The invention provides compounds to treat the phosphate excess or

hyperphosphatemia associated with chronic kidney disease (CKD), dialysis patients with end stage renal disease (ESRD), and related cardiovascular disease.

In patients with impaired renal function, such as chronic kidney disease and dialysis patients with end stage renal disease, phosphorus accumulates in the body resulting in a rise in phosphorus concentration in the blood and a phosphate excess.

In some patients this phosphate burden reaches a state referred to as

hyperphosphatemia. The elevated phosphate burden in CKD and ESRD in turn brings about the hypersecretion of parathyroid hormones, i.e., secondary hyperparathyroidism, and causes bone lesions. Hyperphosphatemia has been linked with calcification of the coronary arteries and aorta, as well as cardiovascular and all-cause mortality. Vascular calcification is considered to promote dysfunction of the heart leading to death. Dysfunction of phosphate regulation has serious clinical consequences, and studies show that even small increases in serum phosphate levels, within the normal or near-normal range, may correlate with increased morbidity and mortality. Phosphate excess in CKD stage three and four patients, and the body's compensating response to the the phosphate excess, has been implicated in the associated cardiovascular morbidity and mortality. Decreasing phosphate absorption in CKD stage three and four patients may mitigate or prevent these responses and preserve cardiovascular health. Controlling phosphate load early in CKD may mitigate or prevent morbidity and mortality in affected patients (C. S. Ritter and E. Siatopolsky, Phosphate Toxicity in CKD: The Killer Among Us, Clin. J. Am. Soc. Nephrol, 1 1 : 1088-1100, 2016),

Three isoforms of NaPi-II have been identified. NaPi-IIa (type Ila, also referred to as SLC34A1) is mainly expressed in the kidney, while NaPi-IIb (type lib, also referred to as SLC34A2) is expressed in the small intestine and can be regulated by vitamin D. NaPi-IIc (type lie, also referred to as SLC34A3) is also expressed in the kidney. Phosphate absorption in the gastrointestinal tract is performed in large part by NaPi-IIb, whereas phosphate in the blood is filtered by renal glomeruli and reabsorbed in necessary amounts mainly by NaPi-IIa and 'NaPi-IIc in the renal tubule (Miyamoto, et al . Sodium-Dependent Phosphate

Cotransporters: Lessons from Gene Knockout and Mutation Studies, J. Pharm. Science, 100(9):3719-30, 2011).

In spite of progress made for treatment of phosphate excess, and/or

hyperphosphatemia, there remains a significant unmet need for safe and effective therapies to treat these conditions. Current treatments employ phosphate adsorbents to suppress phosphate absorption in the gastrointestinal tract. These include for example nonmetallic polymer adsorbents, for example sevelamer carbonate and sevelamer hydrochloride, calcium salt preparations, for example precipitated calcium carbonate, and metallic adsorbents, for example lanthanum carbonate. However, these agents have each been reported to have adverse effects such as constipation, diarrhea, hypercalcemia, and metal accumulation. In addition, treatment with adsorbents requires daily intake on the order of a few grams of adsorbent, and noncompliance with therapy is a common problem. Accordingly, there remains an unmet need for treatment of phosphate excess, and/or hyperphosphatemia, which provide improved safety, efficacy, and convenience.

Inhibition of NaPi-IIb may suppress phosphate absorption in the gastrointestinal tract resulting in decreased phosphate concentration in blood as an approach to treat

hyperphosphatemia (Sabbagh et al, Intestinal Phosphate Transport, Adv. Chronic Kidney Dis., 18(2):85–90, 2011). Suppression of phosphate absorption by NaPi-IIb inhibition employs a different mechanism of action, as compared to current phosphate adsorbents, and may provide clinically useful advantages for prevention and or treatment of phosphate excess and/or hyperphosphatemia. Further, NaPi-IIb transporter inhibitors may provide additional benefits for secondary hyperparathyroidism, chronic kidney disease, and/or cardiovascular disease associated with chronic kidney disease more generally, by decreasing the absorption of dietary phosphate.

The compounds of the present invention are inhibitors of NaPi-IIb transporter and demonstrate potent inhibition of NaPi-IIb. As such, compounds of the present invention are believed to be useful for the treatment of conditions in which NaPi-IIb mediated phosphate absorption plays a role, such as chronic kidney disease and hyperphosphatemia.

United States Application Publication US 2013/0053369 discloses certain

tetrahydrobenzothiophene compounds as inhibitors of NaPi-IIb, and recites the compounds as useful in treating a number of diseases including hyperphosphatemia.

The need for a safe and convenient treatment of phosphate excess,

hyperphosphatemia, chronic kidney disease, and/or cardiovascular disease associated with chronic kidney disease, without the disadvantages possessed by adsorbents, or other agents known in the field, continues to be a concern for treatment of patients renal disease. The present invention provides alternative compounds which are useful in treatment of phosphate excess, hyperphosphatemia, chronic kidney disease, and/or cardiovascular disease associated with chronic kidney disease. In addition, the compounds provided address the need for treatments of conditions associated with NaPi-IIb activity with improved efficacy and/or advantageous side effect and tolerability profiles.

The present invention provides a compound of the formula:

wherein Y is a fused cyclohexane ring or a fused phenyl ring,

wherein A is or , wherein the crossed lines indicate bonds for the point of attachement to the core of Formula II, and the dashed lines indicate bonds for the point of attachment to R2,

wherein R2 is selected from the group consisting of

-CH 3 , - (CH 2 ) 3 OH, - (CH 2 ) 3 OCG 3 , - (CH 2 ) 3 CO 2 H, -COOCH 3 , -Red 3 , -CO (CH 2 ) 3 CH 3 , - RED (CH 3 ) 2 , -CO (CH2) 2CO2H, -Red 2 NH 2 , -Red 2 n (CH 3 ) 2 ,

-SO 2 N [(CH The 2 ) 2 OCH 3 ] 2 , -SO 2 NHCH 3 , -SO 2 (CH The 2 ) 2 OCH 3 , -CONH (CH The 2 ) 4 OH,

-CONH(CH2)4OCH3, -CONHCH3, -CONH(CH2)2CO2H, -CONH(CH2)2OCH3,

Cone (CH

2 CH The 2 OCH 3 ) 2 , -CSNHCH 3 ,,,

and , wherein the dashed lines represent the point of attachment, wherein R’ is -CO2H or -CONH2,

or a pharmaceutically acceptable salt thereof.

The present invention further provides a compound of Formula II as described above

wherein Y is a fused cyclohexane ring , A is , and R’ is -CO2H, or a pharmaceutically acceptable salt thereof.

The present invention further provides a compound of Formula II as described above

wherein Y is a fused cyclohexane ring, A is , and R’ is

-CO2H, or a pharmaceutically acceptable salt thereof.

Further, the present invention provides a compound of the formula:

Formula I

wherein R is selected from the group consisting of -(CH2)3OH, -(CH2)3OCH3,

-(CH2)3CO2H, -CONH(CH2)4OH, -COCH2NH2, -SO2N[(CH2)2OCH3]2,

-CONH(CH2)4OCH3, and -CO(CH2)2CO2H,

wherein R’ is -CO2H or -CONH2,

or a pharmaceutically acceptable salt thereof.

The present invention further provides a compound of Formula I as described above wherein R’ is -CO2H, or a pharmaceutically acceptable salt thereof.

The following particular embodiments are compounds and/or salts of Formula I and/ or II.

The present invention provides a compound which is 4-[2-[2,6-difluoro-4-[[2-[[3-[[4-(4-hydroxybutylcarbamoyl)-2,2-dimethyl-piperazin-1-yl]methyl]benzoyl]amino]-4,5,6,7- tetrahydrobenzothiophene-3-carbonyl]amino]phenyl]ethyl]benzoic acid, or a pharmaceutically acceptable salt thereof.

The present invention provides a compound which is 4-[2-[2,6-difluoro-4-[[2-[[3-[[4-(3-hydroxypropyl)-2,2-dimethyl-piperazin-1-yl]methyl]benzoyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carbonyl]amino]phenyl]ethyl]benzoic acid, or a

pharmaceutically acceptable salt thereof.

The present invention provides a compound which is 4-[2-[4-[[2-[[3-[[4-[bis(2-methoxyethyl)sulfamoyl]-2,2-dimethyl-piperazin-1-yl]methyl]benzoyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carbonyl]amino]-2,6-difluoro-phenyl]ethyl]benzoic acid, or a pharmaceutically acceptable salt thereof.

The present invention provides a compound which is 4-[2-[4-[[2-[[3-[[4-(3-carboxypropyl)-2,2-dimethyl-piperazin-1-yl]methyl]benzoyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carbonyl]amino]-2,6-difluoro-phenyl]ethyl]benzoic acid, or a pharmaceutically acceptable salt thereof.

The present invention provides a compound which is 4-[2-[2,6-difluoro-4-[[2-[[3-[[4-(3-methoxypropyl)-2,2-dimethyl-piperazin-1-yl]methyl]benzoyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carbonyl]amino]phenyl]ethyl]benzoic acid, or a

pharmaceutically acceptable salt thereof.

The present invention provides a compound which is 4-[2-[4-[[2-[[3-[[4-(2-aminoacetyl)-2,2-dimethyl-piperazin-1-yl]methyl]benzoyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carbonyl]amino]-2,6-difluoro-phenyl]ethyl]benzoic acid, or a pharmaceutically acceptable salt thereof.

The present invention provides a compound which is 4-[2-[2,6-difluoro-4-[[2-[[3-[[4-(4-methoxybutylcarbamoyl)-2,2-dimethyl-piperazin-1-yl]methyl]benzoyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carbonyl]amino]phenyl]ethyl]benzoic acid, or a

pharmaceutically acceptable salt thereof.

The present invention provides a compound which is 4-[4-[[3-[[3-[[4-[2-(4-carbamoylphenyl)ethyl]-3,5-difluoro-phenyl]carbamoyl]-4,5,6,7-tetrahydrobenzothiophen-2- yl]carbamoyl]phenyl]methyl]-3,3-dimethyl-piperazin-1-yl]-4-oxo-butanoic acid, or a pharmaceutically acceptable salt thereof.

The present invention provides a salt which is 4-[2-[2,6-difluoro-4-[[2-[[3-[[4-(4-hydroxybutylcarbamoyl)-2,2-dimethyl-piperazin-1-yl]methyl]benzoyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carbonyl]amino]phenyl]ethyl]benzoic acid, disodium.

The present invention provides a solid dispersion formulation of 4-[2-[2,6-difluoro-4-[[2-[[3-[[4-(4-hydroxybutylcarbamoyl)-2,2-dimethyl-piperazin-1-yl]methyl]benzoyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carbonyl]amino]phenyl]ethyl]benzoic acid, disodium, wherein the formulation comprises 30% 4-[2-[2,6-difluoro-4-[[2-[[3-[[4-(4-hydroxybutylcarbamoyl)-2,2-dimethyl-piperazin-1-yl]methyl]benzoyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carbonyl]amino]phenyl]ethyl]benzoic acid, disodium, and 70% polyvinylpyrrolidone-vinyl acetate.

The present invention further provides a compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

4-[2-[2,6-difluoro-4-[[2-[[3-[(2,2,4-trimethylpiperazin-1-yl)methyl]benzoyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carbonyl]amino]phenyl]ethyl]benzoic acid formic acid salt; 4-[2-[4-[[2-[[3-[[2,2-dimethyl-4-(methylcarbamoyl)piperazin-1-yl]methyl]benzoyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carbonyl]amino]-2,6-difluoro-phenyl]ethyl]benzoic acid;

4-[2-[4-[[2-[[3-[[2,2-dimethyl-4-(methylcarbamothioyl)piperazin-1-yl]methyl]benzoyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carbonyl]amino]-2,6-difluoro-phenyl]ethyl]benzoic acid;

4-[2-[4-[[2-[[3-[[4-(2-carboxyethylcarbamoyl)-2,2-dimethyl-piperazin-1-yl]methyl]benzoyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carbonyl]amino]-2,6-difluoro-phenyl]ethyl]benzoic acid;

4-[2-[2,6-difluoro-4-[[2-[[3-[[8-(methylcarbamoyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]methyl]benzoyl]amino]benzothiophene-3-carbonyl]amino]phenyl]ethyl]benzoic acid, formic acid salt;

4-[2-[2,6-difluoro-4-[[2-[[3-[(4-methoxycarbonyl-2,2-dimethyl-piperazin-1-yl)methyl]benzoyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carbonyl]amino]phenyl]ethyl]benzoic acid;

4-(2,6-difluoro-4-(2-(3-(((1R,5S)-8-pentanoyl-3,8-diazabicyclo[3.2.1]octan-3-yl)methyl)benzamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamido)phenethyl)benzoic acid;

4-[2-[4-[[2-[[3-[[2,2-dimethyl-4-(methylsulfamoyl)piperazin-1-yl]methyl]benzoyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carbonyl]amino]-2,6-difluoro-phenyl]ethyl]benzoic acid;

4-[2-[2,6-difluoro-4-[[2-[[3-[[8-(tetrahydropyran-4-ylcarbamoyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]methyl]benzoyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carbonyl]amino]phenyl]ethyl]benzoic acid;

4-[2-[4-[[2-[[3-[(8-acetyl-3,8-diazabicyclo[3.2.1]octan-3-yl)methyl]benzoyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carbonyl]amino]-2,6-difluoro-phenyl]ethyl]benzoate;

4-[2-[2,6-difluoro-4-[[2-[[3-[[8-(2-methoxyethylsulfonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]methyl]benzoyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carbonyl]amino]phenyl]ethyl]benzoate;

4-[2-[2,6-difluoro-4-[[2-[[3-[[8-(2-methoxyethylcarbamoyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]methyl]benzoyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carbonyl]amino]phenyl]ethyl]benzoate;

4-[2-[2,6-difluoro-4-[[2-[[3-[[8-(4-methoxybutylcarbamoyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]methyl]benzoyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carbonyl]amino]phenyl]ethyl]benzoate;

4-[2-[4-[[2-[[3-[[8-[bis(2-methoxyethyl)carbamoyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]methyl]benzoyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carbonyl]amino]-2,6-difluoro-phenyl]ethyl]benzoate;

4-[2-[2,6-difluoro-4-[[2-[[3-[[8-(2-methylpropanoyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]methyl]benzoyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carbonyl]amino]phenyl]ethyl]benzoate;

4-[2-[4-[[2-[[3-[[8-[2-(dimethylamino)acetyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]methyl]benzoyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carbonyl]amino]-2,6-difluoro-phenyl]ethyl]benzoic acid;

4-[2-[2,6-difluoro-4-[[2-[[3-[[8-[1-(methoxymethyl)cyclopropanecarbonyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]methyl]benzoyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carbonyl]amino]phenyl]ethyl]benzoic acid;

4-[2-[2,6-difluoro-4-[[2-[[3-[[8-[2-(4-methylpiperazin-1-yl)acetyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]methyl]benzoyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carbonyl]amino]phenyl]ethyl]benzoic acid;

4-[2-[2,6-difluoro-4-[[2-[[3-[[4-(4-hydroxybutylcarbamoyl)-2,2-dimethyl-piperazin-1-yl]methyl]benzoyl]amino]benzothiophene-3-carbonyl]amino]phenyl]ethyl]benzoic acid; and 4-[2-[4-[[2-[[3-[(4-acetyl-2,2-dimethyl-piperazin-1-yl)methyl]benzoyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carbonyl]amino]-2,6-difluoro-phenyl]ethyl]benzoic acid.

Further, the present invention provides a pharmaceutical composition comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient. Further, the present invention provides a

pharmaceutical composition comprising a compound of formula II, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.

Further, the present invention provides a compound of formula I or II, or a pharmaceutically acceptable salt thereof, for use in therapy. The present invention provides a salt which is 4-[2-[2,6-difluoro-4-[[2-[[3-[[4-(4-hydroxybutylcarbamoyl)-2,2-dimethyl-piperazin-1-yl]methyl]benzoyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carbonyl]amino]phenyl]ethyl]benzoic acid, disodium, for use in therapy.

Further, the present invention provides a compound of formula I, or a

pharmaceutically acceptable salt thereof, for use in the treatment of hyperphosphatemia. Further, the present invention provides a compound of formula II, or a pharmaceutically acceptable salt thereof, for use in the treatment of hyperphosphatemia. Further, the present invention provides a compound of formula I or II, or a pharmaceutically acceptable salt thereof, for use in the treatment of chronic kidney disease. The present invention provides a salt which is 4-[2-[2,6-difluoro-4-[[2-[[3-[[4-(4-hydroxybutylcarbamoyl)-2,2-dimethyl-piperazin-1-yl]methyl]benzoyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carbonyl]amino]phenyl]ethyl]benzoic acid, disodium, for use in the treatment of

hyperphosphatemia. The present invention provides a solid dispersion formulation of 4-[2-[2,6-difluoro-4-[[2-[[3-[[4-(4-hydroxybutylcarbamoyl)-2,2-dimethyl-piperazin-1-yl]methyl]benzoyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carbonyl]amino]phenyl]ethyl]benzoic acid, disodium, wherein the formulation comprises 30% 4-[2-[2,6-difluoro-4-[[2-[[3-[[4-(4-hydroxybutylcarbamoyl)-2,2-dimethyl-piperazin-1-yl]methyl]benzoyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carbonyl]amino]phenyl]ethyl]benzoic acid, disodium, and 70% polyvinylpyrrolidone-vinyl acetate for use in the treatment of hyperphosphatemia.

The present invention provides a salt which is 4-[2-[2,6-difluoro-4-[[2-[[3-[[4-(4-hydroxybutylcarbamoyl)-2,2-dimethyl-piperazin-1-yl]methyl]benzoyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carbonyl]amino]phenyl]ethyl]benzoic acid, disodium, for use in the treatment of chronic kidney disease. The present invention provides a solid dispersion formulation of 4-[2-[2,6-difluoro-4-[[2-[[3-[[4-(4-hydroxybutylcarbamoyl)-2,2-dimethyl-piperazin-1-yl]methyl]benzoyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carbonyl]amino]phenyl]ethyl]benzoic acid, disodium, wherein the formulation comprises 30% 4-[2-[2,6-difluoro-4-[[2-[[3-[[4-(4-hydroxybutylcarbamoyl)-2,2-dimethyl-piperazin-1-yl]methyl]benzoyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carbonyl]amino]phenyl]ethyl]benzoic acid, disodium, and 70% polyvinylpyrrolidone-vinyl acetate for use in the treatment of chronic kidney disease.

The present invention provides a compound or salt which is 4-[2-[2,6-difluoro-4-[[2-[[3-[[4-(4-hydroxybutylcarbamoyl)-2,2-dimethyl-piperazin-1-yl]methyl]benzoyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carbonyl]amino]phenyl]ethyl]benzoic acid, or a pharmaceutically acceptable salt thereof, for use in the treatment of cardiovascular disease associtated with chronic kidney disease. The present invention provides a salt which is 4-[2-[2,6-difluoro-4-[[2-[[3-[[4-(4-hydroxybutylcarbamoyl)-2,2-dimethyl-piperazin-1-yl]methyl]benzoyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-

carbonyl]amino]phenyl]ethyl]benzoic acid, disodium, for use in the treatment of

cardiovascular disease associtated with chronic kidney disease. The present invention provides a method of treating cardiovascular disease associtated with chronic kidney disease comprising administrating to a patient in need thereof an effective amount of a compound or salt which is 4-[2-[2,6-difluoro-4-[[2-[[3-[[4-(4-hydroxybutylcarbamoyl)-2,2-dimethyl-piperazin-1-yl]methyl]benzoyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carbonyl]amino]phenyl]ethyl]benzoic acid, or a pharmaceutically acceptable salt thereof.

Further, the present invention provides the use of a compound of formula I or II, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating hyperphosphatemia, and/or chronic kidney disease.

Further, the present invention provides a method of treating hyperphosphatemia, comprising administering to a patient in need thereof an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof. Further, the present invention provides a method of treating hyperphosphatemia, comprising administering to a patient in need thereof an effective amount of a compound of formula II, or a pharmaceutically acceptable salt thereof.

Further, the invention provides a method of treating hyperphosphatemia comprising administrating to a patient in need thereof an effective amount of 4-[2-[2,6-difluoro-4-[[2-[[3-[[4-(4-hydroxybutylcarbamoyl)-2,2-dimethyl-piperazin-1-yl]methyl]benzoyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carbonyl]amino]phenyl]ethyl]benzoic acid, or a pharmaceutically acceptable salt thereof. Further, the invention provides a method of treating hyperphosphatemia comprising administrating to a patient in need thereof an effective amount of 4-[2-[2,6-difluoro-4-[[2-[[3-[[4-(4-hydroxybutylcarbamoyl)-2,2-dimethyl-piperazin-1-yl]methyl]benzoyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carbonyl]amino]phenyl]ethyl]benzoic acid, disodium. Further, the invention provides a method of treating hyperphosphatemia comprising administrating to a patient in need thereof an effective amount of a solid dispersion formulation of 4-[2-[2,6-difluoro-4-[[2-[[3-[[4-(4-hydroxybutylcarbamoyl)-2,2-dimethyl-piperazin-1-yl]methyl]benzoyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carbonyl]amino]phenyl]ethyl]benzoic acid, disodium, wherein

the formulation comprises 30% 4-[2-[2,6-difluoro-4-[[2-[[3-[[4-(4-hydroxybutylcarbamoyl)-2,2-dimethyl-piperazin-1-yl]methyl]benzoyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carbonyl]amino]phenyl]ethyl]benzoic acid, disodium, and 70% polyvinylpyrrolidone-vinyl acetate.

The term“pharmaceutically acceptable salt” includes an acid addition salt that exists in conjunction with the basic portion of a compound of formula I or II, or basic addition salt that exists in conjunction with the acidic portion of a compound of formula I or II. Such salts include the pharmaceutically acceptable salts, for example those listed in Handbook of Pharmaceutical Salts: Properties, Selection and Use, P. H. Stahl and C. G. Wermuth (Eds.), Wiley-VCH, New York, 2002 which are known to the skilled artisan.

In addition to pharmaceutically acceptable salts, other salts are contemplated in the invention. They may serve as intermediates in the purification of compounds or in the preparation of other pharmaceutically-acceptable salts, or are useful for identification, characterization or purification of compounds of the invention.

As used herein, the term“patient” refers to a warm blooded animal such as a mammal and includes a human. A human is a preferred patient.

Cardiovascular disease associated with chronic kidney disease may include sudden cardiac death, arrhythmia, angina, myocardial infarction, and heart failure (Kestenbaum et al., Serum Phosphate Levels and Mortality Risk Among People with Chronic Kidney Disease, J. Am. Soc. Nephrol.16: 520-528, 2005).

One skilled in the art may treat hyperphosphatemia and/or chronic kidney disease by administering to a patient presently displaying symptoms an effective amount of the compound of formula I. Thus, the terms“treatment” and“treating” are intended to refer to all processes wherein there may be a slowing, interrupting, arresting, controlling, or stopping of the progression of an existing disorder and/or symptoms thereof, but does not necessarily indicate a total elimination of all symptoms.

One skilled in the art may treat hyperphosphatemia and/or chronic kidney disease by administering to a patient having recognized risk factors for hyperphosphatemia and/or chronic kidney disease an effective amount of the compound of formula I. For instance,

Patients having phosphate levels in the high end of the normal range, in consideration with other factors such as hypertension and/or diabetes, may be considered as having recognized risk for hyperphosphatemia and/or chronic kidney disease, and cardiovascular diease associated with chronic kidney disease.

As used herein, the term“effective amount” of a compound of formula I or II refers to an amount which is effective in treating a disorder, such as hyperphosphatemia and/or chronic kidney disease described herein. One skilled in the art can determine an effective amount by the use of conventional techniques and by observing results obtained under circumstances considered to be informative to the current patient. In determining an effective amount or dose of a compound of formula I or II, a number of factors are considered, including, which compound of formula I or II is administered; whether co-administration of other agents exists; the species of mammal; its size, age, and general health; the degree of involvement or the severity of the disorder, such as hyperphosphatemia and/or chronic kidney disease; the response of the individual patient; the mode of administration; the bioavailability characteristics of the preparation administered; the dose regimen selected; and other relevant circumstances.

The compounds of the present invention can be administered alone or in the form of a pharmaceutical composition combined with pharmaceutically acceptable carriers or excipients, the proportion, and nature of which are determined by the solubility and chemical properties, including stability, of the compound selected, the chosen route of administration, and standard pharmaceutical practice. The compounds of the present invention, while effective themselves, may also be formulated and administered in the form of their pharmaceutically acceptable salts.

One skilled in the art of preparing formulations can readily select the proper form and mode of administration depending upon the particular characteristics of the compound selected, the disorder or condition to be treated, the stage of the disorder or condition, and other relevant circumstances (See, e.g., Remington: The Science and Practice of Pharmacy, L.V. Allen, Editor, 22nd Edition, Pharmaceutical Press, 2012).

Certain abbreviations are defined as follows:“AcOH” refers to acetic acid;“ACN” refers to acetonitrile;“BOP” refers to benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate;“DCM” refers to dichloromethane or methylene chloride;“DIPEA” refers to N,N-diisopropylethylamine;“DMF” refers to N,N-dimethylformamide;“DMSO” refers to dimethylsulfoxide;“EDCI” refers to 3-(ethyliminomethyleneamino)-N,N-dimethylpropan-1-amine;“EtOAc” refers to ethyl acetate; “EtOH” refers to ethanol;“FBS” refers to fetal bovine serum;“HATU” refers to 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid

hexafluorophosphate;“HEPES” refers to 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid’“HOBT” refers to hydroxybenzotriazole;‘hr” refers to hour or hours;“IC50” refers to the concentration of an agent that produces 50% of the maximal inhibitory response possible for that agent;“LC-ES/MS” refers to Liquid Chromatography Electrospray Mass

Spectrometry;“min” refers to minute or minutes;“MeOH” refers to methanol or methyl alcohol;“MTBE” refers to methyl-tert-butyl ether;“33P” refers to phosphorus-33;“psi” refers to pounds per square inch;“PyBOP” refers to benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate;“RT” refers to room temperature;

“TEA” refers to triethylamine;“TFA” refers to trifluoroacetic acid;“THF” refers to tetrahydrofuran;“Tris” refers to 2-amino-2-hydroxymethyl-propane-1,3-diol ;“U/mL” refers to units per milliliter;“PVP-VA” refers to polyvinylpyrrolidone-vinyl acetate.

Scheme 1 depicts the synthetic route to compounds of Formula Ix. Generally, the alkyl halide compound II may be aminated under various conditions well appreciated in the art, for example, using an amine and an appropriate non-nucleophilic base such as TEA, DIPEA, or in a suitable organic solvent such as THF, ACN, or DMF. More specifically, about 2 equivalents of tert-butyl 3,3-dimethylpiperazine-1-carboxylate may be heated in a microwave reaction vessel at 110 oC in the presence of about 1 equivalent of alkyl halide II and about 12 equivalents of DIPEA in ACN to obtain the alkyl amine III. The Boc protecting group of Compound III may be removed under acidic conditions well described in the art. More specifically, compound II may be treated with an excess of HCl in 1,4-dioxane in DCM to yield the hydrochloride salt IV.

Subsequent alkylation of compound IV may be carried out under a wide array of conditions well known in the art, such as treatment with an alkyl halide under alkylation conditions, for example, with an appropriately substituted alkyl halide and the amine IV in the presence of a non-nucleophilic base, such as TEA, DIPEA, pyridine, or 1,8-diazabicycloundec-7-ene, in an appropriate organic solvent such as DCM, ACN or DMF. Additionally, alkylation of compound IV may be performed under reductive amination conditions, such as with an appropriately substituted aldehyde in the presence of a reducing agent such as sodium borohydride, sodium triacetoxyborohydride, or sodium

cyanoborohydride, and a catalytic amount of an organic acid, such as AcOH or TFA, in an appropriate organic solvent, such as MeOH, EtOH, ACN, DCM, THF, or DMF. More specifically, compound IV may be treated with about 2 equivalents DIPEA and subsequently treated with 3-methoxyproprionaldehyde or 4-oxobutanoic acid methyl ester in the presence of about 2 equivalents of sodium triacetoxyborohydride and catalytic AcOH in DCM, to obtain compounds Va and Vb, respectively.

Acylation or sulfonylation of compound IV may be accomplished under conditions well known in the art, for example, using an acyl halide or sulfonyl halide under basic conditions using an excess of an appropriate non-nucleophilic base such as TEA or DIPEA in a suitable organic solvent such as DCM, THF, ACN, or DMF. More specifically, compound IV may be treated with about 4 equivalents of DIPEA and about 2 equivalents of N-(4-hydroxybutyl)-3,3-dimethyl-piperazine-1-carboxamide hydrochloride in a mixture of about 1:10 MeOH:ACN and heated in a microwave reactor at 100 oC, to obtain the compound Vc. Acylation of the amine IV may also be performed under standard amide coupling conditions well known in the art, for example, using EDCI and HOBT, HATU, BOP, or PyBOP, in the presence of a non-nucleophilic base such as TEA or DIPEA, and in a suitable organic solvent such as MeOH, ACN, THF, DCM, or DMF, or a combination thereof. More specifically, about 1.2 equivalents of compound IV may be treated with about 0.9 equivalents of 1,8-diazabicyclo [5.4.0]undec-7-ene and subsequently treated with about 1 equivalent N-(tert- butoxycarbonyl)glycine, 0.5 equivalents HOBT, and 1.2 equivalents EDCI in DMF to obtain compound Vd. Sulfonylation of compound IV may be achieved in the presence of about 1.5 equivalents bis(2-methoxyethyl)sulfamoyl chloride and about 5 equivalents TEA in DMF with heating, to obtain compound Ve.

Moreover, acylation of amines to obtain ureas, by nucleophilic addition of an amine to an isocyanate under basic conditions, are also well described in the art. Specifically, about 1 equivalent of compound IV may be treated with about 2 equivalents of 1-isocyanato-4-methoxy-butane in the presence of about 4 equivalents TEA in DCM to obtain compound Vf.

The compounds of Formula Ix may be prepared by saponification of the methyl ester moiety of compounds V under either acidic or basic conditions as well known in the art. More specifically, compounds Va-Vf may be treated with about 1-5 equivalents of LiOH in THF, MeOH, H2O, or an appropriate mixture thereof, to obtain compounds of Formula Ia-f. These conditions may simultaneously saponify the additional ester moiety in compound Vb. Additional protecting groups may be removed by well-known methods, for example, treatment of compound Ve with an excess of 4 M HCl in dioxane, after the ester

saponification is completed. Moreover, additional heteroatom-protected alkyl aldehydes, specifically 3-[(tert-butyldimethylsilyl)oxy]-1-propanal, may be treated with compound IV under reductive amination conditions as described above, deprotected in situ, and ultimately saponified as described above. More specifically, 3-[(tert-butyldimethylsilyl)oxy]-1-propanal and compound IV may be treated to reductive amination conditions, using sodium triacetoxyborohydride and catalytic AcOH as described over, with subsequent removal of the silyl group in situ, using excess HCl in 1,4-dioxane. Final saponification with LiOH, as described above, may be performed to obtain compound of Formula Ig.

An alternative synthesis to compound of Formula Ic is depicted in Scheme 2. A mixture of about 1 equivalent methyl 4-[2-(4-amino-2,6-difluoro-phenyl)ethyl]benzoate XII and 1.1 equivalents 3-(tert-butoxycarbonylamino)-4,5,6,7-tetrahydrobenzothiophene-2- carboxylic acid (Aurum Pharmatech) in DCM may be treated with about 1.25 equivalents bis-(2-oxo-3-oxazolidinyl)phosphinic chloride in the presence of about 5 equivalents DIPEA to give the product compound VII, which may be deprotected under standard conditions well known in the art, specifically with excess 4 N HCl in 1,4-dioxane and DCM as solvent, to obtain amine compound VIII. Amine VIII may be subjected to acylation conditions as described above, specifically with about 1.1 equivalents 3-(chloromethyl)benzoyl chloride in the presence of pyridine with DCM as solvent, to obtain compound IX. The alkyl chloride IX may be aminated under a wide array of amination conditions well known in the art, more specifically with about 2 equivalents N-(4-hydroxybutyl)-3,3-dimethyl-piperazine-1- carboxamide hydrochloride in the presence of about 4 equivalents DIPEA in a mixture of ACN/MeOH as described above to obtain compound X, and subsequent saponification as described above may yield the compound of Formula Ic.

The synthesis of aniline compound XII is depicted in Scheme 3. Generally, palladium-copper mediated Sonogashira cross-coupling between an aryl halide and a substituted acetylene are well known in the art. Specifically, about 1 equivalent 3,5-difluoro- 4-iodoaniline (AstaTech) and about 1 equivalent methyl 4-ethynylbenzoate (Alfa Aesar) may be heated in the presence of about 0.4 equivalents bis(triphenylphosphine)-palladium(II) dichloride and 0.07 equivalents CuI with about 10 equivalents DIPEA in THF to give the diaryl acetylene compound XI, which may be reduced under standard conditions well described in the art, specifically catalytic hydrogenation at about 60 psi in the presence of palladium black in a solvent mixture of THF/H2O, to obtain the requisite aniline compound XII.

Scheme 4 illustrates the synthesis of amine XV. Nucleophilic addition of 1 equivalent t-butyl 2,2-dimethylpiperazine-1-carboxylate to about 1.1 equivalent of methyl 4-isocyanatobutanoate in the presence of 3 equivalents DIPEA with DCM as reaction solvent may yield the urea compound XIII. Reduction of the ester moiety may be accomplished using a wide array of conditions well described in the literature, including BH3, lithium borohydride, and diisobutyl aluminum hydride. More specifically, 1 equivalent of ester XII may be treated with about 3 equivalents of lithium borohydride in THF to give reduced

product XIV; subsequent removal of the BOC protecting group as described above gives the requisite compound XV.

Scheme 5 depicts the synthesis of compound of Formula Iy. Hydrolysis of the ester moiety in compound XVI may be achieved under conditions well known in the art, such as with an alkaline base such as NaOH, KOH, or LiOH in aqueous, organic, or biphasic solvent mixtures. More specifically, the ester XVI may be treated with 5 equivalents LiOH in a mixture of aqueous THF; mild acidification of the saponified acid may yield compound XVII. Subsequent direct amidation via the acid chloride may be accomplished under mild conditions (E. Valeur and M. Bradley, Chem. Soc. Rev., 2009, 38, 606–631). More specifically, the acid chloride of acid compound XVII may be generated in situ with 1.2-2.5 equivalents of bis(2-oxo-3-oxazolidinyl)phosphinic chloride at room temperature followed by treatment with excess ammonia to obtain the desired primary amide XVIII. Removal of the BOC protecting group as described above gives the requisite compound XIX as described above. Acylation of the unmasked piperizine nitrogen may be achieved under conditions well known in the art, specifically treatment of compound XIX with 5 equivalents of a suitable non-nucleophilic base such as DIPEA in the presence of an acylating agent such as succinic anhydride to obtain the compound of Formula Iy. Other compounds of Formula I and/or II may be prepared by the skilled artisan by procedures analogous to those described herein using appropriate starting materials and modifications as needed.

The synthesis of compound X is depicted in Scheme 6. A BOPCl mediated amide coupling yields compound A. Removal of the BOC protecting group as described above gives the requisite compound B. Acylation of the amino group maybe achieved under conditions well known in the art, specifically treatment of B with 3-(chloromethyl)-benzoyl chloride in presence of pyridine to obtain compound C. Nucleophilic substitution of benzylic chloride with substituted piperazine yields methyl benzoate D. Subsequent saponification as described above affords the compound X.

Preparations and Examples

The following Preparations and Examples further illustrate the invention and represent typical synthesis of the compound of the invention. The reagents and starting materials are readily available or may be readily synthesized by one of ordinary skill in the art. It should be understood that the Preparations and Examples are set forth by way of illustration and not limitation, and that various modifications may be made by one of ordinary skill in the art.

LC-ES/MS is performed on an AGILENT® HP1100 liquid chromatography system. Electrospray mass spectrometry measurements (acquired in positive and/or negative mode) are performed on a Mass Selective Detector quadrupole mass spectrometer interfaced to the HP1100 HPLC. LC-MS conditions (low pH): column: PHENOMENEX® GEMINI® NX C182.1 × 50 mm 3.5 Pm; gradient: 5-100% B in 3 min, then 100% B for 0.75 min, or 5-95% B in 1.5 min, then 95% B for 0.25 min; column temperature: 50 °C +/-10 °C; flow rate: 1.2 mL/min; Solvent A: deionized water with 0.1% HCOOH; Solvent B: ACN with 0.1% formic acid; wavelength 214 nm. Alternate LC-MS conditions (high pH): column:

XTERRA® MS C18 columns 2.1×50 mm, 3.5 Pm; gradient: 5% of solvent A for 0.25 min, gradient from 5% to 100% of solvent B in 3 min and 100% of solvent B for 0.5 min or 10% to 100% of solvent B in 3 min and at 100% of solvent B for 0.75 min or 5-95% B in 1.5 min, then 95% B for 0.25 min; column temperature: 50 °C +/-10 °C; flow rate: 1.2 mL/min; Solvent A: 10 mM NH4HCO3 pH 9; Solvent B: ACN ; wavelength: 214 nm.

NMR spectra are performed on a Bruker AVIII HD 400 MHz NMR Spectrometer or a Varian VNMRS 300 or 400 MHz NMR Spectrometer, obtained as CDCl3 or DMSO-d6 solutions reported in ppm, using residual solvent [CDCl3, 7.26 ppm; DMSO-d6, 2.50 ppm] as reference standard. When peak multiplicities are reported, the following abbreviations may be used: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br s (broad singlet), dd (doublet of doublets), dt (doublet of triplets). Coupling constants (J), when reported, are reported in hertz (Hz).

Preparation 1

methyl 4-[2-(4-amino-2,6-difluoro-phenyl)ethynyl]benzoate

A suspension of 3,5-difluoro-4-iodoaniline (14.7 g, 55.9 mmol), CuI (0.745 g, 3.91 mmol), bis(triphenylphosphine)palladium(II) dichloride (1.59 g, 2.24 mmol), methyl 4-ethynylbenzoate (9.05 g, 55.9 mmol), TEA (114 mL) and THF (44.1 mL) is stirred at 60 ºC for 3 hr. The mixture is cooled to RT and the solvent evaporated to dryness under reduced pressure. EtOAc (100 mL) and H2O (100 mL) are added, and the resulting solid is filtered over diatomaceous earth. The organic layer from the filtrate is separated, dried over MgSO4, and evaporated to dryness under reduced pressure. A 1:1 mixture of DCM:heptane (400 mL) is added to the resulting residue and the mixture is stirred at RT overnight. The resulting solid is collected by filtration and dried under vacuum to obtain the title compound (8.0 g, 45.8% yield) as a brown solid. 1H NMR (300 MHz, DMSO-d6) G 3.86 (s, 3H), 6.26-6.37 (m, 4H), 7.59 (d, J = 8.2 Hz, 2H), 7.96 (d, J = 8.5 Hz, 2H).

Preparation 2

methyl 4-[2-(4-amino-2,6-difluoro-phenyl)ethyl]benzoate

A 500 mL Parr shaker is charged with Pd black (0.53 g, 5.0 mmol) under N2. A degassed 4:1 solution of MeOH/THF (25 mL) is added followed by a degassed solution of methyl 4-[2-(4-amino-2,6-difluoro-phenyl)ethynyl]benzoate (1.17 g, 3.38 mmol) in a 4:1 mixture of MeOH/THF (25 mL) under N2. The resulting mixture is purged with N2 and pressurized with H2 to 60 psi. The sealed vessel is heated at 40 oC for 14 hr. The resulting suspension is filtered through a pad of diatomaceous earth under N2 and evaporated to dryness in vacuo. The resulting residue is purified by chromatography over silica, eluting with a gradient of 25-35% hexanes/THF, to afford the title compound as a white solid (404 mg, 40% yield) after solvent evaporation and drying under vacuum. 1H NMR (400.13 MHz, DMSO-d6) G, 2.71-2.83 (m, 4H), 3.84 (s, 3H), 5.52 (s, 2H), 6.10-6.15 (m, 2H), 7.28 (d, J = 8.3 Hz, 2H), 7.85 (d, J = 8.2 Hz, 2H). LC-ES/MS (m/z) 292 [M+1].

Preparation 3

tert-butyl 4-[(4-methoxy-4-oxo-butyl)carbamoyl]-2,2-dimethyl-piperazine-1-carboxylate

A 30 mL scintillation vial is charged with t-butyl 2,2-dimethylpiperazine-1-carboxylate (500 mg, 2.28 mmol) and DCM (12 mL). The resulting solution is cooled in an ice/water bath and DIPEA (1.20 mL, 6.85 mmol) is added in one portion. A solution of methyl 4-isocyanatobutanoate (447 mg, 2.97 mmol) in DCM (3 mL) is added drop wise over 5 min. The reaction mixture is slowly warmed to RT and stirred for a further 15 min. The mixture is partitioned between 5% aqueous citric acid (100 mL) and DCM (20mL). The organic layer is separated, and the aqueous layer is extracted twice more with DCM (20 mL each). The combined organic extracts are washed sequentially with saturated aqueous NaHCO3 (30 mL) and saturated aqueous NaCl (30 mL), dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure. The resulting residue is purified by chromatography over silica, eluting with a gradient of 30-50% hexanes/acetone, to obtain the title compound as colorless viscous oil (848mg, 95% yield) after solvent removal and drying under vacuum. 1H NMR (399.8 MHz, CDCl3) G 1.34 (s, 6H), 1.45 (s, 9H), 1.83 (t, J = 6.9 Hz, 2H), 2.37 (t, J = 7.1 Hz, 2H), 3.25-3.30 (m, 2H), 3.37 (t, J = 5.7 Hz, 2H), 3.47 (s, 2H), 3.65 (s, 3H), 3.71 (t, J = 5.7 Hz, 2H), 4.65-4.68 (m, 1H). LC-ES/MS (m/z) 358 [M+1].

Preparation 4

tert-butyl 4-(4-hydroxybutylcarbamoyl)-2,2-dimethyl-piperazine-1-carboxylate

A 2 M solution of LiBH4 in THF (3.02 mL, 6.04 mmol) is added drop wise to a 100 mL round bottom flask containing tert-butyl 4-[(4-methoxy-4-oxo-butyl)carbamoyl]-2,2-dimethyl-piperazine-1-carboxylate (783 mg, 2.01 mmol) and THF (2 mL) at RT. The resulting mixture is stirred for 12 hr at RT. The reaction mixture is quenched with 0.5 mL of MeOH, stirred at RT for 20 min, and partitioned between 5% aqueous NaHCO3 (150 mL) and DCM (50 mL). The organic layer is separated, and the aqueous layer is extracted twice more with DCM (50 mL each). The combined organic layers are washed with saturated aqueous NaCl (50 mL), dried over anhydrous Na2SO4, filtered, and evaporated to dryness under reduced pressure to afford the title compound as a white solid (634mg, 96% yield). 1H NMR (399.8 MHz, CDCl3) G 1.36 (s, 6H), 1.46 (s, 9H), 1.58-1.63 (m, 4H), 3.31-3.28 (m, 2H), 3.49 (s, 2H), 3.66-3.69 (m, 2H), 3.71-3.74 (m, 2H), 3.37-3.39 (m, 2H). LC-ES/MS (m/z) 330 [M+1].

Preparation 5

N-(4-hydroxybutyl)-3,3-dimethyl-piperazine-1-carboxamide hydrochloride

A 30 mL scintillation vial is charged with a solution of tert-butyl 4-(4-hydroxybutylcarbamoyl)-2,2-dimethyl-piperazine-1-carboxylate (631 mg, 1.92 mmol) in DCM (20 mL). A 4 N solution of HCl in dioxane (2.4 mL, 9.58 mmol) is added drop wise over 5 min and the resulting solution is stirred at RT for 2 hr. The volatiles are removed in vacuo and the residue is dried under vacuum to afford the title compound as a hygroscopic white oily solid (100% yield, quantitative), suitable for use in the next step without further purification. LC-ES/MS (m/z) 230 [M+1].

Preparation 6

methyl 4-[2-[4-[[2-(tert-butoxycarbonylamino)-4,5,6,7-tetrahydrobenzothiophene-3- carbonyl]amino]-2,6-difluoro-phenyl]ethyl]benzoate

A 100mL round bottom flask is charged with methyl 4-[2-(4-amino-2,6-difluoro-phenyl)ethyl]benzoate (2.11 g, 7.24 mmol), 3-(tert-butoxycarbonylamino)-4,5,6,7-

tetrahydrobenzothiophene-2-carboxylic acid (2.37 g, 7.97mmol), and DCM (60 mL). The resulting suspension is cooled in an ice/water bath, and DIPEA (5.05 mL, 29.0 mmol) is added drop wise to afford a yellow-brown turbid solution. Solid bis-(2-oxo-3-oxazolidinyl)phosphinic chloride (2.30 g, 9.05 mmol) is added in small portions over 30 min at 0 oC. The reaction mixture is then warmed to RT and stirred for 24 hr. Additional solid 3-(tert-butoxycarbonylamino)-4,5,6,7-tetrahydrobenzothiophene-2-carboxylic acid (0.6 g, 2.0 mmol) is added followed by additional DIPEA (1.26 mL, 7.25 mmol) and solid bis-(2-oxo-3-oxazolidinyl)phosphinic chloride (0.58 g, 2.26 mmol) in small portions over 5 min. The resulting turbid brown reaction mixture is stirred at RT for 12 hr. The reaction mixture is partitioned between 5% aqueous citric acid (150 mL) and DCM (25 mL), the organic layer is separated, and the aqueous layer is extracted twice more with DCM (50 mL each). The combined organic extracts are washed sequentially with 10% aqueous NaHCO3 (50 mL), saturated aqueous NaCl (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting brown oily solid is purified by chromatography over silica, eluting with a gradient of 15-40% hexanes/(10% MTBE in DCM). The collected fractions containing desired product are combined and concentrated under reduced pressure, and the resulting residue is triturated with MTBE (15 mL). The resulting solid is collected by filtration and dried under vacuum to afford the title compound (2.75 g, 66% yield). 1H NMR (400.1 MHz, DMSO-d6) G 1.44 (s, 9H), 1.69-1.77 (m, 4H), 2.53-2.65 (m, 4H), 2.91 (br s, 4H), 3.84 (s, 3H), 7.30-7.34 (m, 4H), 7.86 (d, J = 8.3 Hz, 2H), 9.80 (br s, 1H), 9.94 (s, 1H). LC-ES/MS (m/z) 569 [M-1].

Preparation 7

methyl 4-[2-[4-[(2-amino-4,5,6,7-tetrahydrobenzothiophene-3-carbonyl)amino]-2,6-difluoro- phenyl]ethyl]benzoate hydrochloride

A 30 mL scintillation vial is charged with methyl 4-[2-[4-[[2-(tert-butoxycarbonylamino)-4,5,6,7-tetrahydrobenzothiophene-3-carbonyl]amino]-2,6-difluoro-phenyl]ethyl]benzoate (351 mg, 0.61 mmol) and DCM (6 mL). The resulting light yellow solution is degased by passing through a gentle stream of N2. A solution of 4 N HCl in dioxane (155 mL, 6.1 mmol) is added drop wise over 5 min and the resulting solution is stirred at RT for 12 hr. The reaction mixture is concentrated in vacuo and the resulting pale yellow residue is triturated with a minimal amount of DCM. The resulting solid is collected by filtration and dried under vacuum to afford the title compound as an off-white powder (337 mg, 99% yield).1H NMR (399.8 MHz, DMSO-d6) G 1.73-1.75 (m, 4H), 2.40-2.44 (m, 2H), 2.56-2.59 (m, 2H), 2.85 (s, 4H), 3.80 (s, 3H), 7.26-7.28 (m, 4H),7.81-7.83 (m, 2H), 9.21 (s, 1H). LC-ES/MS (m/z) 571 [M+1].

Preparation 8

methyl 4-[2-[4-[[2-[[3-(chloromethyl)benzoyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3- carbonyl]amino]-2,6-difluoro-phenyl]ethyl]benzoate

A suspension of methyl 4-[2-[4-[(2-amino-4,5,6,7-tetrahydrobenzothiophene-3-carbonyl)amino]-2,6-difluoro-phenyl]ethyl]benzoate hydrochloride (2.43 g, 4.55 mmol) in DCM (80 mL) in a 250mL round bottom flask is cooled to 0 oC with an ice/water bath. Pyridine (0.92 mL, 11 mmol) is added drop wise with stirring over 5 min. The resulting pale yellowish solution is stirred for an additional 5 min at 0 oC, and a solution of 3-(chloromethyl)benzoyl chloride (0.71 mL, 5.0 mmol) in DCM (20 mL) is added drop wise over 5 min. The reaction mixture is stirred for additional 30 min at 0 oC. The reaction mixture is diluted with 150 mL of 10% aqueous citric acid and stirred at RT for 1 hr. The organic layer is separated and the aqueous layer is extracted twice more with DCM (50 mL each). The combined organic extracts are washed sequentially with 5% aqueous NaHCO3 (2 x 50 mL) and saturated aqueous NaCl (50 mL), dried over anhydrous Na2SO4, filtered, and evaporated to dryness under reduced pressure. The resulting residue is triturated with EtOH (30 mL), and the resulting solid is collected by filtration, washed with EtOH (15 mL), and dried under vacuum to yield the title compound as a tan solid (2.61 g, 92% yield). 1H NMR (400.1 MHz, DMSO-d6) G), 1.73-1.81 (m, 4H), 2.68 (m, 4H), 2.92 (s, 4H), 3.84 (s, 3H), 4.83 (s, 2H), 7.32 (d, J = 8.3 Hz, 2H) 7.38-7.344 (m, 2H), 7.56 (t, J = 7.7 Hz, 1H), 7.69 (d, J = 7.8 Hz, 1H), 7.82 (d, J = 7.9 Hz, 1H), 7.87 (d, J = 8.2 Hz, 2H), 7.96 (br s, 1H), 10.10 (s, 1H), 11.34 (s, 1H). LC-ES/MS (m/z-) 621 [M-1].

Preparation 9

methyl 4-[2-[2,6-difluoro-4-[[2-[[3-[[4-(4-hydroxybutylcarbamoyl)-2,2-dimethyl-piperazin- 1-yl]methyl]benzoyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3- carbonyl]amino]phenyl]ethyl]benzoate

A 2 mL microwave vial is charged with methyl 4-[2-[4-[[2-[[3-(chloromethyl)benzoyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carbonyl]amino]-2,6-difluoro-phenyl]ethyl]benzoate (50 mg, 0.08 mmol), N-(4-hydroxybutyl)-3,3-dimethyl-piperazine-1-carboxamide hydrochloride (42.7 mg, 0.16 mmol) and DIPEA (0.056 mL, 0.32 mmol) in a mixture of ACN (1.5 mL) and MeOH (50 PL). The resulting yellow suspension is heated in a BIOTAGE® Initiator microwave synthesizer at 110 °C for 4 hr. The reaction mixture is concentrated in vacuo and the residue is partitioned between 5% aqueous NaHCO3 (75 mL) and DCM (25 mL). The organic layer is separated, the aqueous layer is extracted with twice more with DCM (25 mL each), and the combined organic extracts are washed with saturated aqueous NaCl (25 mL), dried over anhydrous Na2SO4, filtered, and evaporated to dryness under reduced pressure. The resulting residue is purified by reverse phase chromatography over C-18 silica, eluting with a gradient of 0-100% of a mixture of 5% HCOOH in H2O/ACN, to afford the title compound as a light yellow foamy solid (30.2 mg, 46% yield) after solvent evaporation. 1H NMR (400.1 MHz, DMSO-d6) G 1.05 (s, 6H), 1.37-1.44 (m, 4H), 1.80-1.85 (m, 4H), 2.25-2.27 (m, 2H), 2.65-2.677 (m, 4H), 2.91 (br s, 4H), 2.96-3.05 (m, 2H), 3.12 (s, 2H), 3.17-3.26 (m, 2H), 3.35-3.41 (m, 2H), 3.51 (s, 2H), 3.84 (s, 3H), 4.36 (t, J = 5.1 Hz, 1H), 6.35-6.39 (m, 1H), 7.32 (d, J = 8.3 Hz, 2H), 7.51-7.56 (m, 4H), 7.70-7.80 (m, 1H), 7.87 (m, 3H), 10.01 (br s, 1H), 11.45 (br s, 1H). LC-ES/MS (m/z) 816 [M+1].

We claim:

1. A compound of the formula:

Formula II

wherein Y is a fused cyclohexane ring or a fused phenyl ring,

wherein A is or , wherein the crossed lines indicate bonds for the point of attachement to the core of Formula II, and the dashed lines indicate bonds for the point of attachment to R2,

wherein R2 is selected from the group consisting of

-CH 3 , - (CH The 2 ) 3 OH, - (CH The 2 ) 3 OCH 3 , - (CH The 2 ) 3 CO 2 the H, -COOCH 3 , -COCH 3 , - CO (CH The 2 ) 3 CH The 3 , - COCH (CH The 3 ) 2 , -CO ( and CH2) 2CO2H, -COCH 2 the NH 2 , -COCH 2 N (CH The 3 ) 2 , -SO 2 N [(CH The 2 ) 2 OCH 3 ] 2 , -SO 2NHCH 3 , -SO 2 (CH The 2 ) 2 OCH 3 , -CONH (CH The 2 ) 4 OH,

-CONH(CH2)4OCH3, -CONHCH3, -CONH(CH2)2CO2H, -CONH(CH2)2OCH3,

Cone (CH

2 CH The 2 OCH 3 ) 2 , -CSNHCH 3 ,,,

and
, wherein the dashed lines represent the point of attachment, wherein R’ is -CO2H or -CONH2,

or a pharmaceutically acceptable salt thereof.

2. A compound of Claim 1, wherein Y is a fused cyclohexane ring , A is

, and R’ is -CO2H, or a pharmaceutically acceptable salt thereof. 3. A compound of Claim 1, wherein Y is a fused cyclohexane ring, A is

, and R’ is -CO2H, or a pharmaceutically acceptable salt thereof.

4. A compound of the formula:

R'

wherein R is selected from the group consisting of -(CH2)3OH, -(CH2)3OCH3, -(CH2)3CO2H, -CONH(CH2)4OH, -COCH2NH2, -SO2N[(CH2)2OCH3]2, -CONH(CH2)4OCH3, and -CO(CH2)2CO2H,

wherein R’is -CO2H or -CONH2, or a pharmaceutically acceptable salt thereof. 5. A compound or salt of Claim 4 wherein R’ is -CO2H.

6. The compound or salt of Claim 1 which is 4-[2-[2,6-difluoro-4-[[2-[[3-[[4-(4- hydroxybutylcarbamoyl)-2,2-dimethyl-piperazin-1-yl]methyl]benzoyl]amino]- 4,5,6,7-tetrahydrobenzothiophene-3-carbonyl]amino]phenyl]ethyl]benzoic acid, which can be structurally represented as:

,

or a pharmaceutically acceptable salt thereof.

7. The compound or salt of Claim 1 which is 4-[2-[2,6-difluoro-4-[[2-[[3-[[4-(3- hydroxypropyl)-2,2-dimethyl-piperazin-1-yl]methyl]benzoyl]amino]-4,5,6,7- tetrahydrobenzothiophene-3-carbonyl]amino]phenyl]ethyl]benzoic acid, which can be structurally represented as:

,

or a pharmaceutically acceptable salt thereof.

8. The compound or salt of Claim 1 which is 4-[2-[4-[[2-[[3-[[4-[bis(2- methoxyethyl)sulfamoyl]-2,2-dimethyl-piperazin-1-yl]methyl]benzoyl]amino]- 4,5,6,7-tetrahydrobenzothiophene-3-carbonyl]amino]-2,6-difluoro- phenyl]ethyl]benzoic acid, which can be structurally represented as:

, or a pharmaceutically acceptable salt thereof.

9. The compound or salt of Claim 1 which is 4-[2-[4-[[2-[[3-[[4-(3-carboxypropyl)-2,2- dimethyl-piperazin-1-yl]methyl]benzoyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3- carbonyl]amino]-2,6-difluoro-phenyl]ethyl]benzoic acid, which can be structurally represented as:

,

or a pharmaceutically acceptable salt thereof.

10. The compound or salt of Claim 1 which is 4-[2-[2,6-difluoro-4-[[2-[[3-[[4-(3- methoxypropyl)-2,2-dimethyl-piperazin-1-yl]methyl]benzoyl]amino]-4,5,6,7- tetrahydrobenzothiophene-3-carbonyl]amino]phenyl]ethyl]benzoic acid, which can be structurally represented as:

or a pharmaceutically acceptable salt thereof.

11. The compound or salt of Claim 1 which is 4-[2-[4-[[2-[[3-[[4-(2-aminoacetyl)-2,2- dimethyl-piperazin-1-yl]methyl]benzoyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3- carbonyl]amino]-2,6-difluoro-phenyl]ethyl]benzoic acid, which can be structurally represented as:

,

or a pharmaceutically acceptable salt thereof.

12. The compound or salt of Claim 1 which is 4-[2-[2,6-difluoro-4-[[2-[[3-[[4-(4- methoxybutylcarbamoyl)-2,2-dimethyl-piperazin-1-yl]methyl]benzoyl]amino]-4,5,6,7- tetrahydrobenzothiophene-3-carbonyl]amino]phenyl]ethyl]benzoic acid, which can be structurally represented as:

,

or a pharmaceutically acceptable salt thereof.

13. The compound or salt of Claim 1 which is 4-[4-[[3-[[3-[[4-[2-(4- carbamoylphenyl)ethyl]-3,5-difluoro-phenyl]carbamoyl]-4,5,6,7- tetrahydrobenzothiophen-2-yl]carbamoyl]phenyl]methyl]-3,3-dimethyl-piperazin-1- yl]-4-oxo-butanoic acid, which can be structurally represented as:

,

or a pharmaceutically acceptable salt thereof.

14. A compound of Claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

4-[2-[2,6-difluoro-4-[[2-[[3-[(2,2,4-trimethylpiperazin-1-yl)methyl]benzoyl]amino]- 4,5,6,7-tetrahydrobenzothiophene-3-carbonyl]amino]phenyl]ethyl]benzoic acid formic acid salt;

4-[2-[4-[[2-[[3-[[2,2-dimethyl-4-(methylcarbamoyl)piperazin-1- yl]methyl]benzoyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carbonyl]amino]-2,6- difluoro-phenyl]ethyl]benzoic acid;

4-[2-[4-[[2-[[3-[[2,2-dimethyl-4-(methylcarbamothioyl)piperazin-1- yl]methyl]benzoyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carbonyl]amino]-2,6- difluoro-phenyl]ethyl]benzoic acid;

4-[2-[4-[[2-[[3-[[4-(2-carboxyethylcarbamoyl)-2,2-dimethyl-piperazin-1-yl]methyl]benzoyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carbonyl]amino]-2,6-difluoro-phenyl]ethyl]benzoic acid;

4-[2-[2,6-difluoro-4-[[2-[[3-[[8-(methylcarbamoyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]methyl]benzoyl]amino]benzothiophene-3-carbonyl]amino]phenyl]ethyl]benzoic acid, formic acid salt;

4-[2-[2,6-difluoro-4-[[2-[[3-[(4-methoxycarbonyl-2,2-dimethyl-piperazin-1-yl)methyl]benzoyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carbonyl]amino]phenyl]ethyl]benzoic acid;

4-(2,6-difluoro-4-(2-(3-(((1R,5S)-8-pentanoyl-3,8-diazabicyclo[3.2.1]octan-3-yl)methyl)benzamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamido)phenethyl)benzoic acid;

4-[2-[4-[[2-[[3-[[2,2-dimethyl-4-(methylsulfamoyl)piperazin-1-yl]methyl]benzoyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carbonyl]amino]-2,6-difluoro-phenyl]ethyl]benzoic acid;

4-[2-[2,6-difluoro-4-[[2-[[3-[[8-(tetrahydropyran-4-ylcarbamoyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]methyl]benzoyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carbonyl]amino]phenyl]ethyl]benzoic acid;

4-[2-[4-[[2-[[3-[(8-acetyl-3,8-diazabicyclo[3.2.1]octan-3-yl)methyl]benzoyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carbonyl]amino]-2,6-difluoro-phenyl]ethyl]benzoate;

4-[2-[2,6-difluoro-4-[[2-[[3-[[8-(2-methoxyethylsulfonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]methyl]benzoyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carbonyl]amino]phenyl]ethyl]benzoate;

4-[2-[2,6-difluoro-4-[[2-[[3-[[8-(2-methoxyethylcarbamoyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]methyl]benzoyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carbonyl]amino]phenyl]ethyl]benzoate;

4-[2-[2,6-difluoro-4-[[2-[[3-[[8-(4-methoxybutylcarbamoyl)-3,8- diazabicyclo[3.2.1]octan-3-yl]methyl]benzoyl]amino]-4,5,6,7- tetrahydrobenzothiophene-3-carbonyl]amino]phenyl]ethyl]benzoate;

4-[2-[4-[[2-[[3-[[8-[bis(2-methoxyethyl)carbamoyl]-3,8-diazabicyclo[3.2.1]octan-3- yl]methyl]benzoyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carbonyl]amino]-2,6- difluoro-phenyl]ethyl]benzoate;

4-[2-[2,6-difluoro-4-[[2-[[3-[[8-(2-methylpropanoyl)-3,8-diazabicyclo[3.2.1]octan-3- yl]methyl]benzoyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3- carbonyl]amino]phenyl]ethyl]benzoate;

4-[2-[4-[[2-[[3-[[8-[2-(dimethylamino)acetyl]-3,8-diazabicyclo[3.2.1]octan-3- yl]methyl]benzoyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carbonyl]amino]-2,6- difluoro-phenyl]ethyl]benzoic acid;

4-[2-[2,6-difluoro-4-[[2-[[3-[[8-[1-(methoxymethyl)cyclopropanecarbonyl]-3,8- diazabicyclo[3.2.1]octan-3-yl]methyl]benzoyl]amino]-4,5,6,7- tetrahydrobenzothiophene-3-carbonyl]amino]phenyl]ethyl]benzoic acid;

4-[2-[2,6-difluoro-4-[[2-[[3-[[8-[2-(4-methylpiperazin-1-yl)acetyl]-3,8- diazabicyclo[3.2.1]octan-3-yl]methyl]benzoyl]amino]-4,5,6,7- tetrahydrobenzothiophene-3-carbonyl]amino]phenyl]ethyl]benzoic acid;

4-[2-[2,6-difluoro-4-[[2-[[3-[[4-(4-hydroxybutylcarbamoyl)-2,2-dimethyl-piperazin- 1-yl]methyl]benzoyl]amino]benzothiophene-3-carbonyl]amino]phenyl]ethyl]benzoic acid; and

4-[2-[4-[[2-[[3-[(4-acetyl-2,2-dimethyl-piperazin-1-yl)methyl]benzoyl]amino]- 4,5,6,7-tetrahydrobenzothiophene-3-carbonyl]amino]-2,6-difluoro- phenyl]ethyl]benzoic acid.

15. The salt of Claim 1 which is 4-[2-[2,6-difluoro-4-[[2-[[3-[[4-(4- hydroxybutylcarbamoyl)-2,2-dimethyl-piperazin-1-yl]methyl]benzoyl]amino]- 4,5,6,7-tetrahydrobenzothiophene-3-carbonyl]amino]phenyl]ethyl]benzoic acid, disodium.

16. A pharmaceutical composition comprising a compound or salt according to any one of Claims 1 to 15, and a pharmaceutically acceptable carrier, diluent or excipient. 17. A solid dispersion formulation of 4-[2-[2,6-difluoro-4-[[2-[[3-[[4-(4- hydroxybutylcarbamoyl)-2,2-dimethyl-piperazin-1-yl]methyl]benzoyl]amino]- 4,5,6,7-tetrahydrobenzothiophene-3-carbonyl]amino]phenyl]ethyl]benzoic acid, disodium, wherein the formulation comprises 30% 4-[2-[2,6-difluoro-4-[[2-[[3-[[4-(4- hydroxybutylcarbamoyl)-2,2-dimethyl-piperazin-1-yl]methyl]benzoyl]amino]- 4,5,6,7-tetrahydrobenzothiophene-3-carbonyl]amino]phenyl]ethyl]benzoic acid, disodium, and 70% polyvinylpyrrolidone-vinyl acetate.

18. A method of treating hyperphosphatemia comprising administrating to a patient in need thereof an effective amount of a compound or salt according to any one of claims 1 to 15.

19. A method of treating chronic kidney disease comprising administrating to a patient in need thereof an effective amount of a compound or salt according to any one of claims 1 to 15.

20. A method of treating cardiovascular diease associated with chronic kidney disease comprising administrating to a patient in need thereof an effective amount of a compound or salt according to any one of claims 1 to 15.

21. A compound or salt as claimed in any one of claims 1 to 15, for use in therapy.

22. A compound or salt as claimed in any one of claims 1 to 15, for use in the treatment of hyperphosphatemia.

23. A compound or salt as claimed in any one of claims 1 to 15, for use in the treatment of chronic kidney disease and the cardiovascular diease associated with chronic kidney disease.

24. A method of treating cardiovascular disease associtated with chronic kidney disease comprising administrating to a patient in need thereof an effective amount of a salt which is 4-[2-[2,6-difluoro-4-[[2-[[3-[[4-(4-hydroxybutylcarbamoyl)-2,2-dimethyl- piperazin-1-yl]methyl]benzoyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3- carbonyl]amino]phenyl]ethyl]benzoic acid, disodium.