Excipient” or “pharmaceutically acceptable excipient” means a pharmaceutically-acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, solvent, or encapsulating material. Excipients include, for example, encapsulating materials or additives such as absorption accelerators, antioxidants, binders, buffers, coating agents, coloring agents, diluents, disintegrating agents, emulsifiers, extenders, fillers, flavoring agents, humectants, lubricants, perfumes, preservatives, propellants, releasing agents, sterilizing agents, sweeteners, solubilizers, wetting agents and mixtures thereof. In one embodiment, each component is “pharmaceutically acceptable” in the sense of being compatible with the other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit/risk ratio. See, e.g., Remington: The Science and Practice of Pharmacy, 21st ed.; Lippincott Williams & Wilkins: Philadelphia, Pa., 2005; Handbook of Pharmaceutical Excipients, 6th ed.; Rowe et al., Eds.; The Pharmaceutical Press and the American Pharmaceutical Association: 2009; Handbook of Pharmaceutical Additives, 3rd ed.; Ash and Ash Eds.; Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd ed.; Gibson Ed.; CRC Press LLC: Boca Raton, Fla., 2009.

“Pharmaceutically acceptable salt” refers to a formulation of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound. In certain instances, pharmaceutically acceptable salts are obtained by reacting a compound described herein, with acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, formic acid, acetic acid, trifluoroacetic acid, or salicylic acid. In some instances, pharmaceutically acceptable salts are obtained by reacting a compound described herein with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, and salts with amino acids such as arginine, or lysine, or by other methods previously determined. The pharmacologically acceptable salts are not specifically limited as far as it can be used in medicaments.

The term “pharmaceutical composition” refers to a mixture of a compound described herein with other chemical components, such as an excipient. The pharmaceutical composition facilitates administration of the compound to an organism. Multiple techniques of administering a compound exist in the art including, but not limited to, intravenous, oral, aerosol, parenteral, ophthalmic, pulmonary and topical administration.

“Subject” refers to an animal, including, but not limited to, a primate (e.g., human), monkey, cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. The terms “subject” and “patient” are used interchangeably. In certain embodiments, the subject is a mammal. In certain embodiments, the subject is a human. In certain embodiments, the subject is an adult human. In certain embodiments, the subject is a human child.

In certain embodiments, the subject is a mammal. In certain embodiments, the subject is a human. In certain embodiments, the subject is an adult human. In certain embodiments, the subject is a human child.

“Treat,” “treating,” and “treatment,” in the context of treating a disease or disorder, are meant to include alleviating or abrogating a disorder, disease, or condition, or one or more of the symptoms associated with the disorder, disease, or condition; or to slowing the progression, spread or worsening of a disease, disorder or condition or of one or more symptoms thereof. Often, the beneficial effects that a subject derives from a therapeutic agent do not result in a complete cure of the disease, disorder or condition.

The term “disease or disorder characterized by high oxalate content in the urine” refers to an oxylate content that is at least 10% higher than a reference level observed in a healthy patient. For example, in certain embodiments, the disease or disorder characterized by high oxalate content in the urine refers to an oxylate content that is at least 20% higher than a reference level observed in a healthy patient, such as at least 20%, at least 30%, at least 40%, at least 50%, at least 100%, or at least 200%, higher than a reference level observed in a healthy patient. In certain embodiments, the disease or disorder characterized by high oxalate content in the urine refers to an oxylate content that is about 10% higher than a reference level observed in a healthy patient, such as about 20%, about 30%, about 40%, about 50%, about 100%, about 200%, or more than 200%, higher than a reference level observed in a healthy patient. In certain embodiments, the disease or disorder characterized by high oxalate content in the urine refers to an oxylate content that is about 1.25 times higher than a reference level observed in a healthy patient, such as about 1.25 times, about 1.5 times, about 1.75 times, about 2 times, about 3 times, or more than 3 times, higher than a reference level observed in a healthy patient.

Embodiments

The following paragraphs present a number of embodiments of the compounds disclosed herein. In each instance the embodiment includes both the recited compound(s) as well as a single stereoisomer or mixture of stereoisomers thereof, as well as a pharmaceutically acceptable salt thereof.

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

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wherein:

Ring C is selected from:

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wherein the wavy lines () indicate the points of attachment of the C₁carbon to the carbonyl of C(O)—OR¹, and the C₂carbon to L;

L is a bond, CH₂, CF₂, O, NR^L, S, S(═O), C(═O), CH₂-Q, or Q-CH₂; wherein Q is O, NR^L, or S;

R^Lis hydrogen, C_1-4alkyl, C_3-6cycloalkyl, phenyl, or benzyl; wherein the C_1-4alkyl is optionally substituted with hydroxycarbonyl, alkoxycarbonyl, hydroxycarbonylalkyl, or alkylcarbonyloxy; and the phenyl group alone or as a part of the benzyl group is optionally substituted with one or two groups selected from halo and haloalkoxy;

Ring A is C_3-8cycloalkyl, C_8-11spirocycloalkyl, 5-8 membered heterocycloalkyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, thienyl, phenyl, naphthyl, indanyl, tetrahydronaphthyl, dihydronaphthyl, pyridyl, indolyl, benzothiazolyl, quinolinyl, isoquinolinyl, indolinyl, isoindolinyl, tetrahydroquinolinyl, dihydroisoquinolinyl, tetrahydroisoquinolinyl, 2,3-dihydrobenzo[b][1,4]dioxinyl, or tetrahydro-methanonaphthalenyl;

Ring B is present or not present; wherein:

when Ring B is present, then Ring A is optionally substituted with one or two groups independently selected from halo, alkyl, alkoxy, cyano, hydroxy, haloalkoxy, (cycloalkyl)alkoxy, and cycloalkyl;

when Ring B is not present and Ring A is phenyl, then Ring A is substituted with:
- (i) one or two R^AAgroups;
- (ii) 2 halo groups when L is other than O;
- (iii) 2 halo groups when L is O, and R²and R³are not hydrogen or alkyl;
- (iv) one halo group when L is CH₂NR^L;
- (v) one halo group and one group selected from the group consisting of haloalkoxy, cycloalkyloxy, (cycloalkyl)alkoxy, and (phenyl)alkoxy, when L is bond, O, S, or S(═O), wherein the phenyl is optionally substituted with halo, cyano, haloalkyl, or haloalkoxy; or
- (vi) one cyano group and one (phenyl)alkoxy group, when L is bond or O, wherein the phenyl as part of the (phenyl)alkoxy group is optionally substituted with halo or haloalkoxy;

when Ring B is not present and Ring A is other than phenyl, then
- (i) Ring A is substituted with one or two R^ABgroups or
- (ii) Ring A is unsubstituted, wherein:
  - 1) when Ring A is unsubstituted tetrahydroquinolinyl, then L is bond;
  - 2) when Ring A is unsubstituted 2,3-dihydrobenzo[b][1,4]dioxinyl, then L is O;
  - 3) when Ring A is unsubstituted tetrahydronaphthyl, then L is O, and R¹is not hydrogen or ethyl; or
  - 4) when Ring A is unsubstituted spirocycloalkyl, then L is O, S, or CH₂S;

each R^AAis independently alkyl; haloalkyl; haloalkoxy; cycloalkyloxy; (cycloalkyl)alkoxy; phenoxy optionally substituted with one or two halo groups; or alkylcarbonylaminoalkoxy;

each R^ABis independently halo; alkyl; hydroxy; alkoxy; haloalkyl; haloalkoxy; cycloalkyloxy; (cycloalkyl)alkoxy; or phenoxy optionally substituted with one or two halo groups;

Ring B, when present, is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each is optionally substituted with 1, 2, or 3 R^Bgroups;

each R^Bis independently halo; cyano; alkyl; hydroxyalkyl; alkylsulfonyl; aminosulfonyl; alkylaminosulfonyl; dialkylaminosulfonyl; haloalkyl; alkoxy; aminoalkoxy; alkylaminoalkoxy; dialkylaminoalkoxy; hydroxyalkoxy; haloalkoxy; alkylcarbonyl; alkoxyalkoxy; aminocarbonyl; alkylaminocarbonyl; dialkylaminocarbonyl; alkylcarbonylaminoalkoxy; cycloalkyl; (cycloalkyl)alkyl; cycloalkyloxy; (cycloalkyl)alkoxy wherein cycloalkyl group is optionally substituted with hydroxyalkyl; cycloalkylcarbonyl; cycloalkylcarbonyloxy; heterocycloalkyl optionally substituted with one or two groups independently selected from halo, alkyl, and alkylcarbonyl; (5-6-membered heterocycloalkyl-one)alkyl; 5-6-membered heterocycloalkyl-one; (heterocycloalkyl)alkyl; heterocycloalkylcarbonyl; or 5-6 membered heteroaryl optionally substituted with one group selected from alkyl, hydroxyalkyl, (hydroxycycloalkyl)alkyl, alkoxyalkyl, and hydroxycycloalkyl;

R¹is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, or W; wherein W is alkyl substituted with amino, alkylamino, dialkylamino, alkylcarbonyloxy, alkoxycarbonyl, phenylcarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkoxycarbonyloxy, cycloalkylcarbonyloxy, —N(R^1A)C(O)R^1B, —N(R^1A)C(O)OR^1B, or —N(R^1A)C(O)NR^1BR^1C; wherein R^1A, R^1B, and R^1Care each independently hydrogen or C_1-6alkyl;

R²and R³are independently hydrogen, alkyl, phenyl, benzyl, or alkoxy-substituted benzyl; wherein the alkyl is optionally substituted with halo, alkoxy, haloalkoxy, alkylcarbonyloxy, cycloalkylcarbonyloxy, or heterocycloalkylcarbonyloxy optionally substituted with alkoxycarbonyl;

provided:
- i. when L is S or CH₂, and Ring A is phenyl other than phenyl substituted with (cycloalkyl)alkoxy, then Ring B cannot be halo-substituted phenyl;
- ii. when L is O, Ring A is phenyl, and Ring B is not present, then R^AAcannot be alkyl;
- iii. when L is O, Ring A is phenyl substituted with 1 R^AA, and Ring B is not present, then R^AAcannot be meta-substituted trifluoromethyl;
- iv. when L is O, Ring A is phenyl, Ring B is not present, and R¹is ethyl, then R^AAcannot be trifluoromethoxy;
- v. when L is bond, Ring A is other than phenyl, Ring B is not present, and R¹is H, then R^ABcannot be methyl, and
- vi. when L is NH, Ring A is pyridyl, indolyl, or indolinyl, and Ring B is not present, then R^ABcannot be alkyl; and
  
  optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.

In certain embodiments, Ring B cannot be mono or di-substituted halo.

In certain embodiments, Ring B cannot be unsubstituted phenyl or phenyl substituted with one or two groups independently selected from alkyl, halo, or haloalkyl.

In certain embodiments, Ring A cannot be unsubstituted phenyl or phenyl substituted with one or two groups independently selected from alkyl, halo, or haloalkyl, and Ring B cannot be unsubstituted phenyl or phenyl substituted with one or two groups independently selected from alkyl, halo, or haloalkyl.

In certain embodiments, when L is S or CH₂, Ring B cannot be mono or di-substituted halo.

In certain embodiments, when L is S or CH₂, Ring B cannot be unsubstituted phenyl or phenyl substituted with one or two groups independently selected from alkyl, halo, or haloalkyl.

In certain embodiments, when L is S or CH₂, Ring A cannot be unsubstituted phenyl or phenyl substituted with one or two groups independently selected from alkyl, halo, or haloalkyl, and Ring B cannot be unsubstituted phenyl or phenyl substituted with one or two groups independently selected from alkyl, halo, or haloalkyl.

In certain embodiments, the compound of Formula (I):

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is that wherein:

ring C is selected from:

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wherein the wavy lines () indicate the points of attachment of the C₁carbon to the carbonyl of C(O)—OR¹, and the C₂carbon to L;

L is a bond, CH₂, CF₂, O, NR^L, S, S(═O), C(═O), CH₂-Q, or Q-CH₂; wherein Q is O, NR^L, or S;

R^Lis hydrogen, C_1-4alkyl, C_3-6cycloalkyl, phenyl, or benzyl; wherein the C_1-4alkyl is optionally substituted with hydroxycarbonyl, alkoxycarbonyl, or alkylcarbonyloxy; and the phenyl group alone or as a part of the benzyl group is optionally substituted with one or two groups selected from halo and haloalkoxy;

Ring A is cycloalkyl, spirocycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where each is optionally substituted with 1 or 2 R^AAgroups;

when Ring B is present, then Ring A is optionally substituted with one or two groups selected from halo, alkyl, alkoxy, haloalkoxy, (cycloalkyl)alkoxy, and cycloalkyl;

each R^AAis independently alkyl; halo; hydroxy; alkoxy; haloalkyl; haloalkoxy; cycloalkyloxy; (cycloalkyl)alkoxy; alkylcarbonylaminoalkoxy; phenoxy optionally substituted with one or two halo; or (phenyl)alkoxy wherein the phenyl is optionally substituted with halo, cyano, haloalkyl, or haloalkoxy;

Ring B, when present, is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each is optionally substituted with 1, 2, or 3 R^Bgroups;

each R^Bis independently halo; cyano; alkyl; alkylsulfonyl; aminosulfonyl; alkylaminosulfonyl; dialkylaminosulfonyl; haloalkyl; alkoxy; haloalkoxy; alkylcarbonyl; alkoxyalkoxy; aminocarbonyl; alkylaminocarbonyl; dialkylaminocarbonyl; alkylcarbonylaminoalkoxy; cycloalkyl; (cycloalkyl)alkyl; cycloalkyloxy; (cycloalkyl)alkoxy; cycloalkylcarbonyl; cycloalkylcarbonyloxy; heterocycloalkyl optionally substituted with one or two groups independently selected from halo, alkyl, and alkylcarbonyl; (5-6-membered heterocycloalkyl-one)alkyl; 5-6-membered heterocycloalkyl-one; (heterocycloalkyl)alkyl; heterocycloalkylcarbonyl; or 5-6 membered heteroaryl;

R¹is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, or W; wherein W is alkyl substituted with amino, alkylamino, dialkylamino, alkylcarbonyloxy, alkoxycarbonyl, phenylcarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkoxycarbonyloxy, cycloalkylcarbonyloxy, —N(R^1A)C(O)R^1B, —N(R^1A)C(O)OR^1B, or —N(R^1A)C(O)NR^1BR^1C; wherein R^1A, R^1B, and R^1Care each independently hydrogen or C_1-6alkyl;

R²and R³are independently hydrogen, alkyl, phenyl, benzyl, or alkoxy-substituted benzyl; wherein the alkyl is optionally substituted with halo, alkoxy, haloalkoxy, alkylcarbonyloxy, cycloalkylcarbonyloxy, or heterocycloalkylcarbonyloxy optionally substituted with alkoxycarbonyl; and

optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.

In certain embodiments, the compound of Formula (I):

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is that wherein:

ring C is selected from:

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wherein the wavy lines () indicate the points of attachment of the C₁carbon to the carbonyl of C(O)—OR¹, and the C₂carbon to L;

L is a bond, CH₂, CF₂, O, NR^L, S, C(═O), CH₂-Q, or Q-CH₂; wherein Q is O, NR^L, or S;

R^Lis hydrogen or C_1-4alkyl optionally substituted with hydroxycarbonyl, alkoxycarbonyl, or alkylcarbonyloxy;

Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where each is optionally substituted with 1 or 2 R^AAgroups;

each R^AAis independently alkyl, haloalkyl, haloalkoxy, cycloalkyloxy, (cycloalkyl)alkoxy, alkylcarbonylaminoalkoxy, or phenoxy optionally substituted with one or two halo;

each R^ABis independently halo, alkyl, hydroxy, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, (cycloalkyl)alkoxy, or phenoxy optionally substituted with one or two halo;

Ring B, when present, is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each is optionally substituted with one or two R^Bgroups;

each R^Bis independently halo, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylcarbonyl, alkoxyalkoxy, alkylcarbonylaminoalkoxy, cycloalkyl, (cycloalkyl)alkyl, cycloalkyloxy, (cycloalkyl)alkoxy, cycloalkylcarbonyl, cycloalkylcarbonyloxy, heterocycloalkyl optionally substituted with alkyl or alkylcarbonyl, (5-6-membered heterocycloalkyl-one)alkyl, (heterocycloalkyl)alkyl, or heterocycloalkylcarbonyl;

R¹is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, or W; where W is alkyl substituted with amino, alkylamino, dialkylamino, alkylcarbonyloxy, alkoxycarbonyl, or phenylcarbonyloxy;

R²and R³are independently hydrogen, alkyl, phenyl, benzyl, or alkoxy-substituted benzyl; wherein the alkyl is optionally substituted with halo, alkoxy, haloalkoxy, alkylcarbonyloxy, cycloalkylcarbonyloxy, or heterocycloalkylcarbonyloxy optionally substituted with alkoxycarbonyl; and

optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.