TWI659030B - Ip receptor agonist heterocyclic compounds - Google Patents

Abstract

The present invention provides heterocyclic derivatives that activate IP receptors. The activated IP receptor signaling pathway can be used to treat various forms of PAH, pulmonary fibrosis, and exert beneficial effects in fibrotic conditions in animal models and various organs of patients. The invention also encompasses pharmaceutical compositions comprising such derivatives.

Description

Heterocyclic compounds of IP receptor agonists

The invention relates to compounds as described herein, methods of using them, and uses thereof. Examples of the compound of the present invention include a compound of any one of Formula I, Ia, II or IIa or a pharmaceutically acceptable salt thereof and a compound of the examples.

Prostacyclin (or PGI2) is a member of the lipid molecule family called eicosanoids. It is an effective vasodilator, antiproliferative agent, and antithrombotic agent that mediates its effects as an IP receptor agonist. IP is regulated by the system G protein-coupled receptor, which, after being activated by prostacyclin, stimulates the formation of cyclic adenosine monophosphate (cAMP). Prostacyclin counteracts the thrombolytic activity of vasoconstrictors and endothelin.

Pulmonary hypertension (PAH) is a life-threatening disease characterized by progressive pulmonary vascular disease that leads to right ventricular hypertrophy. Exogenous administration of IP receptor agonists has become an important strategy for the treatment of PAH. (See, for example, Tuder et al., Am. J. Respir. Crit. Care. Med., 1999, 159: 1925-1932; Humbert et al., J. Am. Coll. Cardiol., 2004, 43: 13S-24S; Rosenzweig, Expert Opin. Emerging Drugs, 2006, 11: 609-619; McLaughlin et al., Circulation, 2006, 114: 1417-1431; Rosenkranz, Clin. Res. Cardiol., 2007, 96: 527-541; Driscoll et al. , Expert Opin. Pharmacother., 2008, 9: 65-81.).

Prostacyclin analog epoprostenol (flolan) is at least as effective as transplantation in terms of survival. Nevertheless, it is not used as a cutting-edge therapy due to significant tolerability, convenience, and cost issues. Instead, PAH patients are often first treated with endothelin receptor antagonists (e.g., bosentan) and / or PDE5 inhibitors (e.g., sildenafil). Good, but efficacy may be limited. Prostacyclin analogs are used primarily as additional treatments when the disease progresses to a severe degree and tolerance and convenience become less important.

Two key issues prevent current prostacyclin analogs from being used as cutting-edge therapies in PAH. First, it is extremely unstable and has a very short half-life, which means that it must be continuously infused via an indwelling intravenous (i.v.) catheter, which is neither convenient for patients but also associated with a significant risk of infection and sepsis. Second, it is associated with significant side effects, including nausea, jaw pain, headaches, and other side effects associated with systemic hypotension.

One solution to these problems is iloprost, which can be used as an aerosol formulation. The formulation has reduced tolerance problems, but the short half-life makes the daily dosing regimen 6 to 9 times. Recently, researchers are working to produce stable IP receptor agonists that can be used orally. These ligands can improve patient convenience and compliance, but require high concentrations of systemic drugs to achieve pharmacodynamic effects in the lungs; therefore, they may have similar side effects as their intravenous Floran observers.

This invention describes stable, highly selective IP receptor agonists suitable for oral and inhaled delivery. The present invention provides improvements that are significantly better than existing prostacyclin analogs and make them useful in patients with less severe severity. In addition, long-term activation of the IP receptor has been shown to reverse PAH-associated remodeling; therefore, early intervention with the present invention can have a significant effect on disease progression and may show reversal.

In addition, medical research has considerable interest in the development of IP receptor agonists for the treatment of pulmonary fibrosis. IP-deficient mice have been shown to be more susceptible to bleomycin-induced pulmonary fibrosis than wild-type animals (Lovgren AK et al. (2006) Am J Physiol Lung Cell Mol Physiol . 291: L144-56) and IP Receptor agonist iloprost can prolong the survival of bleomycin-treated mice (Zhu et al. (2010) Respir Res. 11 (1): 34).

In addition, IP receptor signaling has been shown to exert beneficial effects in fibrotic conditions in animal models and various organs of patients. IP receptor agonists have been shown to be beneficial for fibrosis of the heart, lungs, skin, pancreas, and liver as well as systemic sclerosis. (Gayraud M (2007) Joint Bone Spine . 74 (1): e1-8; Hirata Y et al. (2009) Biomed Pharmacother . 63 (10): 781-6; Kaneshig T et al. (2007) J Vet Med Sci . 69 (12): 1271-6; Sahsivar MO et al. (2009) Shock 32 (5): 498-502; Sato N et al. (2010) Diabetes 59 (4): 1092-100; Shouval DS et al. (2008) Clin Exp Rheumatol . 26 (3 Supplement 49): S105-7; Spargias K et al. (2009) Circulation . 120 (18): 1793-9; Stratton R et al. (2001) J Clin Invest . 108 (2): 241 -50; Takenaka M et al. (2009) Prostaglandins Leukot Essent Fatty Acids. 80 (5-6): 263-7; Watanabe M et al. (2009) Am J Nephrol . 30 (1): 1-11; Yano T et al. (2005) Am J Pathol . 166 (5): 1333-42; Zardi EM et al. (2007) Expert Opin Biol Ther . 7 (6): 785-90; Zardi EM et al. (2006) In Vivo 20 (3 ): 377-80; Rehberger P et al. (2009) Acta Derm Venereol . 89 (3): 245-9). Fibrotic conditions can be secondary to chronic inflammation indications throughout the body and occur in most organs and may share common causes.

Therefore, anti-fibrotic agents, such as the IP receptor agonist of the present invention, have potential benefits in all indications related to fibrotic tissue remodeling.

There is considerable interest in the development of IP receptor agonists for the treatment of other diseases, such as atherosclerotic thrombosis, pre-eclampsia. There is a great need to develop stable inhaled IP receptor agonists, which can improve the control of PAH.

Accordingly, the present invention provides compounds of Formula Ia:

Or a pharmaceutically acceptable salt thereof, wherein A is N or CR ';R' is H, optionally a C ₁ -C ₈ alkyl group substituted with one or more halogen atoms; R ¹ is H, optionally Or more than one halogen atom, C ₁ -C ₄ alkyl, OH, OR ', -NR ¹⁹ R ²¹ , CN or C ₃ -C ₇ cycloalkyl substituted C ₁ -C ₈ alkyl; or R ¹ is- XY; or R ¹ series -WR ⁷ -XY; or R ¹ series -S (O) ₂ -WXY; or R ¹ series -S (O) ₂ -WR ⁷ -XY; R ² series H, as appropriate Or more than one halogen atom, C ₁ -C ₄ alkyl, OH, OR ¹ , -NR ¹⁹ R ²¹ , CN or C ₃ -C ₇ cycloalkyl substituted C ₁ -C ₈ alkyl; or R ^2- XY; or R ² series -WR ⁷ -XY; or R ² series -S (O) ₂ -WXY; R ² series -S (O) ₂ -WR ⁷ -XY; where R ¹ or R ² series -XY, -WR ⁷ -XY, -S (O) ₂ -WXY; or -S (O) ₂ -WR ⁷ -XY; R ^2a is hydrogen; or R ² and R ^2a are pendant oxygen groups together; R ³ is H, C ₁ -C ₄ alkoxy, OH, -NR ¹⁹ R ²¹ , CN, halogen, C ₃ -C ₇ cycloalkyl or C ₁ -C ₈ alkyl optionally substituted with one or more halogen atoms; R ^4- series H, C ₁ -C ₄ alkoxy, OH, -NR ¹⁹ R ²¹ , CN, halogen, C ₃ -C ₇ cycloalkyl or C ₁ -C ₈ optionally substituted with one or more halogen atoms Alkyl; R ⁵ series Optionally substituted with one or more halogen atoms, C ₁ -C ₄ alkyl, OH, OR ', - NR 19 R 21, CN or C ₃ -C ₇ substituted cycloalkyl group of C ₁ -C ₈ alkyl; view C ₁ -C ₈ alkoxy substituted with one or more halogen atoms; C ₆ -C ₁₄ aryl;-(C ₀ -C ₄ alkyl) -4 to 14-membered heteroaryl or-(C ₀ -C ₄ alkyl) -3 to 14-membered heterocyclyl, wherein the heteroaryl and heterocyclyl contain at least one heteroatom selected from N, O and S, wherein the aryl, heteroaryl and heterocyclyl Each optionally substituted with one or more Z substituents; R ⁶ is C ₆ -C ₁₄ aryl;-(C ₀ -C ₄ alkyl) -4 to 14-membered heteroaryl,-(C ₀ -C ₄ Alkyl) -3 to 14-membered heterocyclyl, wherein the heteroaryl and heterocyclyl contain at least one heteroatom selected from N, O, and S, wherein the aryl, heteroaryl, and heterocyclyl are each optionally Substituted by one or more Z substituents; W is C ₁ -C ₈ alkyl which is optionally substituted by hydroxyl, halogen or C ₁ -C ₄ alkyl; X is optionally substituted by hydroxyl, halogen or C ₁ -C _4- alkyl substituted C ₁ -C ₈ alkylene; Y-based carboxyl, alkoxycarbonyl, tetrazolyl, aminoformyl, monoalkylaminoformyl, dialkylaminoformyl Or -CONH-S (O) _q -R ^x , wherein R ^x is -C ₁ -C ₄ alkyl or -NR ¹⁹ R ²¹ ; q is 0, 1 or 2; R ⁷ is a divalent moiety represented by: -O-, -NHC (O _{) -, - CH 2 = CH} 2 -, - C 6 -C 14 aryl group -D -; - 3 to 14-membered heterocyclic group -D-, wherein the heterocyclic group containing at least one heteroatom selected from N, O and S Heteroatoms where D is O, S, NH or absent; Z is independently OH, aryl, O-aryl, benzyl, O-benzyl, optionally via one or more OH groups or NH ₂ of substituent group C ₁ -C ₆ alkyl, optionally substituted with one or more of halogen atoms, C ₁ -C ₆ alkyl, optionally substituted by one or more OH groups of the C ₁ -C ₆ alkyl group, optionally substituted with one or more of halogen, C ₁ -C ₆ alkoxy, optionally substituted with one or more of C ₁ -C ₄ alkoxy-substituted C ₁ -C ₆ alkoxy, NR ¹⁸ (SO ₂ ) R ²¹ , (SO ₂ ) NR ¹⁹ R ²¹ , (SO ₂ ) R ²¹ , NR ¹⁸ C (O) R ²¹ , C (O) NR ¹⁹ R ²¹ , NR ¹⁸ C (O) NR ¹⁹ R ²¹ , NR ¹⁸ C (O) OR ¹⁹ , NR ¹⁹ R ²¹ , C (O) OR ¹⁹ , C (O) R ¹⁹ , SR ¹⁹ , OR ¹⁹ , side oxygen, CN, NO ₂ , halogen or 3 to 14 membered heterocyclyl group, wherein the heterocyclic group containing at least one heteroatom selected from N, O, and S heteroatoms of atoms; R ¹⁸ is independently H or C ₁ -C ₆ alkyl group; R ¹⁹ and R ²¹ are each independently H; C ₁ -C ₈ alkyl; C ₃ -C ₈ cycloalkyl; C ₁ -C ₄ alkoxy, -C ₁ - C ₄ alkyl; (C ₀ -C ₄ alkyl) -aryl, optionally substituted with one or more groups selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy and halogen ; (C ₀ -C ₄ alkyl) -3 to 14-membered heterocyclyl, the heterocyclyl includes one or more heteroatoms selected from N, O, and S, and optionally one or more selected from halogens , Pendant oxy, C ₁ -C ₆ alkyl and C (O) C ₁ -C ₆ alkyl groups; (C ₀ -C ₄ alkyl) -O-aryl groups, optionally by one or A plurality of substituents selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, and halogen; and (C ₀ -C ₄ alkyl) -O-3 to 14-membered heterocyclic group, the hetero cycloalkyl group comprising one or more heteroatoms selected from N, O, and S heteroatoms of which is optionally substituted with one or more substituents selected from halo, C ₁ -C ₆ alkyl or C (O) C ₁ -C ₆ alkyl group of Group substitution; wherein the alkyl groups are optionally substituted by one or more halogen atoms, C ₁ -C ₄ alkoxy, C (O) NH ₂ , C (O) NHC ₁ -C ₆ alkyl, or C (O ) N (C ₁ -C ₆ alkyl) ₂ substituents; or R ¹⁹ and R ²¹ form a 5-10 heterocyclyl group together with the nitrogen atom of the heterocyclic group package One or more other heteroatoms selected from N, O and S, the heterocyclyl optionally substituted with one or more substituents selected from: OH; halogen; aryl; 5- to 10-membered heterocyclyl , Which includes one or more heteroatoms selected from N, O, and S; S (O) ₂ -aryl; S (O) ₂ -C ₁ -C ₆ alkyl; C ₁ -C ₆ alkyl, Optionally substituted with one or more halogen atoms; C ₁ -C ₆ alkoxy, optionally substituted with one or more OH groups or C ₁ -C ₄ alkoxy; and C (O) OC _1- C ₆ alkyl, in which the aryl and heterocyclyl substitution is basically physically substituted with C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl or C ₁ -C ₆ alkoxy.

Various embodiments of the invention are described herein. It should be recognized that the features specified in each embodiment may be combined with other designated features to provide other embodiments.

In embodiments of the invention as described herein, A is N.

In an embodiment of the invention as described anywhere herein, A is CR '.

In embodiments of the invention as described herein, A is CR ', where R' is H.

In embodiments of the invention as described herein, wherein R ¹ is H, optionally C ₁ -C ₈ substituted with one or more halogen atoms, C ₁ -C ₄ alkyl, OH or OR 'Alkyl; or R ¹ is -XY; or R ¹ is -WR ⁷ -XY; or R ¹ is -S (O) ₂ -XY or R ² is -S (O) ₂ -WR ⁷ -XY; R ² Department of H, optionally substituted with one or more 'substituents of a halogen atom, C ₁ -C ₄ alkyl, OH or oR C ₁ -C ₈ alkyl group; R ² -XY system; or R ² based -WR ⁷ -XY ; Or R ² series -S (O) ₂ -XY; R ² series -S (O) ₂ -WR ⁷ -XY; wherein R ¹ or R ² series -XY, -WR ⁷ -XY, -S (O) ₂ -WXY; or -S (O) ₂ -WR ⁷ -XY; W is a C ₁ -C ₆ alkylene group optionally substituted with a hydroxyl group, a halogen or a C ₁ -C ₄ alkyl group; X is optionally a hydroxyl group , halogen or C ₁ -C ₄ alkyl group substituted with the C ₁ -C ₆ alkylene; the Y-based -C (O) OH, -C ( O) oR x, tetrazolyl, acyl urethane, monoalkyl Aminoaminomethylmethyl, dialkylaminomethylmethyl, or -CONH-S (O) _q -R ^x , where R ^x is -C ₁ -C ₄ alkyl or -NR ¹⁹ R ²¹ ; and q is 2; R 'Department of H, optionally substituted by one or more of halogen atoms, C ₁ -C ₄ alkyl; R ⁷ by the line ₆ -C ₁₄ represents a divalent moiety of the aryl group -D- -C; -3 to 14-membered heterocyclyl-D-, where the The heterocyclic group contains at least one heteroatom selected from N, O, and S, wherein D is O; R ¹⁹ and R ^{21 are} each independently H; C ₁ -C ₈ alkyl.

In an embodiment of the invention as described herein, wherein R ¹ is -XY; or -WR ⁷ -XY; R ² is H, optionally via one or more halogen atoms, C ₁ -C ₄ alkane group, OH or oR 'substituted with the C ₁ -C ₈ alkyl radical; W is optionally substituted with a hydroxyl group-based, halogen or C ₁ -C ₄ alkyl group substituted with the C ₁ -C ₆ extending alkyl; X system optionally substituted with hydroxy, Halo or C ₁ -C ₄ alkyl substituted C ₁ -C ₆ alkylene; Y is -C (O) OH, -C (O) OR ^x , tetrazolyl, aminoformyl, monoalkyl Aminoformyl, dialkylaminoformyl, or -CONH-S (O) _q -R ^x , wherein R ^x is -C ₁ -C ₄ alkyl or -NR ¹⁹ R ²¹ ; and q is 2 ; R 'Department of H, optionally substituted by one or more of halogen atoms, C ₁ -C ₄ alkyl; R ⁷ by the line ₆ -C ₁₄ represents a divalent moiety of the aryl group -D- -C; -3 to 14 -Membered heterocyclyl-D-, wherein the heterocyclyl contains at least one heteroatom selected from N, O, and S, wherein D is O; R ¹⁹ and R ^{21 are} each independently H; C ₁ -C ₈ alkyl .

In embodiments of the invention as described herein, wherein R ¹ is -XY; or -WR ⁷ -XY; R ² is H, optionally C ₁ -C ₄ substituted with one or more halogen atoms. alkyl; W is optionally substituted with a hydroxyl group-based, halogen or C ₁ -C ₄ alkyl group substituted with the C ₁ -C ₆ extending alkyl; X optionally substituted Department of hydroxy, halogen, C ₁ -C ₄ alkyl or C ₁ -C ₆ alkylene; the Y-based -C (O) OH; R ⁷ by the line ₆ -C ₁₄ represents a divalent moiety of the aryl group -D- -C; -3 to 14-membered heterocyclic group -D-, in which The heterocyclic group contains at least one heteroatom selected from N, O and S, wherein D is O.

In the embodiment of the present invention as described herein, wherein R ¹ is a C ₁ -C ₄ alkyl group optionally substituted with one or more halogen atoms,-(CH ₂ ) _m -C (O) OR "Or-(CH ₂ ) _m -R ^7- (CH ₂ ) _n -C (O) OR"; R ² is H, a C ₁ -C ₄ alkyl group optionally substituted with one or more halogen atoms; m Is 1, 2, 3, 4, 5, 6, 7, or 8; n is 0, 1, 2, or 3; R "is H or a C ₁ -C ₄ alkyl group optionally substituted with one or more halogen atoms ; R ⁷ by the line ₆ -C ₁₄ represents a divalent moiety of the aryl group -D- -C; -3 to 14-membered heterocyclic group -D-, wherein the heterocyclic group containing at least one heteroatom selected from N, O and S of Heteroatom, where D is O.

In an embodiment of the invention as described herein, wherein R ¹ is-(CH ₂ ) _m -C (O) OR "or-(CH ₂ ) _m -R ^7- (CH ₂ ) _n -C (O) OR "; R ² is H, optionally a C ₁ -C ₄ alkyl group substituted with one or more halogen atoms; m is 1, 2, 3, 4, 5, 6, 7, or 8; n is 2 or 3; R "is H or system optionally substituted with one or more substituents of halogen atoms, C ₁ -C ₄ alkyl; R ⁷ based -C ₆ -C ₁₄ aryl group represented by the bis -D- Valence part; -3 to 14-membered heterocyclyl-D-, wherein the heterocyclyl contains at least one heteroatom selected from N, O and S, wherein D is O.

In the embodiment of the present invention as described herein, wherein R ¹ is-(CH ₂ ) _m -C (O) OR "; R ² is H, and C is optionally substituted with one or more halogen atoms. _1- C ₄ alkyl; m is 1, 2, 3, 4, 5, 6, 7, or 8; R "is H or C ₁ -C ₄ alkyl substituted with one or more halogen atoms, as appropriate.

In an embodiment of the invention as described herein, wherein R ¹ is-(CH ₂ ) _m -C (O) OR "; R ² is H; R" is H; m is 4, 5, or 6 .

In an embodiment of the invention as described herein, wherein R ¹ is

R ² series H, , -CH ₃ or .

In an embodiment of the invention as described herein, wherein R ¹ is H,

R ² series or .

In embodiments of the invention as described herein, wherein R ³ is H, C ₁ -C ₄ alkoxy, OH, -NR ¹⁹ R ²¹ , CN, halogen, C ₃ -C ₇ cycloalkyl Or C ₁ -C ₄ alkyl optionally substituted with one or more halogen atoms; R ⁴ is H, C ₁ -C ₄ alkoxy, OH, -NR ¹⁹ R ²¹ , CN, halogen, C ₃ -C ₇ cycloalkyl, or optionally substituted by one or more of halogen atoms, C ₁ -C ₄ alkyl.

In the embodiment of the present invention as described herein, wherein R ³ is H, C ₁ -C ₄ alkoxy, OH, CN, halogen, C ₃ -C ₇ cycloalkyl, or optionally by one or C ₁ -C ₄ alkyl substituted with multiple halogen atoms; R ⁴ is H, C ₁ -C ₄ alkoxy, OH, CN, halogen, C ₃ -C ₇ cycloalkyl or optionally one or more C ₁ -C ₄ alkyl substituted with a halogen atom.

In embodiments of the invention as described herein, wherein R ³ is H, methoxy, OH, CN, halogen, cyclopropyl, or methyl; R ⁴ is H, methoxy, OH, CN , Halogen, cyclopropyl, or methyl.

In embodiments of the invention as described herein, wherein R ³ is H, OH, cyclopropyl or methyl; R ⁴ is H, OH, cyclopropyl or methyl.

In embodiments of the invention as described herein, wherein R ³ is H or OH; R ⁴ is H or OH.

In embodiments of the invention as described herein, wherein R ⁵ is C ₆ -C ₁₄ aryl;-(C ₀ -C ₄ alkyl) -4 to 14-membered heteroaryl or-(C ₀ -C ₄ alkyl) -3 to 14-membered heterocyclyl, wherein the heteroaryl and heterocyclyl contain at least one heteroatom selected from N, O and S, wherein the aryl, heteroaryl and heterocyclyl Each optionally substituted with one or more Z substituents; and R ⁶ is a C ₆ -C ₁₄ aryl;-(C ₀ -C ₄ alkyl) -4 to 14-membered heteroaryl,-(C ₀ -C _4- alkyl) -3 to 14-membered heterocyclyl, wherein the heteroaryl and heterocyclyl contain at least one heteroatom selected from N, O, and S, wherein each of the aryl, heteroaryl, and heterocyclyl is It is substituted with one or more Z substituents.

In embodiments of the invention as described herein, wherein R ⁵ is C ₆ -C ₁₄ aryl; -5 to 6-membered heteroaryl or -5 to 6-membered heterocyclic, wherein the heteroaryl And heterocyclyl contain at least one heteroatom selected from N, O, and S, wherein the aryl, heteroaryl, and heterocyclyl are each optionally substituted with one or more Z substituents; and R ⁶ is C _6- C ₁₄ aryl; -5 to 6-membered heteroaryl, -5 to 6-membered heterocyclyl, wherein the heteroaryl and heterocyclyl contain at least one heteroatom selected from N, O, and S, wherein the aryl , Heteroaryl and heterocyclyl are each optionally substituted with one or more Z substituents.

In embodiments of the invention as described herein, wherein R ⁵ is phenyl; 2-pyridyl, 3-pyridyl or 4-pyridyl, and R ⁶ is phenyl; 2-pyridyl, 3 -Pyridyl or 4-pyridyl, wherein phenyl, 2-pyridyl, 3-pyridyl, and 4-pyridyl are each optionally substituted with one or more Z substituents.

In an embodiment of the invention as described herein, wherein R ⁵ is phenyl, optionally substituted with the following groups: OH, optionally with one or more OH groups or NH ₂ groups C ₁ -C ₄ alkyl, optionally substituted with one or more of halogen atoms, C ₁ -C ₄ alkyl, optionally substituted by one or more OH groups or C ₁ -C ₄ alkoxy C ₁ of -C ₄ alkoxy, NR ¹⁹ R ²¹ , C (O) OR ¹⁹ , C (O) R ¹⁹ , SR ¹⁹ , OR ¹⁹ , CN, NO ₂ or halogen; and R ⁶ is phenyl, as appropriate the following groups: OH, optionally substituted with one or more OH groups of NH ₂ groups or C ₁ -C ₄ alkyl, optionally substituted with one or more of halogen atoms, C ₁ -C ₄ alkyl , optionally substituted with one or more of OH groups or C ₁ -C ₄ alkoxy C ₁ -C ₄ ^{alkoxy, NR 19 R 21, C (} O) oR 19, C (O) R 19, SR ¹⁹ , OR ¹⁹ , CN, NO ₂ or halogen.

In an embodiment of the invention as described herein, wherein R ⁵ is phenyl, optionally substituted by: C ₁ optionally substituted by one or more OH groups or NH ₂ groups -C ₄ alkyl, optionally substituted with one or more of halogen atoms, C ₁ -C ₄ alkyl, optionally substituted by one or more OH groups or C ₁ -C ₄ alkoxy groups C ₁ -C ₄ alkoxy or halogen; and R ⁶ is phenyl, optionally substituted with the following groups: C ₁ -C ₄ alkyl optionally substituted with one or more OH or NH ₂ groups, optionally C ₁ -C ₄ alkyl substituted with one or more halogen atoms, optionally C ₁ -C ₄ alkoxy or halogen substituted with one or more OH groups or C ₁ -C ₄ alkoxy.

In the embodiment of the present invention as described anywhere herein, wherein R ⁵ is a phenyl group, optionally substituted by the following group: a C ₁ -C ₄ alkyl group optionally substituted with one or more halogen atoms, C ₁ -C ₄ alkoxy or halogen; and R ⁶ is phenyl, optionally substituted with the following groups: C ₁ -C ₄ alkyl, optionally substituted with one or more halogen atoms, C ₁ -C ₄ alkoxy or halogen.

In the embodiment of the present invention as described anywhere herein, wherein R ⁵ is a phenyl group, optionally substituted by the following group: a C ₁ -C ₄ alkyl group optionally substituted with one or more halogen atoms, C ₁ -C ₄ alkoxy or halogen; and R ⁶ is phenyl, optionally substituted with the following groups: C ₁ -C ₄ alkyl, optionally substituted with one or more halogen atoms, C ₁ -C ₄ alkoxy or halogen.

In an embodiment of the invention as described herein, wherein R ⁵ is

R ⁶ series

Another embodiment of the invention, as defined above, provides a compound of formula II, which is represented by

In an embodiment of the invention as described in Formula II herein, A is N.

In an embodiment of the invention as described in Formula II herein, A is CR '.

In an embodiment of the invention as described in Formula II herein, A is CR ', and R' is H.

In an embodiment of the invention as described in Formula II herein, wherein R ¹ is H, optionally a C ₁ -C ₈ alkane substituted with one or more halogen atoms, C ₁ -C ₄ alkyl, OH or OR ′ Base; or R ¹ system -XY; or R ¹ system -WR ⁷ -XY; or R ¹ system -S (O) ₂ -XY or R ² system -S (O) ₂ -WR ⁷ -XY; R ² system H, optionally a C ₁ -C ₈ alkyl group substituted with one or more halogen atoms, C ₁ -C ₄ alkyl, OH or OR '; R ² -XY; or R ² -WR ⁷ -XY; Or R ² is -S (O) ₂ -XY; R ² is -S (O) ₂ -WR ⁷ -XY; wherein R ¹ or R ² is -XY, -WR ⁷ -XY, -S (O) ₂ -WXY; or ^{_{-S (O) 2 -WR 7 -XY}} ; W system optionally substituted with hydroxy, halogen or C ₁ -C ₄ alkyl group substituted with the C ₁ -C ₆ extending alkyl; X system optionally substituted with hydroxy, Halogen or C ₁ -C ₄ alkyl substituted C ₁ -C ₆ alkylene; Y-based carboxyl, alkoxycarbonyl, tetrazolyl, aminoformyl, monoalkylaminoformyl, dioxane Aminoaminomethyl or -CONH-S (O) _q -R ^x , where R ^x is -C ₁ -C ₄ alkyl or -NR ¹⁹ R ²¹ ; and q is 2; R 'is H, as appropriate substituted with one or more of halogen atoms, C ₁ -C ₄ alkyl; R ⁷ by the line ₆ -C ₁₄ represents a divalent moiety of the aryl group -D- -C; -3 to 14-membered heterocyclic group -D-, Where the The heterocyclic group contains at least one heteroatom selected from N, O, and S, wherein D is O; R ¹⁹ and R ^{21 are} each independently H; C ₁ -C ₈ alkyl.

In the embodiment of the present invention as described in Formula II herein, wherein R ¹ is -XY; or -WR ⁷ -XY; R ² is H, optionally via one or more halogen atoms, C ₁ -C ₄ alkyl , OH or oR 'substituted with the C ₁ -C ₈ alkyl radical; W is optionally substituted with a hydroxyl group-based, halogen or C ₁ -C ₄ alkyl group substituted with the C ₁ -C ₆ extending alkyl; X system optionally substituted with hydroxy, halogen, Or C ₁ -C ₄ alkyl substituted C ₁ -C ₆ alkylene; Y is -C (O) OH, -C (O) OR ^x , tetrazolyl, aminoformyl, monoalkylamine Methylformyl, dialkylaminoformyl, or -CONH-S (O) _q -R ^x , where R ^x is -C ₁ -C ₄ alkyl or -NR ¹⁹ R ²¹ ; and q is 2; p is 0, 1, 2, 3, or 4; R 'is H, optionally a C ₁ -C ₄ alkyl group substituted with one or more halogen atoms; R ⁷ is -C ₆ -C ₁₄ aryl-D -A divalent moiety represented by -3 to 14-membered heterocyclyl-D-, wherein the heterocyclyl contains at least one heteroatom selected from N, O, and S, wherein D is O; R ¹⁹ and R ^{21 are} each independently Ground is H; C ₁ -C ₈ alkyl.

In the embodiment of the present invention as described in Formula II herein, wherein R ¹ is -XY; or -WR ⁷ -XY; R ² is H, optionally a C ₁ -C ₄ alkane substituted with one or more halogen atoms. group; W is optionally substituted Department of hydroxy, halogen, C ₁ -C ₄ alkyl or C ₁ -C ₆ extending alkyl; X optionally substituted Department of hydroxy, halogen, C ₁ -C ₄ alkyl or C ₁ - C ₆ alkylene; the Y-based -C (O) OH; p lines 2, 3 or 4; R ⁷ by the line ₆ -C ₁₄ represents a divalent moiety of the aryl group -D- -C; -3 To 14-membered heterocyclyl-D-, wherein the heterocyclyl contains at least one heteroatom selected from N, O and S, wherein D is O.

In the embodiment of the present invention as described in Formula II herein, wherein R ¹ is-(CH ₂ ) _m -C (O) OR "or-(CH ₂ ) _m -R ^7- (CH ₂ ) _n -C ( O) OR "; R ² is H, optionally C ₁ -C ₄ alkyl substituted with one or more halogen atoms; m is 1, 2, 3, 4, 5, 6, 7, or 8; n is 0 , 1, 2, or 3; p is 0, 1, 2, 3, or 4; R "is H or C ₁ -C ₄ alkyl optionally substituted with one or more halogen atoms; R ⁷ is -C ₆ -C ₁₄ aryl-D- represents a divalent moiety; -3 to 14-membered heterocyclyl-D-, wherein the heterocyclyl contains at least one heteroatom selected from N, O, and S, wherein D is O.

In the embodiment of the present invention as described in Formula II herein, wherein R ¹ is-(CH ₂ ) _m -C (O) OR "or-(CH ₂ ) _m -R ^7- (CH ₂ ) _n -C ( O) OR "; R ² is H, optionally C ₁ -C ₄ alkyl substituted with one or more halogen atoms; m is 1, 2, 3, 4, 5, 6, 7, or 8; n is 0 , 1, 2, or 3; p is 0, 1, 2, 3, or 4; R "is H or C ₁ -C ₄ alkyl optionally substituted with one or more halogen atoms; R ⁷ is -C ₆ -C ₁₄ aryl-D- represents a divalent moiety; -3 to 14-membered heterocyclyl-D-, wherein the heterocyclyl contains at least one heteroatom selected from N, O, and S, wherein D is O.

In the embodiment of the present invention as described in Formula II herein, wherein R ¹ is-(CH ₂ ) _m -C (O) OR "; R ² is H, optionally C ₁ substituted with one or more halogen atoms -C ₄ alkyl; m is 1, 2, 3, 4, 5, 6, 7, or 8; p is 0, 1, 2, 3, or 4; R "is H or optionally one or more halogen atoms Substituted C ₁ -C ₄ alkyl.

In the embodiment of the present invention as described in Formula II herein, wherein R ¹ is-(CH ₂ ) _m -C (O) OR "; R ² is H; R" is H; m is 4, 5, or 6; p is 0.

In the embodiment of the present invention as described in Formula II herein, R ¹ is

R ² series H, , -CH ₃ or ; P is 0 or 1.

In the embodiment of the present invention as described in Formula II herein, R ¹ is H,

R ² series or ; P is 0 or 1.

In an embodiment of the present invention as described in Formula II herein, R ³ and R ^{4 are} independently H, OH, C ₁ -C ₆ alkyl, C ₁ -C ₄ alkoxy, cyano, or halogen.

In the embodiment of the present invention as described in Formula II herein, R ³ and R ^{4 are} independently H, OH, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, or halogen.

In the embodiment of the present invention as described in Formula II herein, R ³ and R ^{4 are} independently H, OH, methyl, ethyl, isopropyl, third butyl, methoxy, ethoxy, Propoxy, butoxy, fluorine, bromine or chlorine.

In embodiments of the invention as described herein, wherein Z is independently OH, C ₆ -aryl, OC ₆ -aryl, benzyl, O-benzyl, optionally via one or more OH the substituent group NH ₂ groups or C ₁ -C ₄ alkyl, optionally substituted with one or more of halogen atoms, C ₁ -C ₄ alkyl, optionally substituted with one or more OH groups or a C ₁ - C ₄ alkoxy substituted C ₁ -C ₄ alkoxy, NR ¹⁸ (SO ₂ ) R ²¹ , (SO ₂ ) NR ¹⁹ R ²¹ , (SO ₂ ) R ²¹ , NR ¹⁸ C (O) R ²¹ , C (O) NR ¹⁹ R ²¹ , NR ¹⁸ C (O) NR ¹⁹ R ²¹ , NR ¹⁸ C (O) OR ¹⁹ , NR ¹⁹ R ²¹ , C (O) OR ¹⁹ , C (O) R ¹⁹ , SR ¹⁹ OR ¹⁹ , pendant oxygen, CN, NO ₂ , halogen, or a 4- to 6-membered heterocyclic group, wherein the heterocyclic group contains at least one heteroatom selected from N, O, and S; R ¹⁸ is H or C _1- C ₄ alkyl; R ¹⁹ and R ^{21 are} each independently H; C ₁ -C ₄ alkyl; C ₃ -C ₆ cycloalkyl; C ₁ -C ₄ alkoxy-C ₁ -C ₄ alkyl; (C ₀ -C ₄ alkyl) -aryl, optionally substituted with one or more groups selected from C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, and halogen; (C _0- C ₄ alkyl) -4- to 6-membered heterocyclyl group, the heterocyclyl group comprises one or more heteroatoms selected from N, O and S atoms of Which is optionally substituted with one or more substituents selected from halogen, oxo, C ₁ -C ₄ alkyl and C (O) C ₁ -C ₄ alkyl group the group; (C ₀ -C ₄ alkyl) - O-aryl, optionally substituted with one or more groups selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, and halogen; and (C ₀ -C ₄ alkyl) -O 3 to 14-membered heterocyclyl group, the heterocyclyl group comprises one or more selected from N, O, and S heteroatoms of which is optionally substituted with one or more substituents selected from halo, C ₁ -C ₆ alkyl or C (O) C ₁ -C ₆ alkyl group substitution; wherein the alkyl groups are optionally substituted by one or more halogen atoms, C ₁ -C ₄ alkoxy, C (O) NH ₂ , C (O) NHC ₁ -C ₆ alkyl or C (O) N (C ₁ -C ₆ alkyl) ₂ substitution; or R ¹⁹ and R ²¹ together with the nitrogen atom to which they are attached form a 5- to 6-membered heterocyclic group, the heterocyclic ring Group includes one or more other heteroatoms selected from N, O, and S, and the heterocyclic group is optionally substituted with one or more substituents selected from: OH; halogen; aryl; 5- to 6-membered hetero A cyclic group including one or more heteroatoms selected from N, O, and S; S (O) ₂ -aryl; S (O) ₂ -C ₁ -C ₆ alkyl; C ₁ -C ₆ alkyl , which is optionally substituted by one or more halogen atoms; C ₁ -C ₄ alkoxy Which is optionally substituted with one or more OH groups or C ₁ -C ₄ alkoxy; and C (O) OC ₁ -C ₆ alkyl, wherein the aryl and heterocyclic group substituents may themselves optionally substituted with C _1- C ₆ alkyl, C ₁ -C ₆ haloalkyl or C ₁ -C ₆ alkoxy substituted.

In embodiments of the invention as described herein, wherein Z is independently OH, a C ₁ -C ₄ alkyl group optionally substituted with one or more OH groups or NH ₂ groups, and optionally substituted with one or more of halogen atoms, C ₁ -C ₄ alkyl, optionally substituted with one or more of OH groups or C ₁ -C ₄ alkoxy C ₁ -C ₄ alkoxy, NR ¹⁹ R ²¹ , C (O) OR ¹⁹ , C (O) R ¹⁹ , SR ¹⁹ , OR ¹⁹ , CN, NO ₂ or halogen; R ¹⁹ and R ^{21 are} each independently H; C ₁ -C ₄ alkyl; C _3- C ₆ cycloalkyl; or C ₁ -C ₄ alkoxy-C ₁ -C ₄ alkyl, where all alkyl groups are optionally substituted with halogen.

In embodiments of the invention as described herein, wherein Z is independently OH, a C ₁ -C ₄ alkyl group optionally substituted with one or more OH groups or NH ₂ groups, and optionally substituted with one or more of halogen atoms, C ₁ -C ₄ alkyl, optionally substituted by one or more OH groups or C ₁ -C ₄ alkoxy groups C ₁ -C ₄ alkoxy, C (O) OR ¹⁹ , C (O) R ¹⁹ , OR ¹⁹ , CN or halogen; R ¹⁹ is H; C ₁ -C ₄ alkyl; C ₃ -C ₆ cycloalkyl; or C ₁ -C ₄ alkoxy-C _1- C ₄ alkyl, where all alkyl groups are optionally substituted with halogen.

In an embodiment of the invention as described herein, wherein Z is independently C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy or halogen, optionally substituted with one or more halogen atoms; It should be understood that any and all embodiments of the present invention can be combined with any other embodiments to illustrate additional embodiments of the present invention. In addition, any element of an embodiment is intended to be combined with any and all other elements of any embodiment to illustrate additional embodiments. Those skilled in the art should understand that, if not possible, the combination of substituents is not the aspect of the present invention.

Another embodiment of the invention, as defined above, provides compounds of Formula I and Formula II, which are represented by: 7- (2,3-diphenyl-7,8-dihydropyrido [3,2-b ] Pyrazine-5 (6H) -yl) heptanoic acid; 7- (2,3-bis (4-fluorophenyl) -7,8-dihydropyrido [2,3-b] pyrazine-5 ( 6H) -yl) heptanoic acid; 7- (2,3-di-p-tolyl-7,8-dihydropyrido [2,3-b] pyrazin-5 (6H) -yl) heptanoic acid; 7- (2,3-bis (4-methoxyphenyl) -7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -yl) heptanoic acid; 6- (2 , 3-diphenyl-7,8-dihydropyrido [3,2-b] pyrazine-5 (6H) -yl) hexanoic acid; 5- (2,3-diphenyl-7,8- Dihydropyrido [3,2-b] pyrazine-5 (6H) -yl) pentanoic acid; 7- (6,7-diphenyl-3,4-dihydro-1,8-naphthyridine-1 (2H) -yl) heptanoic acid; 7- (6,7-diphenyl-3,4-dihydro-1,8-naphthyridin-1 (2H) -yl) heptanoic acid ethyl ester; racemic- 6- (1-methyl-6,7-diphenyl-1,2,3,4-tetrahydro-1,8-naphthyridin-2-yl) hexanoic acid; 7- (2-methyl-6 Enantiomer 1 of 7,7-diphenyl-3,4-dihydro-1,8-naphthyridin-1 (2H) -yl) heptanoic acid; 7- (1-methyl-6,7- Enantiomer 2 of diphenyl-1,2,3,4-tetrahydro-1,8-naphthyridin-2-yl) heptanoic acid 2; 2- (3-((6,7-diphenyl -3,4-dihydro-1,8-naphthyridin-1 (2H) -yl) methyl) phenoxy) acetic acid; 2- (3-((6, 7-diphenyl-3,4-dihydro-1,8-naphthyridin-1 (2H) -yl) methyl) phenoxy) ethyl acetate; 7- (2-methyl-6,7- Enantiomer 2 of diphenyl-3,4-dihydro-1,8-naphthyridin-1 (2H) -yl) heptanoic acid; 6- (1-methyl-6,7-diphenyl Enantiomers 1 and 2 of -1,2,3,4-tetrahydro-1,8-naphthyridin-2-yl) hexanoic acid; 6- (6,7-diphenyl -3,4-dihydro-1,8-naphthyridin-1 (2H) -yl) hexanoic acid; and 7- (1-methyl-6,7-diphenyl-1,2,3,4- Enantiomer 1 of tetrahydro-1,8-naphthyridin-2-yl) heptanoic acid.

Particularly preferred specific compounds of formula I, Ia, II or IIa or their pharmaceutically acceptable salts are those described in the examples below.

definition

The terms used in this specification have the following meanings: "Substituted as appropriate" means that the mentioned group may be substituted at any one or more positions with any of the groups listed below or any combination of those groups.

"Substituted by one or more Z groups as appropriate" means that the relevant group may include one or more substituents, each independently selected from a group falling within the definition of Z. Thus, when two or more Z group substituents are present, the substituents may be the same or different.

The term "halo" or "halogen" as used herein may be fluorine, chlorine, bromine or iodine.

As used herein, "C ₁ -C ₈ -alkyl" means a straight or branched chain alkyl group having 1 to 8 carbon atoms. If different numbers of carbon atoms are specified (such as C ₆ or C ₃ ), the definition should be modified accordingly. For example, "C ₁ -C ₄ -alkyl" represents methyl, ethyl, propyl, isopropyl, butyl , Isobutyl, second butyl, and third butyl.

As used herein, "C ₁ -C ₈ -alkoxy" means a straight or branched chain alkoxy group having 1 to 8 carbon atoms. If you specify a different number of carbon atoms (such as C ₆ or C ₃ ), the definition should be modified accordingly. For example, "C ₁ -C ₄ -alkoxy" represents methoxy, ethoxy, propoxy, isopropyl Oxy, butoxy, isobutoxy, second butoxy and third butoxy.

As used herein, "C ₁ -C ₄ -haloalkyl" means a straight or branched chain alkyl group having 1 to 4 carbon atoms in which at least one hydrogen is substituted with halogen. If you specify a different number of carbon atoms (such as C ₆ or C ₃ ), the definition should be modified accordingly. For example, "C ₁ -C ₄ -haloalkyl" represents methyl, ethyl, or propyl with at least one hydrogen substituted with halogen. Group, isopropyl group, butyl group, isobutyl group, second butyl group, and third butyl group, for example, halogen-based fluorine: CF ₃ CF _2- , (CF ₃ ) ₂ CH-, CH ₃ -CF _2- , CF ₃ CF _2- , CF ₃ , CF ₂ H-, CF ₃ CF ₂ CHCF ₃ or CF ₃ CF ₂ CF ₂ CF _2- .

The term "alkylene" refers to a straight or branched alkylene (divalent alkyl chain) having 1 to 8 carbon atoms, such as methylene, ethylidene, 1-methylalkylidene, 2 -Methylethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, hexamethylene and octamethylene.

As used herein, "C ₃ -C ₁₅ -cycloalkyl" means a saturated or partially saturated carbocyclic group having 3 to 15 ring carbon atoms, such as C ₃ -C ₈ -cycloalkyl. Examples of C ₃ -C ₁₅ -carbocyclic groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl or bicyclic groups, such as bicyclooctyl Group, bicyclononyl (including dihydroindenyl and indenyl) and bicyclodecyl. If a different number of carbon atoms is specified (such as C ₆ ), the definition should be modified accordingly.

As used herein, "aryl" or "C ₆ -C ₁₅ -aromatic carbocyclic group" means an aromatic group having 6 to 15 ring carbon atoms. Examples of C ₆ -C ₁₅ -aromatic carbocyclic groups include, but are not limited to, phenyl, phenylene, phenyltriyl, naphthyl, naphthyl, naphthyl, or anthracenyl. If a different number of carbon atoms is specified (for example, C ₁₀ ), the definition should be modified accordingly.

"4- to 8-membered heterocyclyl", "5- to 6-membered heterocyclyl", "3- to 10-membered heterocyclyl", "3- to 14-membered heterocyclyl", "4- to 14-membered heterocyclyl" "Heterocyclyl" and "5- to 14-membered heterocyclyl" respectively refer to 4- to 8-membered, 5- to 6-membered, 3- To 10-membered, 3- to 14-membered, 4- to 14-membered, and 5- to 14-membered heterocyclic rings, which may be saturated, partially saturated, or unsaturated (aromatic). Heterocyclic groups include monocyclic groups, fused ring groups, and bridging groups. Examples of this heterocyclyl include, but are not limited to, furan, pyrrole, pyrrolidine, pyrazole, imidazole, triazole, isotriazole, tetrazole, thiadiazole, isothiazole, oxadiazole, pyridine, hexahydropyridine , Pyrazine, oxazole, isoxazole, pyrazine, pyridazine, pyrimidine, hexahydropyrazine, pyrrolidine, pyrrolidone, morpholine, triazine, oxazine, tetrahydrofuran, tetrahydrothiophene, tetrahydrothioan , Tetrahydropyran, 1,4-dioxane, 1,4-oxetane, indazole, quinoline, indazole, indole, 8-aza-bicyclo [3.2.1] octane Alkane, 2,3-dihydrobenzofuran or thiazole.

"Heteroaryl" is a subset of heterocyclyl, where heterocyclyl is completely unsaturated (aromatic). Examples of such groups are pyridine and pyrazine.

The term "hydroxy or hydroxyl" includes a group having -OH.

The term "heteroatom" includes an atom of any element other than carbon or hydrogen. Heteroatoms are preferably nitrogen, oxygen, sulfur and phosphorus. In one embodiment, "heteroatoms" include nitrogen, sulfur, and oxygen.

The term "carboxy" refers to a carboxylic acid.

The term "alkoxycarboxy" refers to an ester.

The term "acyl group A" based -C (O) NH _2. The terms "monoalkylaminomethylamido" and "dialkylaminomethylamido" are aminomethylamido, wherein one or more hydrogens on the nitrogen are substituted with a C ₁ -C ₈ alkyl as described above .

A second aspect of the invention provides a compound of formula I, Ia, II or IIa or a pharmaceutically acceptable salt thereof, as defined herein, for use as a pharmaceutical preparation.

Activated IP receptors have been shown to have beneficial effects or treat the following diseases or disorders: PAH selected from: idiopathic PAH; familial PAH; PAH associated with collagen vascular disease selected from: scleroderma, CREST syndrome , Systemic lupus erythematosus (SLE), rheumatoid arthritis, Takayasu's arteritis, polymyositis, and dermatomyositis; PAHs associated with congenital heart disease selected from the following: individual atrial septal defect (ASD), Ventricular Septal Defect (VSD) and Open Arterial Catheter; PAH related to portal hypertension; PAH related to HIV infection; PAH related to drug or toxin uptake; Related to hereditary bleeding telangiectasia PAH; PAH associated with splenectomy; PAH (PAH associated with significant venous or capillary involvement) associated with extensive venous or capillary involvement; PAH associated with pulmonary venous occlusive disease (PVOD); and pulmonary capillary hemangioma (PCH) related PAH; Raynaud's phenomenon, including Raynaud's disease and Raynaud's syndrome; fibrotic diseases, including pulmonary fibrosis, systemic sclerosis / Scleroderma, liver fibrosis / sclerosis, renal fibrosis; thrombotic diseases, coronary artery disease, myocardial infarction, transient ischemic attack, colic, stroke, Ischemia-reperfusion injury, restenosis, atrial fibrillation, blood clot formation, atherosclerosis, atherosclerotic thrombosis, asthma, asthma symptoms, diabetes-related disorders, diabetic peripheral neuropathy, diabetic nephropathy, Diabetic retinopathy, glaucoma or other eye diseases with abnormal intraocular pressure, hypertension, preeclampsia, inflammation, prevention of unwanted side effects of COX-1, COX-2 and non-selective COX inhibitors, psoriasis, Psoriasis arthritis, rheumatoid arthritis, Crohn's disease, transplant rejection, multiple sclerosis, systemic lupus erythematosus (SLE), ulcerative colitis, ischemia-reperfusion injury, restenosis, atherosclerosis Sclerosis, acne, type 1 diabetes, type 2 diabetes, sepsis, and chronic obstructive pulmonary disease (COPD).

Yet another aspect of the present invention provides a compound of Formula I, Ia, II or IIa or a pharmaceutically acceptable salt thereof for use in treating PAH as described above.

Another aspect of the present invention provides a compound of Formula I, Ia, II or IIa or a pharmaceutically acceptable salt thereof for use in treating a condition selected from the above-mentioned diseases and disorders.

Yet another aspect of the present invention provides the use of a compound of formula I, Ia, II or IIa as defined in any of the above embodiments in the form of a free or pharmaceutically acceptable salt for use in the manufacture of a pulmonary hypertension Of the potion.

Embodiments of the present invention provide the use of a compound of formula I, Ia, II or IIa as defined in any of the above embodiments in the form of a free or pharmaceutically acceptable salt for the manufacture of a PAH selected from Agents: idiopathic PAH; familial PAH; PAH related to collagen vascular diseases selected from the group consisting of scleroderma, CREST syndrome, systemic lupus erythematosus (SLE), rheumatoid arthritis, high arteritis, Polymyositis and dermatomyositis; PAHs associated with congenital heart disease selected from the group: Individual atrial septal defect (ASD), ventricular septal defect (VSD), and open arterial ducts; PAH associated with portal hypertension; and PAHs related to HIV infection; PAHs related to drug or toxin uptake; PAHs related to hereditary hemorrhagic telangiectasia; PAHs related to splenectomy; PAHs related to extensive venous or capillary involvement diseases; PAHs related to pulmonary veins PAH associated with occlusive disease (PVOD); and PAH associated with pulmonary capillary hemangioma (PCH).

Embodiments of the present invention provide a method for preventing or treating a condition or disease mediated by an IP receptor, comprising administering to a subject in need thereof an effective amount of at least one compound as described herein. The condition or disease mediated by the IP receptor is selected from the group consisting of PAH: idiopathic PAH; familial PAH; PAH associated with collagen vascular disease selected from: scleroderma, CREST syndrome, systemic lupus erythematosus (SLE), rheumatoid arthritis, Gao'an's arteritis, polymyositis, and dermatomyositis; PAHs associated with congenital heart disease selected from the group: atrial septal defect (ASD), ventricular septal defect (VSD) ) And open arterial catheters; PAH related to portal hypertension; PAH related to HIV infection; PAH related to drug or toxin uptake; PAH related to hereditary hemorrhagic capillary telangiectasia; PAH related to splenectomy ; PAH associated with extensive venous or capillary involvement; PAH associated with pulmonary venous occlusive disease (PVOD); and PAH associated with pulmonary capillary hemangioma (PCH).

Other IP receptor-mediated conditions or diseases are selected from platelet aggregation, coronary artery disease, myocardial infarction, transient ischemic attack, colic, stroke, ischemia-reperfusion injury, restenosis, atrial fibrillation, blood clot Formation, atherosclerosis, atherosclerotic thrombosis, asthma, asthma symptoms, diabetes-related disorders, diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy, glaucoma, or other eyes with abnormal intraocular pressure Disease, hypertension, inflammation, psoriasis, psoriatic arthritis, rheumatoid arthritis, Crohn's disease, transplant rejection, multiple sclerosis, systemic lupus erythematosus (SLE), ulcerative colitis, ischemia-reperfusion injury, reperfusion Narrowness, atherosclerosis, acne, type 1 diabetes, type 2 diabetes, sepsis, and chronic obstructive pulmonary disease (COPD).

Embodiments of the present invention provide a method for preventing or treating a condition or disease mediated by an IP receptor, comprising administering to a subject in need thereof an effective amount of at least one compound as described herein. The condition or disease mediated by this IP receptor is PAH.

Throughout this specification and the scope of patent application below, unless the context requires otherwise, the word "comprise" or variations (e.g., (comprises) or (comprising)) shall be understood to imply the inclusion of the integer or Step or integer group or step group, but does not exclude any other integer or step or integer group or step group.

The term "pharmaceutically acceptable salt" as used herein refers to a salt that retains the biological effectiveness and properties of the compounds of the present invention and is generally biologically or otherwise desirable. In many cases, the compounds of the invention are capable of forming acidic and / or basic salts by virtue of the presence of amine and / or carboxyl groups or similar groups.

Inorganic and organic acids can be used to form pharmaceutically acceptable acid addition salts, such as acetate, aspartate, benzoate, benzenesulfonate, bromide / hydrobromide, hydrogen carbonate Salt / carbonate, bisulfate / sulfate, camphor sulfonate, chloride / hydrochloride, chlorotheophylline, citrate, ethanedisulfonate, fumarate, glucoheptanoate, glucose Acid salt, glucuronide salt, hippurate, hydroiodate / iodide, isethionate, lactate, lactate, lauryl sulfate, malate, maleate, malonate Acid salt, mandelate, mesylate, methyl sulfate, naphthate, naphthalene sulfonate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate Salt, palmitate, phosphate / hydrogen phosphate / dihydrogen phosphate, polygalacturonate, propionate, stearate, succinate, sulfosalicylate, tartrate, toluene Sulfonates, trifluoroacetates and hydroxyformates.

Salt-derived inorganic acids include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

Salt-derived organic acids include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, Ethanesulfonic acid, toluenesulfonic acid, 1-hydroxy-2-naphthoic acid and sulfosalicylic acid.

Inorganic and organic bases can be used to form pharmaceutically acceptable base addition salts.

Salt-derived inorganic bases include, for example, ammonium salts and metal salts in lines I to XII of the periodic table. In certain embodiments, the salts may be derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium, and magnesium salts.

Salt-derived organic bases can include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, alkali ion exchange resins, and the like. Some organic amines include isopropylamine, benzathine, choline salts, diethanolamine, diethylamine, lysine, meglumine, hexahydropyrazine, and tromethamine.

The pharmaceutically acceptable salts of the present invention can be synthesized from the basic or acidic portion of the parent compound by conventional chemical methods. Generally, these salts can be prepared by reacting the compounds in free acid form with a stoichiometric amount of a suitable base (e.g., hydroxide, carbonate, bicarbonate, or the like) of Na, Ca, Mg or K, Or it can be prepared by reacting these compounds in the form of a free base with a stoichiometric amount of a suitable acid. These reactions are usually carried out in water or an organic solvent, or a mixture of both. Generally, if feasible, it is desirable to use non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, acetone, or acetonitrile. For a list of other suitable salts, see, for example, "Remington's Pharmaceutical Sciences", 20th Edition, Mack Publishing, Easton, Pa., (1985), and "Handbook of Pharmaceutical Salts: Properties, Selection, and Use", Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

In addition, the compounds of the present invention (including their salts) can also be obtained as their hydrates or include other solvents for their crystallization.

Compounds of the invention (ie, compounds of Formula I, Ia, II or IIa) containing groups capable of acting as donors and / or acceptors for hydrogen bonding may be capable of forming co-crystals using suitable co-crystal formers. These co-crystals can be prepared from compounds of formula I, Ia, II or IIa by known co-crystal formation procedures. These procedures include grinding, heating, co-sublimating, co-melting, or contacting and separating the co-crystals formed thereby in a solution of a compound of Formula I, Ia, II or IIa with a co-crystal forming agent under crystallization conditions. Suitable co-crystal formers include those described in WO 2004/078163. Accordingly, the present invention further provides co-crystals comprising a compound of Formula I, Ia, II or IIa.

The term "optical isomer" or "stereoisomer" as used herein refers to any of the various stereoisomeric configurations that may be present in a given compound of the invention and includes geometric isomers. It should be understood that substituents may be attached to the opposite palm center of the carbon atom. Accordingly, the invention includes enantiomers, diastereomers or racemates of the compounds. "Enantiomers" are stereoisomer pairs that are non-superimposable mirror images of each other. A 1: 1 mixture of enantiomeric pairs is a "racemic" mixture. If appropriate, the term can be used to indicate a racemic mixture. "Diastereomers" are stereoisomers that have at least two asymmetric atoms but are not mirror images of one another. The absolute stereochemical structure is specified according to the Cahn-lngold-Prelog R-S system. When the compound is a pure enantiomer, the stereochemical structure of each pair of palm carbons can be designated as R or S. A resolution compound whose absolute configuration is unknown can be designated as (+) or (-) depending on the direction (right-handed or left-handed) of plane polarized light rotation at the wavelength of the sodium D line. Certain compounds described herein contain one or more asymmetric centers or axes and can lead to enantiomers, diastereomers and other stereoisomeric forms, which can be defined according to the absolute stereochemical structure It is (R)-or (S)-. The invention is intended to include all such possible isomers, including racemic mixtures, optically pure forms, and intermediate mixtures. Photoactive (R)-and (S) -isomers may be prepared using palmar synthons or palmar reagents or resolution using conventional techniques. If the compound contains a double bond, the substituent may be in the E or Z configuration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis- or trans-configuration. The invention is also intended to include all tautomeric forms.

Any asymmetric atom (e.g., carbon or the like) of a compound of the invention may exist in racemic or enantiomeric enriched form, such as (R)-, (S)-, or (R, S) -structure. In certain embodiments, each asymmetric atom is at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% para) in the (R)-or (S)-configuration. Enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess. Substituents having unsaturated bonds on the atom may exist in cis- (Z)-or trans- (E)-form if possible.

Thus, the compounds of the invention used herein can exist in one of the possible isomers, rotamers, retarders, tautomers, or mixtures thereof, for example, in a substantially pure geometry (Cis or trans) isomers, diastereomers, optical isomers (enantiomers), racemates or mixtures thereof.

Any resulting mixture of isomers can be separated into pure or substantially pure geometric or optical isomers, diastereomers based on physicochemical differences in their components (e.g., by chromatography and / or fractional crystallization) Isomers, racemates.

Any resulting racemate of the final product or intermediate can be resolved into optical enantiomers by known methods, for example, by separating and releasing its diastereomeric salt obtained using an optically active acid or base Optically active acidic or basic compounds. Specifically, it is thus possible to employ an optically active acid (e.g., tartaric acid, dibenzomethyltartaric acid, diethylfluorenyl tartaric acid, di-o, o'-p-toluene) in a basic part by, for example, fractional crystallization Formyl salts of methyl tartaric acid, mandelic acid, malic acid or camphor-10-sulfonic acid) to resolve the compounds of the invention into their optical enantiomers. It is also possible to resolve racemic products by using palmitic adsorbents by palmitic chromatography (eg, high pressure liquid chromatography (HPLC)).

Since the compounds of the invention are intended for use in pharmaceutical compositions, it should be readily understood that each of these compounds is preferably provided in a substantially pure form, e.g., at least 60% pure, more suitably, at least 75% pure, and preferably at least 85% with a purity of at least 98% (% is based on weight ratio). Impure preparations of these compounds can be used in the more pure forms used in the preparation of pharmaceutical compositions; these less impure preparations of these compounds should contain at least 1%, more suitably, at least 5% and preferably from 10% to 59 % Of a compound of the invention.

The compounds of the invention can be obtained in free form, in the form of their salts, or in the form of their prodrug derivatives.

When both the base group and the acid group exist in the same molecule, the compound of the present invention can also form internal salts, such as zwitterionic molecules.

The invention also provides prodrugs of a compound of the invention that are converted into a compound of the invention in vivo. A prodrug is an active or inactive compound that is chemically modified in vivo by physiological actions (e.g., hydrolysis, metabolism, and the like) after administration to an individual. Those skilled in the art are familiar with the suitability and techniques involved in the preparation and use of prodrugs. Prodrugs can be conceptually divided into two non-exclusive categories, biological precursor prodrugs and carrier prodrugs. See The Practice of Medicinal Chemistry , Ch. 31-32 (edited by Wermuth, Academic Press, San Diego, Calif., 2001). Generally, bioprodrug prodrugs are compounds that are inactive or have low activity compared to the corresponding active drug compound, which contain one or more protecting groups and are converted into the active form by metabolism or solvolysis. Both the active drug form and any released metabolites should have acceptable low toxicity.

A carrier prodrug is a pharmaceutical compound that contains a delivery moiety, such as improved ingestion and / or topical delivery to the site of action. It is expected that in such a carrier prodrug, the link between the drug moiety and the delivery moiety is a covalent bond, the prodrug is inactive or less active than the drug compound, and any release delivery moiety is acceptably non-toxic. For a delivery part intended to enhance prodrug ingestion, the release of the delivery part should generally be rapid. In other cases, it is desirable to utilize a moiety (e.g., certain polymers) or other moiety (e.g., cyclodextrin) that can provide slow release. For example, carrier prodrugs can be used to improve one or more of the following properties: increase lipophilicity, extend the duration of pharmacological effects, increase site specificity, reduce toxicity and side effects, and / or improve drug formulations ( For example, stability, water solubility, inhibition of undesired sensory or physiochemical properties). For example, by (a) esterification of a hydroxyl group with a lipophilic carboxylic acid (e.g., a carboxylic acid having at least one lipophilic moiety), or (b) a carboxylic acid group with a lipophilic alcohol (e.g., having at least Esterification of a lipophilic alcohol (such as a fatty alcohol) to increase lipophilicity.

Exemplary prodrugs are, for example, esters of S-fluorenyl derivatives of free carboxylic acids and thiols and O-fluorenyl derivatives of alcohols or phenols, wherein fluorenyl has the meaning as defined herein. Suitable prodrugs are often pharmaceutically acceptable ester derivatives that can be converted to the parent carboxylic acid by solvolysis under physiological conditions, such as lower alkyl esters, cycloalkyl esters, lower alkylene esters, benzyl Esters, mono- or di-substituted lower carbon alkyl esters, such as omega- (amino, mono- or di-lower alkylamino, carboxyl, lower alkoxycarbonyl) -lower alkyl esters, α- (Lower alkylalkoxy, lower alkoxycarbonyl or dilower alkylaminocarbonyl)-lower alkyl esters, such as neopentyloxymethyl esters and the like used in the industry. In addition, amines are masked as arylcarbonyloxymethyl substituted derivatives that release free drugs and formaldehyde by dissociation of esterases in vivo (Bundgaard, J. Med. Chem. 2503 (1989)). In addition, N-fluorenylmethyl is used to mask drugs containing acidic NH groups such as imidazole, fluorimine, indole, and the like (Bundgaard, Design of Prodrugs, Elsevier (1985)). The hydroxyl groups are masked as esters and ethers. EP 039,051 (Sloan and Little) discloses Mannich-base hydroxamic acid prodrugs, their preparation and uses.

Any formulae given herein are also intended to represent unlabeled and isotopically labeled forms of these compounds. Isotopically labeled compounds have the results shown by the formulae given herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be included in the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as ² H, ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ¹⁵ N, and ¹⁸ F, respectively. , ³¹ P, ³² P, ³⁵ S, ³⁶ Cl, ¹²⁵ I. The present invention includes various isotopically labeled compounds as defined herein, for example, those in which radioisotopes such as ³ H, ¹³ C, and ¹⁴ C are present. These isotope-labeled compounds can be used in metabolic studies ( ¹⁴ C), reaction kinetic studies (for example, ² H or ³ H), detection or imaging techniques such as positron emission tomography (PET), or single-photon emission computers Computed tomography (SPECT), including analysis of drug or matrix tissue distribution), or radiotherapy for patients. In particular, ¹⁸ F or labeled compounds may be particularly needed for PET or SPECT studies. Isotopically-labeled compounds of the invention and their prodrugs can generally be accomplished by implementing procedures disclosed in the protocol or in the examples and preparations described below by replacing un-isotopically-labeled reagents with readily available isotopically-labeled reagents preparation.

In addition, with heavier isotopes, particularly deuterium (i.e., ² H or D) may afford certain therapeutic advantages resulting from greater metabolic stability due to this, e.g., in vivo half-life or reduced dosage requirements or improved therapeutic index. It is understood that deuterium is considered in this context as a substituent of a compound of formula I, Ia, II or IIa. The concentration of this heavier isotope (especially deuterium) can be defined by the isotope enrichment factor. The term "isotopic enrichment factor" as used herein means the ratio between the isotopic abundance and the natural abundance of a given isotope. If the substituent of the compound of the present invention is expressed as deuterium, the isotope enrichment factor of each designated deuterium atom of the compound is at least 3500 (52.5% deuterium is included at each designated deuterium atom), and at least 4000 (60% deuterium is included) , At least 4500 (67.5% deuterium included), at least 5000 (75% deuterium included), at least 5500 (82.5% deuterium included), at least 6000 (90% deuterium included), at least 6333.3 (95% deuterium included), at least 6466.7 (inclusive) 97% deuterium), at least 6600 (99% deuterium included), or at least 6633.3 (99.5% deuterium included).

Isotopically labeled compounds of formula I, Ia, II or IIa can generally be prepared by conventional techniques familiar to those skilled in the art or can be used by methods similar to those illustrated in the accompanying examples and preparations Isotopically labeled reagents were prepared in place of previously unlabeled reagents.

The pharmaceutically acceptable solvates of the present invention include those whose crystallization solvents can be substituted with isotopes, for example, D ₂ O, d ₆ -acetone, d ₆ -DMSO.

synthesis

In general, compounds of formula I, Ia, II or IIa or their pharmaceutically acceptable salts can be synthesized by the pathways described in Schemes A-M and the examples.

Scheme A begins with the reaction in step 1 using commercially available starting materials or starting materials that can be synthesized by those skilled in the art and condensing the materials as shown. Step 2 is hydrogenation. Step 3 is alkylation or reductive amination, depending on the desired product. If an ester is present, step 4 of Scheme A is hydrolyzed to form a free acid. R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are as defined herein.

Scheme B begins with the reaction in step 1 in which commercially available starting materials are used or those skilled in the art can synthesize and condense the materials as shown. Step 2 is hydrogenation. Step 3 is alkylation or reductive amination, depending on the desired product. If an ester is present, step 4 of Scheme B is hydrolyzed to form a free acid. R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are as defined herein.

The skilled person can synthesize the starting material and condense the material as shown. Step 2 is to form an N-oxide. Step 3 optionally inserts chlorine. Step 4 is a Negishi cross coupling at the chlorine on the ring. Step 5 is hydrogenation. Step 6 is alkylation or reductive amination, depending on the desired product. Step 7 involves palm separation of the compound mixture using supercritical fluid chromatography to provide individual enantiomers. If an ester is present, step 8 of Scheme C is hydrolyzed to form a free acid. R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are as defined herein.

Scheme D begins with the reaction in step 1 using commercially available starting materials or starting materials that can be synthesized by those skilled in the art and condensing the materials as shown. Step 2 is to form an N-oxide. Step 3 is a chemically selective addition of a Grignard reagent to the N-oxide derivative. Step 4 is hydrogenation. Step 5 is alkylation or reductive amination, depending on the desired product. Step 6 involves palm separation of the compound mixture using supercritical fluid chromatography to provide individual enantiomers. If an ester is present, step 7 of Scheme D is hydrolyzed to form a free acid. R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are as defined herein.

Scheme E begins with the reaction in step 1 using commercially available starting materials or starting materials that can be synthesized by those skilled in the art and condensing the materials as shown. Step 2 is chlorinated. Steps 3 and 4 are Suzuki cross-coupling reactions. Step 5 is hydrogenation. Step 6 is alkylation or reductive amination, depending on the desired product. If an ester is present, step 7 of Scheme E is hydrolyzed to form a free acid. R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are as defined herein.

Scheme F begins with the reaction in step 1 using commercially available starting materials or starting materials that can be synthesized by those skilled in the art and condensing the materials as shown. Step 2 is chlorinated. Step 3 is a Suzuki cross-coupling reaction. Step 4 is hydrogenation. Step 5 is alkylation or reductive amination, depending on the desired product. If an ester is present, step 6 of Scheme F is hydrolyzed to form a free acid. R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are as defined herein.

Scheme G begins with the reaction in step 1 in which commercially available starting materials are used or those skilled in the art can synthesize and condense the materials as shown. Step 2 is hydrogenation. Step 3 involves introducing a protecting group (PG). Step 4 is bromination. Step 5 is the organometallic reaction or nucleophilic substitution of the halide derivative, depending on the desired product. Step 6 is an optional removal of the protecting group. Step 7 is alkylation or reductive amination, depending on the desired product. If an ester is present, step 8 of Scheme G is an optional deprotection step and hydrolysis to form a free acid. Chiral separation can be performed as in step 7a or step 8a. R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are as defined herein.

Scheme H begins with the reaction in step 1 in which commercially available starting materials are used or those skilled in the art can synthesize and condense the materials as shown. Step 2 is reduction. Step 3 involves introducing a protecting group (PG). Step 4 is the hydroxylation of the olefin. Step 5 is the introduction of a hydroxyl protecting group. Step 6 is the selective removal of the protecting group. Step 7 is alkylation or reductive amination, depending on the desired product. If an ester is present, step 8 is a deprotection step and hydrolysis to form a free acid. Step 9 of Scheme H involves palmitically separating the compound mixture using supercritical fluid chromatography to provide individual enantiomers. R ¹ , R ² , R ⁵ and R ⁶ are as defined herein.

Scheme I begins with the reaction in step 1 in which commercially available starting materials are used or those skilled in the art can synthesize and condense the materials as shown. Step 2 is hydrogenation. Step 3 is alkylation or reductive amination, depending on the desired product. Step 4 is reduction. Step 5 is optional hydrolysis. Step 6 is alkylation. If an ester is present, step 7 of Scheme I is hydrolyzed to form a free acid. R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are as defined herein. n is 0 to 5.

Scheme J begins with the reaction in step 1 using commercially available starting materials or starting materials that can be synthesized by those skilled in the art and condensing the materials as shown. Step 2 is hydrogenation. Step 3 is alkylation or reductive amination, depending on the desired product. Step 4 is an olefin metathesis reaction. Step 6 is the hydroxylation of the olefin. Step 8 is hydrogenation. If an ester is present, steps 5, 7 and 9 of Scheme J are hydrolyzed to form a free acid. R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are as defined herein.

Scheme K begins with the reaction in step 1 by using commercially available starting materials or starting materials that can be synthesized by those skilled in the art and dibrominate the material. Step 2 is a Negishi cross-coupling reaction with intramolecular cyclization. Steps 3 and 8 are alkylation. Steps 4, 7, 11 and 12 are Suzuki cross-coupling reactions. Steps 5, 9 and 13 are hydrolyzed to form a free acid. Steps 10 and 14 are reduced. Step 6 of Scheme K is hydroxylation. R ¹ , R ³ , R ⁴ , R ⁵ and R ⁶ are as defined herein.

Scheme L begins with the reaction in step 1 by using commercially available starting materials or starting materials that can be synthesized by those skilled in the art and condensing the materials as shown. Step 2 is reduction. Step 3 is alkylation or reductive amination, depending on the desired product. Step 4 is the borohydride of the olefin. Step 5 involves palm separation of the compound mixture using supercritical fluid chromatography to provide individual enantiomers. If an ester is present, step 6 of Scheme L is hydrolyzed to form a free acid. R ¹ , R ² , R ⁵ and R ⁶ are as defined herein.

Scheme M begins with the reaction in step 1 in which commercially available starting materials or starting materials that can be synthesized by those skilled in the art are used and the materials are condensed as shown. Step 2 is hydrogenation. Step 3 is alkylation or reductive amination, depending on the desired product. Step 4 is an optional removal of the protecting group. Step 5 is the formation of an amido bond. If an ester is present, step 6 of Scheme M is hydrolyzed to form a free acid. R ₂ , R ³ , R ⁴ , R ⁵ and R ⁶ are as defined herein. n is 1 to 5. PG is a suitable protecting group.

Those skilled in the art will appreciate that the general synthetic pathways detailed above show common reactions to transform starting materials as needed. No specific reaction conditions are provided, but these conditions are already well known to those skilled in the art and appropriate conditions are deemed to be within the general common sense of the skilled person.

The starting materials are commercially available compounds or known compounds and can be prepared by procedures described in organic chemistry techniques.

Compounds of formula I, Ia, II or IIa in free form can be converted to the salt form, and vice versa, in a manner customary to those skilled in the art. Compounds in free or salt form can be obtained in the form of hydrates or solvates containing the solvent used for crystallization. Compounds of formula I, Ia, II or IIa can be recovered and purified from the reaction mixture in a conventional manner. Isomers (e.g. stereoisomers) can be obtained in a conventional manner (e.g. by stepwise crystallization or asymmetric synthesis) from the corresponding asymmetrically substituted (e.g. optically active) starting materials.

Compounds of formula I, Ia, II or IIa or their pharmaceutically acceptable salts can be prepared using reactions and techniques as described below and in the examples. The reaction can be carried out in a solvent suitable for the reagents and materials used and suitable for the transformation being performed. Those familiar with organic synthesis should understand that the functional groups present on the molecule should be consistent with the proposed transformation. Sometimes it is necessary to judge to modify the order of synthetic steps or to choose one specific process scheme over another to obtain the desired compound of the present invention.

The various substituents on the synthetic intermediates and final products shown in the following reaction schemes can exist in their fully elaborate form, if necessary, with suitable protecting groups, as understood by those skilled in the art; or in the form of precursors, It can then be carefully crafted into its final form by methods familiar to those skilled in the art. Such substituents may also be added at different stages throughout the synthesis sequence or after completion of the synthesis sequence. In many cases, common functional group manipulations can be used to convert one intermediate to another intermediate, or to convert one compound of formula I, Ia, II, or IIa to another compound of formula I, Ia, II, or IIa. Examples of such operations are the conversion of esters or ketones to alcohols; the conversion of esters to ketones; the interconversion of esters, acids, and amidines; the alkylation, halogenation, and sulfonation of alcohols and amines; and many other operations. Substituents can also be added using common reactions such as alkylation, halogenation, halogenation or oxidation. Such operations are well known in the industry, and many references outline procedures and methods for such operations. Of organic synthesis used in the art of many functional group manipulations, as well as other transformation of organic synthesis primarily literature provides examples and references to some reference system March's Organic Chemistry, 5th Edition, Wiley and Chichester editor (2001); Comprehensive Organic Transformations, Edited by Larock, VCH (1989); Comprehensive Organic Functional Group Transformations , Katritzky et al. (Series editor), Pergamon (1995); and Comprehensive Organic Synthesis , Trost and Fleming (series editor), Pergamon (1991). It should also be recognized that another major consideration in planning any synthetic pathway in this field is the careful selection of protecting groups for protecting the reactive functional groups present in the compounds described in this invention. Multiple protective groups can be selected in the same molecule, so that each of these protective groups can be removed without removing other protective groups in the same molecule, or several protective groups can be removed using the same reaction step depending on the desired result group. The definitive record for training practitioners on the many alternatives is Greene and Wuts, Protective Groups in Organic Synthesis , Wiley and Sons 4th edition (2006).

Pharmacological activity

The compounds disclosed herein activate IP receptors and can be used to treat a number of diseases and disorders, and to improve their symptoms.

These diseases and symptoms include (but are not limited to) the following:

Pulmonary Arterial Hypertension (PAH)

PAH has a multifactorial pathological biology. In PAH, vasoconstriction, pulmonary vessel wall remodeling, and thrombosis lead to increased pulmonary vascular resistance (Humbert et al., J. Am. Coll. Cardiol., 2004, 43: 13S-24S.). The compounds disclosed herein are useful in the treatment of pulmonary hypertension (PAH) and its symptoms. PAH should be understood to cover the following forms of pulmonary hypertension in the 2003 World Health Organization (WHO) clinical classification of pulmonary arterial hypertension: idiopathic PAH (BPAH) Familial PAH (FPAH); PAH (APAH) related to other conditions, such as PAH related to collagen vascular disease, PAH related to congenital lung shunt, PAH related to portal hypertension, PAH related to HTV infection , PAHs related to drugs or toxins or other related PAHs; and PAHs related to widespread venous or capillary diseases. Idiopathic PAH is PAH of unknown cause. Familial PAH refers to PAH suspected or recorded of hereditary transmission. PAH related to collagen vascular disease should be understood to cover PAH related to scleroderma, PAH related to CREST (cutaneous calcium deposits, Raynaud's phenomenon, esophageal dysfunction, finger sclerosis and capillary dilatation) syndrome, and systemic Lupus erythematosus (SLE) -related PAH, rheumatoid arthritis-related PAH, PAH-related high arteritis, PAH-related polymyositis, and PAH-related dermatomyositis. PAH related to congenital pulmonary shunt should be understood to cover PAH related to atrial septal defect (ASD), PAH related to ventricular septal defect (VSD), and PAH related to open arterial catheters.

Drug- or toxin-related PAHs are understood to cover PAHs related to aminorex uptake, PAHs related to uptake of fenfluramine compounds (e.g., PAHs related to uptake of fenfluramine or PAH related to dexfenfluramine intake, PAH related to certain toxic oil intake (e.g. PAH related to rapeseed oil intake), PAH related to bispyrrolidine alkaloid intake (e.g. , PAH related to shrub tea intake) and PAH related to lylitheine intake. Related to other PAHs should be understood to cover PAHs related to thyroid disorders, PAHs related to glycogen storage diseases, PAHs related to Gaucher disease, and related to hereditary bleeding telangiectasia PAH, PAH associated with heme disease, PAH associated with bone marrow tissue proliferative disorders, and PAH associated with splenectomy. PAH associated with extensive venous or capillary involvement should be understood to cover PAH associated with pulmonary vein occlusive disease (PVOD) and PAH associated with pulmonary capillary hemangioma (PCH). (See, for example, Simonneau et al., J. Am. Coll. Cardiol., 2004, 43: 5S-12S; McGoon et al., Chest, 2004, 126: 14S-34S; Rabinovitch, Annu. Rev. Pathol. Mech. Dis 2007, 2: 369-399; McLaughlin et al., Circulation, 2006, 114: 1417-1431; Strauss et al., Clin. Chest. Med., 2007, 28: 127-142; Taichman et al., Clin. Chest Med., 2007, 28: 1-22.).

Evidence of the correlation between PAH and scleroderma and the beneficial effects of IP receptor agonists on PAH is given by Badesch et al. (Badesch et al., Ann. Intern. Med., 2000, 132: 425-434). Correlation of PAH with collagen vascular disease, connective tissue disease (MCTD), systemic lupus erythematosus (SLE), Sjogren's syndrome and CREST syndrome, and the beneficial effects of IP receptor agonists on PAH Evidence is given by Humbert et al. (Eur. Respir. J., 1999, 13: 1351-1356). The correlation between PAH and CREST syndrome and the beneficial effects of IP receptor agonists on PAH are given by Miwa et al. (Int. Heart J., 2007, 48: 417-422). The evidence for the correlation between PAH and SLE and the beneficial effects of IP receptor agonists on PAH is given by Robbins et al. (Chest, 2000, 117: 14-18). Evidence of the correlation between PAH and HIV infection and the benefits of IP receptor agonists on PAH are given by Aguilar et al. (Am. J. Respir. Crit. Care Med., 2000, 162: 1846-1850). The evidence for the correlation between PAH and congenital heart defects (including ASD, VSD, and open arterial catheters) and the beneficial effects of IP receptor agonists on PAH was given by Rosenzweig et al. (Circulation, 1999, 99: 1858-1865). Out.

Evidence of the correlation between PAH and fenfluramine, dexfenfluramine, and anorexigens was given by Archer et al. (Am. J. Respir. Crit. Care Med., 1998, 158: 1061-1067) Out. Evidence of the correlation between PAH and hereditary hemorrhagic telangiectasia is given by McGoon et al. (Chest, 2004, 126: 14-34). Evidence of the correlation between PAH and splenectomy is given by Hoeper et al. (Ann. Interh. Med., 1999, 130: 506-509). The evidence for the correlation between PAH and portal hypertension and the beneficial effects of IP receptor agonists on PAH is given by Hoeper et al. (Eur. Respir. J., 2005, 25: 502-508).

PAH symptoms include dyspnea, colic, syncope, and edema (McLaughlin et al., Circulation, 2006, 114: 1417-1431). The compounds of the invention disclosed herein are useful for treating symptoms of PAH.

Antiplatelet therapy (conditions related to platelet aggregation)

Antiplatelet agents (antiplatelet) are specified for a variety of conditions. For example, in coronary artery disease, these agents are used to help prevent myocardial infarction or stroke in patients at risk of developing obstructive blood clots (eg, coronary artery thrombosis).

In a myocardial infarction, the heart muscle cannot receive sufficient oxygen-rich blood due to blocked coronary vessels. Antiplatelet agents can reduce heart damage if taken during or immediately after the onset of the disease (preferably within 30 minutes).

Transient ischemic attack ("TIA" or "mini-stroke") occurs when the flow of oxygen to the brain is reduced due to reduced blood flow through the arteries and is generally temporarily interrupted by an obstructive blood clot. Antiplatelet drugs have been found to be effective in preventing TIA. Colic is a temporary and often recurrent chest pain, stress, or discomfort caused by insufficient oxygen-rich blood flow (ischemia) to parts of the heart. In patients with colic, antiplatelet therapy can reduce the effects of colic and the risk of myocardial infarction.

Stroke brains are generally unable to receive enough oxygen-rich blood because blood clots clog cerebral blood vessels. In high-risk patients, regular use of antiplatelet agents has been found to prevent the formation of blood clots that cause the first or second stroke. Angioplasty is a catheter-based technique used to open an artery blocked by a blood clot. Whether or not a stent placement is performed immediately after this procedure to keep the arteries open, antiplatelet agents can reduce the risk of forming additional blood clots after performing the procedure (s).

Coronary artery bypass surgery is a surgical procedure in which arteries or veins are obtained from elsewhere in the body and transplanted to an obstructed coronary artery to re-route blood to bypass the obstruction and pass through newly connected blood vessels. After this procedure, antiplatelet agents reduce the risk of secondary blood clots.

Atrial tremor is the most common type of persistent irregular heart rhythm (arrhythmia). Atrial fibrillation affects about two million Americans each year. In atrial fibrillation, the atrium (the upper chamber of the heart) rapidly triggers electrical signals that tremble rather than contract normally. The result was an abnormally fast and extremely irregular heartbeat. When given after a burst of atrial fibrillation, antiplatelet agents reduce the risk of blood clots forming in the heart and transferring to the brain (embolism).

There is evidence that IP receptor agonists can inhibit platelet aggregation and are therefore a potential treatment as antiplatelet therapy (see, for example, Moncada et al., Lancet, 1977, 1: 18-20). Genetic defects in IP receptors in mice have been shown to increase the propensity for thrombosis (Murata et al., Nature, 1997, 388: 678-682).

IP receptor agonists can be used to treat, for example, claudication or peripheral arterial disease and cardiovascular complications, arterial thrombosis, atherosclerosis, vasoconstriction caused by serotonin, ischemia-reperfusion injury, and angioplasty Or arterial restenosis after stent placement. (See, for example, Fetalvero et al., Prostaglandins Other Lipid Mediat., 2007, 82: 109-118; Arehart et al., Curr. Med. Chem., 2007, 14: 2161-2169; Davi et al., N. Engl. J Med., 2007, 357: 2482-2494; Fetalvero et al., Am. J. Physiol. Heart. Circ. Physiol., 2006, 290: H1337-H1346; Murata et al., Nature, 1997, 388: 678-682 Wang et al., Proc. Natl. Acad. Sci. USA, 2006, 103: 14507-14512; Xiao et al., Circulation, 2001, 104: 2210-2215; McCormick et al., Biochem. Soc. Trans., 2007, 35: 910-911; Arehart et al., Circ. Res., 2008, March 6.).

IP receptor agonists can also be used alone or in combination with thrombolytic therapeutics (such as tissue-type plasminogen activator (t-PA)) to provide cardioprotection after MI or myocardial dysfunction after ischemia Or to protect against ischemic damage and the like during percutaneous coronary intervention (including complications derived therefrom). IP receptor agonists can also be used in antiplatelet therapy with, for example, alpha-tocopherol (vitamin B), snake venom echistatin (depolymerin), or heparin in a hypercoagulable state . (See, for example, Chan., J. Nutr., 1998, 128: 1593-1596; Mardla et al., Platelets, 2004, 15: 319-324; Bernabei et al., Ann. Thorac. Surg., 1995, 59: 149 -153; Gainza et al., J. Nephrol., 2006, 19: 648-655.)

The IP receptor agonists disclosed herein provide beneficial improvements in microcirculation to patients in need of antiplatelet therapy by antagonizing, for example and without limitation, the vasoconstrictive products of platelet aggregation in the above indications.

Accordingly, in some embodiments, the invention provides a method of reducing platelet aggregation in a patient in need thereof, comprising administering to the patient a composition comprising an IP receptor agonist as disclosed herein. In other embodiments, the present invention provides a method for treating coronary artery disease, myocardial infarction, transient ischemic attack, colic, stroke, atrial fibrillation, or any of the symptoms of a patient in need thereof, comprising: The patient is administered a composition comprising an IP receptor agonist as disclosed herein.

In other embodiments, the present invention provides a method for reducing the risk of blood clot formation in patients undergoing angioplasty or coronary artery bypass surgery or in patients suffering from atrial fibrillation, comprising administering to the patient in the presence of such a risk a method comprising the disclosure Composition of IP receptor agonist.

Atherosclerosis

Atherosclerosis is characterized by a complex disease of inflammation, lipid accumulation, cell death, and fibrosis. It is the leading cause of death in many countries, including the United States. As used herein, the term atherosclerosis is understood to encompass conditions that cause large and medium-sized arteries that cause progressive accumulation of smooth muscle cells and lipids in the intima.

IP receptor agonists have been shown to protect against atherosclerosis, such as from atherosclerotic thrombosis (Arehart et al., Curr. Med. Chem., 2007, 14: 2161-2169; Stitham et al. , Prostaglandins Other Lipid Mediat., 2007, 82: 95-108; Fries et al., Hematology Am. Soc. Hematol. Educ. Program, 2005 ,: 445-451; Egan et al., Science, 2004, 306: 1954-1957 Kobayashi et al., J. Clin. Invest, 2004, 114: 784-794; Arehart et al., Circ. Res., 2008, March 6). It has been shown that defective IP receptor signaling appears to accelerate atherosclerotic thrombosis in humans, that is, IP receptor agonists protect humans from atherosclerotic thrombosis (Arehart et al., Circ. Res ., 2008, March 6.)

The compounds of the invention disclosed herein are useful in the treatment of atherosclerosis and its symptoms. Thus, in some embodiments, the invention provides a method of treating atherosclerosis in a patient in need thereof, comprising administering to the patient a composition comprising an IP receptor agonist as disclosed herein. In other embodiments, methods are provided for treating the symptoms of atherosclerosis in a patient in need thereof, comprising administering to the patient a composition comprising an IP receptor agonist as disclosed herein.

asthma

Asthma is an lymphatic-mediated inflammatory airway disorder characterized by airway hypereosinophilia, increased goblet cell mucus production, and structural remodeling of the airway wall. In recent decades, the global incidence of asthma has increased dramatically. Genetic defects in mouse IP receptors have been shown to increase allergic airway inflammation (Takahashi et al., Br J Pharmacol, 2002, 137: 315-322). It has been shown that IP receptor agonists at least partially interfere significantly with the function of antigen presenting dendritic cells in the airway (Idzko et al., J. Clin. Invest., 2007, 117: 464-472; Zhou et al., J. Immunol., 2007, 178: 702-710; Jaffar et al., 2007, 179: 6193-6203; Jozefowski et al., Int. Immunopharmacol., 2003, 3: 865-878), not only Inhibits the occurrence of asthma (when administered during the sensitization phase), and also inhibits the basic characteristics of experimental asthma (when administered during the stimulation phase) (Idzko et al., J. Clin. Invest., 2007, 117: 464-72 , Nagao et al., Am. J. Respir. Cell MoI. Biol., 2003, 29: 314-320). These cells are essential for both the initial and maintenance phases of allergic asthma, because depletion of airway dendritic cells during secondary stimulation of sensitized mice can eliminate all characteristics of asthma, and this effect can be achieved by Wild transfer of wild-type dendritic cells is accepted for complete recovery (van Rijt et al., J. Exp. Med., 2005, 201: 981-991). IP receptor agonists have also been shown to inhibit the proinflammatory cytokine secretion of human alveolar macrophages (Raychaudhuri et al., J. Biol. Chem., 2002, 277: 33344-33348). The compounds disclosed herein are useful in the treatment of asthma and its symptoms. Thus, in some embodiments, the invention provides a method of treating asthma in a patient in need thereof, comprising administering to the patient a composition comprising an IP receptor agonist as disclosed herein.

In other embodiments, a method of treating the symptoms of asthma in a patient in need of treatment is provided, comprising administering to the patient a composition comprising an IP receptor agonist disclosed herein.

Chronic obstructive pulmonary disease

Activation of IP receptors can also be beneficial for chronic obstructive pulmonary disease (COPD). Taprostene, an IP receptor agonist, inhibits the production of CD8 ⁺ T cell chemoattractants CXCL9 and CXCL10 by human airway epithelial cells in vitro. (Ayer, LM, SM Wilson, SL Traves, D. Proud, MA Giembycz. 2008. J. Pharmacol. Exp. Ther. 324: 815-826.) IP receptor agonist beraprost may help Synergistic inhibition of apoptosis, oxidative burden, matrix metalloproteinase performance, and proinflammatory cytokine production protects rats from experimental cigarette smoke-induced emphysema. (Chen, Y., M. Hanaoka, P. Chen, Y. Droma, NF Voelkel, K. Kubo. 2009. Am. J. Physiol. 296 : L648- L656.) In other embodiments, treatment is required to provide treatment A method of COPD in a patient comprising administering to the patient a composition comprising an IP receptor agonist as disclosed herein.

Hyperglycemia

Although hyperglycemia is a major cause of diabetic complications such as diabetic peripheral neuropathy (DPN), diabetic nephropathy (DN), and diabetic retinopathy (DR), it has also been shown Vasoconstriction and platelet aggregation play a role in disease progression (Cameron et al., Naunyn Schmiedebergs Arch. Pharmacol., 2003, 367: 607-614). IP receptor agonists promote vasodilation and inhibit platelet aggregation. Improved microvascular blood flow can be beneficial for diabetic complications (Cameron, Diabetologia, 2001, 44: 1973-1988).

IP receptor agonists have been shown to prevent and reverse streptozotocin-induced diabetic motor and sensory peripheral nerve conduction abnormalities (Cotter et al., Naunyn Schmiedebergs Arch. Pharmacol., 1993, 347: 534- 540). Additional evidence for the beneficial effects of IP receptor agonists in the treatment of diabetic peripheral neuropathy is given by Hotta et al. (Diabetes, 1996, 45: 361-366), Ueno et al. (Jpn. J. Pharmacol. , 1996, 70: 177-182), Ueno et al. (Life Sci., 1996, 59: PL1O5-PL110), Hotta et al. (Prostaglandins, 1995, 49: 339-349), Shindo et al. (Prostaglandins, 1991, 41: 85-96), Okuda et al. (Prostaglandins, 1996, 52: 375-384) and Koike et al. (FASEB J., 2003, 17: 779-781).

Evidence for the beneficial effects of IP receptor agonists in the treatment of diabetic nephropathy is provided by Owada et al. (Nephron, 2002, 92: 788-796) and Yamashita et al. (Diabetes Res. Clin. Pract., 2002, 57: 149 -161). Evidence for the beneficial effects of IP receptor agonists in the treatment of diabetic retinopathy is provided by Yamagishi et al. (MoI. Med., 2002, 8: 546-550), Burnette et al. (Exp. Eye Res., 2006, 83 : 1359-1365) and Hotta et al. (Diabetes, 1996, 45: 361-366). IP receptor agonists have been shown to reduce increased tumor necrosis factor- [α] (TNF- [α]) levels in diabetic patients, suggesting that IP receptor agonists may help prevent the progression of diabetes complications (Fujiwara et al., Exp. Clin. Endocrinol. Diabetes, 2004, 112: 390-394).

Evidence of topical administration of IP receptor agonists can reduce intraocular pressure (IOP) in rabbits and dogs and thereby have a beneficial effect in the treatment of glaucoma. Hoyng et al. (Hoyng et al., Invest. Ophthalmol. Vis. Sci. (1987, 28: 470-476).

IP receptor agonists have been shown to have activity to regulate vascular tone, vasodilation, and improve pulmonary hypertension (see, eg, Strauss et al., Clin Chest Med, 2007, 28: 127-142; Driscoll et al., Expert Opin. Pharmacother., 2008, 9: 65-81). Evidence for the beneficial effects of IP receptor agonists in the treatment of hypertension is given by Yamada et al. (Peptides, 2008, 29: 412-418). Evidence that IP receptor agonists can protect against cerebral ischemia is provided by Dogan et al. (Gen. Pharmacol., 1996, 27: 1163-1166) and Fang et al. (J. Cereb. Blood Flow Metab., 2006, 26 : 491-501).

Anti-inflammatory

Anti-inflammatory agents are specified for a variety of conditions. For example, in inflammatory diseases, it is used to interfere and thereby reduce potential harmful substances.

There is evidence that IP receptor agonists can inhibit inflammation and are therefore a potential treatment as an anti-inflammatory therapy. It has been shown that IP receptor agonists can inhibit the pro-inflammatory cytokines and chemokines of dendritic cells (interleukin-12 (IL-12), tumor necrosis factor- [α] (TNF- [α]), Production of DL-1 [α], EL-6, macrophage inflammatory protein-1α (MIP-1 [α]), monocyte chemoattractant protein-1 (MCP-I)) and T cell stimulation (Jozefowski et al., Int. Immunopharmacol., 2003, 865-878; Zhou et al., J. Immunol., 2007, 178: 702-710; Nagao et al., Am. J. Respir. Cell MoI. Biol., 2003 29: 314-320; Idzko et al., J. Clin. Invest., 2007, 117: 464-472). IP receptor agonists have been shown to inhibit the production of pro-inflammatory cytokines (TNF- [α], IL-1 / 3, EL-6, granulocyte macrophage stimulating factor (GM-CSF)) by macrophages (Raychaudhuri et al., J. Biol. Chem., 2002,277: 33344-33348; Czeslick et al., Eur. J. Clin. Invest., 2003, 33: 1013-1017; Di Renzo et al., Prostaglandin Leukot. Essent Fatty Acids, 2005, 73: 405-410; Shinomiya et al., Biochem. Pharmacol., 2001, 61: 1153-1160). IP receptor agonists have been shown to stimulate dendritic cells to produce anti-inflammatory cytokines (DL-IO) (Jozefowski et al., Int. Immunopharmacol., 2003, 865-878; Zhou et al., J. Immunol., 2007, 178: 702-710). It has been shown that IP receptor agonists can stimulate the production of anti-inflammatory cytokines (DL-10) by macrophages (Shinomiya et al., Biochem. Pharmacol., 2001, 61: 1153-1160). IP receptor agonists have been shown to inhibit the chemotaxis of chemokines (CCL 17) -induced white blood cells (CD4 <+> Th2 T cells) (Jaffar et al., J. Immunol., 2007, 179: 6193 -6203). IP receptor agonists have been found to protect against atherosclerosis, such as atherosclerotic thrombosis (Arehart et al., Curr. Med. Chem., 2007, 14: 2161-2169; Stitham et al. , Prostaglandins Other Lipid Mediat., 2007, 82: 95-108; Fries et al., Hematology Am. Soc. Hematol. Educ. Program, 2005 ,: 445-451; Egan et al., Science, 2004, 306: 1954-1957 Kobayashi et al., J. Clin. Invest, 2004, 114: 784-794; Arehart et al., Circ. Res., 2008, March 6). IP receptor agonists have been shown to reduce asthma (Idzko et al., J. Clin. Invest., 2007, 117: 464-472; Jaffar et al., J. Immunol., 2007, 179: 6193-6203; Nagao Et al. Am. J. Respir. Cell. MoI. Biol., 2003, 29: 314-320). IP receptor agonists have been shown to reduce TNF- [α] production in patients with type 2 diabetes (Fujiwara et al., Exp. Clin. Endocrinol. Diabetes, 2004, 112: 390-394; Goya et al., Metabolism, 2003, 52: 192-198). IP receptor agonists have been shown to inhibit ischemia-reperfusion injury (Xiao et al., Circulation, 2001, 104: 2210-2215). IP receptor agonists have been shown to inhibit restenosis (Cheng et al. Science, 2002, 296: 539-541). IP receptor agonists have been shown to reduce pulmonary vascular injury and shock in rat models of septic shock (Harada et al., Shock, 2008, February 21). IP receptor agonists have been shown to reduce serum TNF- [α] concentrations in vivo in patients with rheumatoid arthritis, and this has been associated with improvement of the clinical course of the disease (Gao et al., Rheumatol. Int., 2002 22: 45-51; Boehme et al., Rheumatol. Int., 2006, 26: 340-347).

The compounds of the invention disclosed herein can be beneficial in reducing inflammation. The compounds of the invention disclosed herein can beneficially reduce harmful inflammatory reactions associated with inflammatory diseases. Accordingly, in some embodiments, the present invention provides a method for reducing inflammation in a patient in need thereof, comprising administering to the patient a composition comprising an IP receptor agonist as disclosed herein. In some embodiments, the invention provides methods for reducing the production of IL-12, TNF- [α], IL-1 [α], IL-IjS, BL-6, MIP-Ia, or MCP-I in a patient in need thereof Comprising administering to the patient a composition comprising an IP receptor agonist as disclosed herein. In some embodiments, the invention provides a method of reducing TNF-[[alpha]] production in a patient in need thereof, comprising administering to the patient a composition comprising an IP receptor agonist as disclosed herein. In some embodiments, the invention provides a method of increasing EL-IO production in a patient in need thereof, comprising administering to the patient a composition comprising an IP receptor agonist as disclosed herein. In some embodiments, the invention provides a method of reducing a harmful inflammatory response associated with an inflammatory disease in a patient in need thereof, comprising administering to the patient a composition comprising an IP receptor agonist as disclosed herein. In some embodiments, the invention provides a method of treating an inflammatory disease or a symptom of a patient in need thereof, comprising administering to the patient a composition comprising an IP receptor agonist disclosed herein. In some embodiments, the invention provides a method of treating an inflammatory disease or a symptom of a patient in need thereof, comprising administering to the patient a composition comprising an IP receptor agonist disclosed herein. In some embodiments, the invention provides a method of treating an inflammatory disease or a symptom of a patient in need thereof, comprising administering to the patient a composition comprising an IP receptor agonist disclosed herein, wherein the inflammatory disease From the group consisting of: psoriasis, psoriatic arthritis, rheumatoid arthritis, Crohn's disease, transplant rejection, multiple sclerosis, systemic lupus erythematosus (SLE), ulcerative colitis, ischemia-reperfusion injury, reperfusion Narrowness, atherosclerosis, acne, diabetes (including type 1 diabetes and type 2 diabetes), sepsis, chronic obstructive pulmonary disease (COPD), and asthma.

Fibrosis

PGI2 signaling has been shown to play a beneficial role in fibrotic diseases of various organs including kidney, heart, lung, skin, pancreas, and liver, as well as systemic sclerosis and related conditions. IP receptor agonists have been shown to improve cardiac fibrosis (Chan EC et al. (2010) J Mol Cell Cardiol . April 18; Hirata Y et al. (2009) Biomed Pharmacother . 63 (10): 781-6 ; Kaneshig T et al. (2007) J vet Med Sci . 69 (12): 1271-6). IP receptor agonists have been shown to reduce renal fibrosis (Takenaka M et al. (2009) Prostaglandins Leukot Essent Fatty Acids. 80 (5-6): 263-7). IP receptor agonists have been shown to protect against pulmonary fibrosis in a bleomycin model (Zhu Y et al. (2010) Respir Res. 20; 11 (1): 34). IP receptor agonists have been shown to inhibit the production of connective tissue growth factor (a key fibrosis mediator) in patients with scleroderma (Stratton R et al. (2001) J Clin Invest . 108 (2): 241-50) . IP receptor agonists have been shown to reduce the incidence of finger ulcers in patients with systemic sclerosis (M. Vayssairat (1999) J Rheumatol 26: 2173-2178). IP receptor agonists have been shown to reduce fingertip necrosis in infants with refractory Raynaud's phenomenon (Shouval DS et al. (2008) Clin Exp Rheumatol . 26 (3 Suppl 49): S105-7). IP receptor agonists have been shown to reduce markers of endothelial activation in patients with systemic sclerosis (Rehberger P et al. (2009) Acta Derm Venereol . 89 (3): 245-9.). IP receptor agonists have been shown to reduce the severity, frequency, and duration of Raynaud's attacks in patients with systemic sclerosis (Torlay et al. (1991) Ann Rheum Dis 50 , 800-804). IP receptor agonists have been shown to improve portal vein hemodynamics in patients with systemic sclerosis and Raynaud's phenomenon (Zardi et al. (2006) In Vivo 20 (3): 377-80). IP receptor agonists have been shown to inhibit pancreatic fibrosis progression in obese Zucker rats (Sato et al. (2010) Diabetes 59 (4): 1092-100).

The IP receptor agonists disclosed herein provide beneficial antifibrotic effects to patients suffering from fibrosis of the kidney, heart, lung, skin, pancreas and liver, which may be idiopathic or secondary to chronic inflammation and systemic sclerosis Symptoms, such as and not limited to the above indications.

In addition, there is substantial evidence that IP receptor agonists can improve renal function in acute and chronic renal failure. IP receptor agonists have been shown to restore renal function in acute renal failure associated with endotoxemia (Johannes T et al. (2009) Crit Care Med . 37 (4): 1423-32). IP receptor agonists have been shown to improve renal function in renal ischemia / reperfusion injury models (Sahsivar MO et al. (2009) Shock 32 (5): 498-502). IP receptor agonists have been shown to prevent contrast-induced nephropathy in patients with renal insufficiency undergoing cardiac surgery (Spargias K et al. (2009) Circulation 3; 120 (18): 1793-9.) It has been shown that IP Receptor agonists can improve renal function and reduce renal inflammation and sclerosis in a diabetic nephropathy model (Watanabe M et al. (2009) Am J Nephrol. 2009; 30 (1): 1-11).

The IP receptor agonists disclosed herein provide beneficial improvements in renal function in patients with acute and chronic kidney injury and kidney disease (such as, but not limited to, the above indications), which are secondary to Dye contrast agent, ischemia-reperfusion injury, systemic inflammation and diabetes.

There is substantial evidence for a causal role of prostacyclin deficiency in the occurrence of preeclampsia (Mills JL et al. (1999) JAMA 282: 356-362; Walsh SW (2004) Prostaglandins Leukot Essent Fatty Acids 70: 223-232). Administration of IP receptor agonists has been shown to reduce blood pressure in rat models of preeclampsia (Zlatnik MG et al. (1999) Am J Obstet Gynecol. 180 (5): 1191-5).

The IP receptor agonists disclosed herein provide beneficial improvements to the hemodynamics of patients with preeclampsia.

The IP receptor agonists disclosed herein can provide beneficial treatments for cystic fibrosis.

The IP receptor agonists disclosed herein can provide chemoprevention. Chemoprevention is the practice of using drugs, vitamins, or nutritional supplements to reduce the risk of developing or recurring cancer. Oral iloprost ( Ventavis ) (prostacyclin analog) has shown promise as a chemopreventive agent for lung cancer. Data supporting chemoprevention of IP receptor agonists are provided by Paul Bunn Jr. MD (the executive director of the International Association for the Study of Lung Cancer) and the American Association for Cancer Research ) Provided at the 102nd annual meeting, showing that the agonist significantly improved bronchoplasty in former smokers.

PGI2 agonists (including compounds of Formula I, Ia, II, or IIa) can also be used as co-therapeutics in combination with secondary agents such as organic nitrates and NO-donors such as sodium nitroprusside, Nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, molsidomine or SIN-1 and inhaled NO; inhibit cyclic guanosine monophosphate (cGMP) and / or cyclic adenosine monophosphate (cAMP) Degraded compounds such as inhibitors of phosphodiesterase (PDE) 1, 2, 3, 4 and / or 5, especially PDE5 inhibitors such as sildenafil, vardenafil and tadalafil (tadalafil); NO-independent but heme-dependent stimulators of guanylate cyclase, such as the compounds described in particular in WO 00/06568, WO 00/06569, WO 02/42301 and WO 03/095451; NO and heme-independent activators of guanylate cyclase, such as described in particular in WO 01/19355, WO 01/19776, WO 01/19778, WO 01/19780, WO 02/070462 and WO 02/070510 Compounds; compounds that inhibit human neutrophil elastase, such as sivelestat or DX-890 (Reltran); inhibit signals Leading cascade compounds such as tyrosine kinase and / or serine / threonine kinase inhibitors, especially imatinib, gefitinib, erlotinib, Sorafenib and sunitinib; compounds that affect cardiac energy metabolism, such as and preferably etomoxir, dichloroacetate, ranolazine or trimetazidine (trimetazidine); antithrombotic agents, for example, and preferably from a group containing platelet aggregation inhibitors, anticoagulants, or fibrinogen solubilizing substances; blood pressure lowering actives, for example, and preferably from a group including: calcium antagonists , Angiotensin II antagonist, ACE inhibitor, endothelin antagonist, renin inhibitor, aldosterone synthase inhibitor, alpha receptor blocker, beta receptor blocker, mineralocorticoid receptor antagonist, Rho-kinase inhibitors and diuretics; and / or active substances that regulate lipid metabolism, for example and preferably from groups comprising: thyroid receptor agonists, cholesterol synthesis inhibitors (for example and preferably HMG-CoA- Reductase inhibitor or squalene synthesis Agent), ACAT inhibitor, CETP inhibitor, MTP inhibitor, PPAR-α, PPAR-γ and / or PPAR-δ agonist, cholesterol absorption inhibitor, lipase inhibitor, polymeric bile acid adsorbent, bile acid Reuptake inhibitors and lipoprotein (a) antagonists, especially for the treatment of PAH or diseases and conditions such as those mentioned above, for example, as potentiators of the therapeutic activity of these drugs or as agents for reducing these drugs Means of dosage or potential side effects are required.

Specifically, the embodiment of the present invention is a pharmaceutical combination comprising a compound of Formula I, Ia, II or IIa or a pharmaceutical salt thereof and a second agent, wherein the second agent is a PDEV inhibitor or a neutral endopeptidase inhibitor.

In a fixed pharmaceutical composition, a compound of formula I, Ia, II or IIa or a pharmaceutically acceptable salt thereof may be mixed with a second agent or it may be administered separately, before, simultaneously with, or after another pharmaceutical substance.

Therefore, as yet another aspect, the present invention includes IP receptor active agents and penetrants (hypertonic saline, dextrose, mannitol, xylitol), ENaC blockers, anti-inflammatory drugs, bronchodilators, anti- A combination of a histamine, an antitussive, an antibiotic, and / or a DNase drug, wherein the IP receptor agonist and another drug can be stored in the same or different pharmaceutical compositions.

Suitable antibiotics include macrolide antibiotics, such as tobramycin (TOBI ^™ ).

Suitable DNase drugs include a high-purity solution of recombinant human deoxyribonuclease I (rhDNase), dornase alfa (Pulmozyme ^™ ), which selectively cleaves DNA. Alpha chain enzymes are used to treat cystic fibrosis.

Other useful combinations of IP receptor agonists and anti-inflammatory drugs are their antagonists with chemokine receptors, such as CCR-1, CCR-2, CCR-3, CCR-4, CCR-5, CCR -6, CCR-7, CCR-8, CCR-9 and CCR10, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, especially CCR-5 antagonists, such as Schering-Plough antagonist SC -351125, SCH-55700 and SCH-D, Takeda antagonist (e.g. N-[[4-[[[6,7-dihydro-2- (4-methyl-phenyl) -5H- Benzo-cycloheptene-8-yl] carbonyl] amino] phenyl] -methyl] tetrahydro-N, N-dimethyl-2H-pyran-4-ammonium chloride (TAK-770)) And CCR-as described in USP 6,166,037 (especially technical solutions 18 and 19), WO 00/66558 (especially technical solution 8), WO 00/66559 (especially technical solution 9), WO 04/018425, and WO 04/026873 5 antagonist.

Suitable anti-inflammatory drugs include steroids, such as corticosteroids. Suitable steroids include budesonide, beclamethasone (e.g. dipropionate), butixocort (e.g. propionate), CHF5188, ciclesonide, dexamethasone Dexamethasone, flunisolide, fluticasone (e.g. propionate or furate), GSK-685698, GSK-870086, LAS40369, methyl prednisolone, molybdenum Mometasone (eg, furoate), prednisolone, rofleponide, and triamcinolone (eg, acetone). In certain preferred embodiments, the steroid is a long-acting corticosteroid, such as budesonide, ciclesonide, fluticasone, or mometasone.

Suitable second active ingredients include beta ₂ agonists. Suitable beta ₂ agonists include armotetrol (e.g. tartrate), albuterol / salbutamol (e.g. racemate or single enantiomer, e.g. R- Enantiomer or its salt, especially sulfate), AZD3199, bambuterol, BI-171800, bitolterol (e.g. mesylate), carmoterol , Clenbuterol, etanterol, fenoterol (e.g. racemates or single enantiomers, e.g. R-enantiomers or Salts, especially hydrobromides), flerbuterol, formoterol (e.g. racemates or mono-diastereomers, e.g. R, R-diastereomers Structure or its salt, especially fumarate or fumarate dihydrate), GSK-159802, GSK-597901, GSK-678007, indacaterol (e.g. racemate or single pair Enantiomers, such as the R-enantiomer or a salt thereof, especially maleate, acetate or hydroxyformate), LAS100977, metaproterenol, milveterol (e.g. Hydrochloride) Naminterol, olodaterol (e.g. racemate or monoenantiomer, e.g. R-enantiomer or its salt, especially the hydrochloride), PF -610355, pirtuberol (e.g. acetate), procaterol, reproterol, salmefamol, salmeterol (e.g. racemic Isomers or monoenantiomers, such as the R-enantiomer or a salt thereof, especially a hydroxyformate), terbutaline (such as sulfate), and vilanterol (Or a salt thereof, especially triflate). In certain preferred embodiments, the beta ₂ agonist is an ultra-long-acting beta ₂ agonist, such as indacaterol or possibly carmoterol, LAS-100977, mivitrol, odadrol, PF -610355 or Vilantro. A preferred embodiment of one of the second active ingredients is indacaterol (i.e. (R) -5- [2- (5,6-diethyl-dihydroinden-2-ylamino) -1- Hydroxyethyl] -8-hydroxy-1H-quinolin-2-one) or a salt thereof. This is a β ₂ adrenergic receptor agonist, which has a particularly long duration of action (ie, more than 24 hours) and a short onset of action (ie, about 10 minutes). This compound was prepared by the methods described in international patent applications WO 2000/75114 and WO 2005/123684. It is capable of forming acid addition salts, especially pharmaceutically acceptable acid addition salts. Comparison of (R) -5- [2- (5,6-diethyl-dihydroinden-2-ylamino) -1-hydroxyethyl] -8-hydroxy-1H-quinolin-2-one Good salt is maleate. Another preferred salt system (R) -5- [2- (5,6-diethyl-dihydroinden-2-ylamino) -1-hydroxyethyl] -8-hydroxy-1H-quinoline -2-ketoacetate. Another preferred salt system (R) -5- [2- (5,6-diethyl-dihydroinden-2-ylamino) -1-hydroxyethyl] -8-hydroxy-1H-quinoline -2-ketohydroxyformate.

Suitable bronchodilators include anticholinergic or antimuscarinic agents such as aclidinium (e.g., bromide), BEA-2108 (e.g., bromide), BEA-2180 (e.g., bromide), CHF- 5407, darifenacin (e.g., bromide), darotropium (e.g., bromide), glycopyrrolate (e.g., racemate or monoenantiomer or Salt, especially bromide), dexpirronium (e.g. bromide), iGSK-202405, GSK-203423, GSK-573719, GSK-656398, ipratropium (e.g. bromide), LAS35201 , LAS186368, otilonium (e.g., bromide), oxitropium (e.g., bromide), oxybutynin, PF-3715455, PF-3635659, pirenzepine, Revatropate (e.g. hydrobromide), solifenacin (e.g. succinate), SVT-40776, TD-4208, terodiline, tiotropium ) (Such as bromide), tolterodine (such as tartrate), and trospium (such as chloride). In certain preferred embodiments, the muscarinic antagonist is a long-acting muscarinic antagonist, such as, for example, darromide, glycopyrrolate, or tiotropium.

Suitable dual anti-inflammatory and bronchodilators include dual beta-2 adrenergic receptor agonists / muscarinic antagonists (e.g., GSK-961081) (e.g., succinate) and they are disclosed in USP 2004/0167167, WO 04 / 74246 and WO 04/74812.

Suitable antihistamines include cetirizine hydrochloride, acetaminophen, clematine fumarate, promethazine, loratidine, and Desloratadine, diphenhydramine and fexofenadine hydrochloride, activastine, astemizole, azelastine, azelastine, Ebastine, epinastine, mizolastine, and tefenadine and those disclosed in JP 2004107299, WO 03/099807, and WO 04/026841.

Therefore, as a further aspect, the present invention includes a combination of an IP receptor agonist and an agent that inhibits ALK5 and / or ALK4 phosphorylation of Smad2 and Smad3.

Therefore, as a further aspect, the present invention includes a combination of an IP receptor agonist and a second agent that is a p-kinase inhibitor.

Therefore, as yet another aspect, the present invention includes a combination of an IP receptor agonist and a second agent that is a tryptophan hydroxylase 1 (TPH1) inhibitor.

Therefore, as yet another aspect, the present invention includes a combination of an IP receptor agonist and a second agent that is a multikinase inhibitor, such as Gleevec. Imatinib is used as a specific inhibitor of various tyrosine kinases. It occupies the active site of TK , resulting in reduced activity. TK enzymes in the body include insulin receptors. Imatinib is specific for the TK domain in Abelson proto-oncogene, c-kit, and PDGF-R (platelet-derived growth factor receptor).

In the embodiment of the present invention, the IP receptor agonist of the present invention is administered in combination with a second active agent selected from the group consisting of a phosphodiesterase V inhibitor, a neutral endopeptidase 1 inhibitor, a THP1 inhibitor, Multikinase inhibitors, endothelin antagonists, diuretics, aldosterone receptor blockers and endothelin receptor blockers.

In the embodiment of the present invention, the IP receptor agonist of the present invention is administered in combination with a second active agent selected from the group consisting of a phosphodiesterase V inhibitor, a neutral endopeptidase 1 inhibitor, a THP1 inhibitor, and Multikinase inhibitors, such as PDGFR or c-Kit.

In another aspect, the present invention provides a compound of formula I, Ia, II or IIa in free form or in the form of a pharmaceutically acceptable salt for use in the manufacture of a compound for treating IP receptor agonist activity, in particular Agent for the condition of PAH.

The medicament of the invention can be administered by appropriate routes, for example, orally in the form of, for example, lozenges or capsules; parenteral administration, such as intravenously; inhalation, for example in the treatment of obstructive airway diseases; Intranasal, for example in the treatment of allergic rhinitis; topical application to the skin; or transrectal administration. In yet another aspect, the present invention also provides a pharmaceutical composition comprising a compound of formula I, Ia, II, or IIa in free form or in the form of a pharmaceutically acceptable salt thereof, and optionally used in combination therewith. Acceptable diluents or carriers. The composition may contain a co-therapeutic agent, for example, an anti-inflammatory drug, a bronchodilator, an antihistamine, or an antitussive, as described above. These compositions can be prepared using conventional diluents or excipients and techniques known in the galenic art. Accordingly, oral dosage forms may include lozenges and capsules. Formulations for topical administration may be in the form of creams, ointments, gels, or transdermal delivery systems (eg, patches). Compositions for inhalation may comprise an aerosol or other nebulizable formulation or a dry powder formulation.

When the composition includes an aerosol formulation, it preferably contains, for example, a hydrogen-fluoro-alkane (HFA) propellant (such as HFA134a or HFA227 or a mixture thereof), and may contain one or more cosolvents known in the art , Such as ethanol (up to 20% by weight); and / or one or more surfactants, such as oleic acid or sorbitan trioleate; and / or one or more bulking agents, such as lactose. When the composition comprises a dry powder formulation, it preferably contains, for example, a compound of formula I, Ia, II or IIa or a pharmaceutical salt thereof having a particle size of up to 10 microns, optionally with a diluent or carrier having a desired particle size distribution. Agents (e.g., lactose) and compounds (e.g., magnesium stearate) that help protect them from degradation of product properties caused by moisture. When the composition comprises an atomizing formulation, it preferably contains, for example, Formula I, dissolved or suspended in an aqueous vehicle, a co-solvent (for example, ethanol or propylene glycol), and a stabilizer (which may be a surfactant). Ia, II or IIa compound or a pharmaceutically acceptable salt thereof.

Other aspects of the invention include:

(a) a compound of formula I, Ia, II or IIa, or a pharmaceutically acceptable salt thereof, in an inhalable form, for example in the form of an aerosol or other nebulizable composition or inhalable particulate (for example micronized);

(b) an inhalable medicament comprising a compound of formula I, Ia, II or IIa or a pharmaceutically acceptable salt thereof in inhalable form;

(c) a pharmaceutical product comprising a compound of formula (I) in an inhalable form, which is associated with an inhalation device; and

(d) An inhalation device comprising a compound of formula I, Ia, II or IIa or a pharmaceutically acceptable salt thereof in an inhalable form.

Of course, the dosage of the compound of formula I, Ia, II or IIa or a pharmaceutically acceptable salt thereof used in practicing the present invention will depend on, for example, the particular condition to be treated, the desired effect, and the mode of administration. Generally, a suitable daily dose by inhalation is about 0.005 mg to 10 mg, and a suitable daily dose for oral administration is about 0.05 mg to 100 mg.

medical Drug use and analysis

Compounds of formula I, Ia, II or IIa and their pharmaceutically acceptable salts (hereinafter also referred to as "medicines of the invention") can be used as pharmaceutical preparations. Specifically, these compounds are suitable IP receptor agonists and can be tested in the following analysis.

The compound's activity against the IP receptor was evaluated by measuring the accumulation of cAMP in CHO cells stably expressing the IP receptor (CHO-IP) using PerkinElmer AlphaScreen analysis. This technique measures the endogenous production of cAMP in non-radioactive luminous proximity homogeneous analysis. Streptavidin-coated donor beads, biotinylated cAMP, and anti-cAMP acceptor beads have a biological reaction to bring the donor and acceptor beads close enough so that after excitation, Generate a fluorescent signal. After the production of endogenous cAMP, competition between biotinylated cAMP and cell-derived cAMP weakens the fluorescent signal. The weakening of the signal is proportional to the amount of cAMP produced, so the amount of cAMP produced after stimulation with a agonist can be quantified.

Test and reference compounds were prepared at 100x [final concentration] in 100% DMSO and diluted 1: 3 using Biomek Fx (Beckman Coulter). Thereafter, an intermediate dilution was performed to give 5x [final concentration] in analysis buffer (HBSS containing 5 mM HEPES, 0.1% (w / v) BSA). Then, 5 μL of 5x [final concentration] test compound, reference compound and buffer / DMSO control were transferred to a 384-well white OptiPlate containing 20 μL of CHO-IP cell suspension (15,000 cells / well, prepared from freezing), And the plate was incubated at room temperature for 1 hour. A cAMP standard curve was constructed for each experiment (concentration range of 10,000 nM to 0.001 nM, stored in analysis buffer) and each concentration was added to the last two rows of analysis plates at 25 μL. By adding 20 units mL ^{-1 of} streptavidin-coated donor beads and biotinylated cAMP (30 minutes pre-incubation) and 20 units mL ^{-1 of} anti-cAMP receptor beads in lysis buffer (dH ₂ O; 0.3% (vv ^-1 ) Tween-20) to terminate the incubation, the beads and biotinylated cAMP were added to the lysis buffer before being added to the analysis plate. The assay plate was then incubated for 60 minutes in the dark at room temperature with gentle shaking and read on an Envision plate reader (Perkin Elmer).

The cAMP standard curve was used in GraphPad Prism (GraphPad Software) to convert the raw data of the reference compound, test compound, and control to cAMP concentration. Using a 4-parameter logistic equation (logistic equation) to determine the agonist's EC ₅₀ and maximum curve agent. The top of the treprostinil concentration-response curve was used to determine the% maximum response values for all test compounds.

The compounds exemplified below generally have EC ₅₀ values of less than 5 μM in the above data measurements. Table 1 provides a list of representative compounds and their EC ₅₀ values.

The compounds listed below belong to the most widely applied patent scope; however, the EC ₅₀ value in the above data measurement is higher than 10 μM: 6- (2,3-bis (4-propylphenyl) -7,8- Dihydropyrido [2,3-b] pyrazine-5 (6H) -yl) hexanoate; 7- (2- (m-tolyl) -3- (p-tolyl) -7,8-di Hydropyrido [2,3-b] pyrazine-5 (6H) -yl) heptanoate; and 5- (6,7-diphenyl-3,4-dihydro-1,8-naphthyridine -1 (2H) -yl) valeric acid.

The invention is illustrated by the following examples.

Examples General conditions:

Mass spectrometry analysis was performed using electrospray ionization with the help of the LCMS system. These systems are an Agilent 1100 HPLC / Micromass Platform mass spectrometer combination or a Waters Acquity UPLC and SQD mass spectrometer. [M + H] ⁺ refers to the molecular weight of a mono-isotope.

NMR spectrum analysis was performed using an open-access Bruker AVANCE 400 NMR spectrometer using ICON-NMR. The spectra were measured at 298 K and quoted using solvent peaks.

The following examples are intended to illustrate the invention and should not be construed as limiting the invention. Temperature is expressed in degrees Celsius. Unless otherwise stated, all evaporations are performed at low pressures, preferably between about 15 mm Hg and 100 mm Hg (= 20 mbar to 133 mbar). The structures of the final products, intermediates, and starting materials are all confirmed by standard analytical methods, such as microanalysis and spectroscopic analysis (such as MS, IR, NMR). The abbreviations used are those familiar to them in the industry. If not defined, these terms have their accepted meanings.

abbreviation:

AcOH

br wide peak

d doublet

DBU 1,8-diazabicyclo [5.4.0] undec-7-ene

DCM methylene chloride

DCE 1,2-dichloroethane

DIPEA Diisopropylethylamine

DMF N , N -dimethylformamide

DMI 1,3-dimethyl-2-imidazolidinone

DMSO dimethylformate

DSC Differential Scanning Calorimetry

EDCI 1-ethyl-3- (3'-dimethylaminopropyl) carbodiimide

Et ₂ O ether

EtOAc / ethyl acetate

EtOH ethanol

h hour

Grubbs Catalyst 2nd Generation (1,3-bis (2,4,6-trimethylphenyl) -2-imidazolidinyl) dichloro (phenylmethylene) (tricyclic Hexylphosphine) ruthenium, benzylidene [1,3-bis (2,4,6-trimethylphenyl) -2-imidazolidinyl] dichloro (tricyclohexylphosphine) ruthenium, [1,3- Bis- (2,4,6-trimethylphenyl) -2-imidazolidinyl] dichloro (phenylmethylene) (tricyclohexylphosphine) ruthenium

HPLC high pressure liquid chromatography

LC-MS Liquid chromatography and mass spectrometry

MeOH methanol

MeCN acetonitrile

MS MS

m multiple

min minutes

ml mL

m / z mass-to-charge ratio

obs cover

NBS N-bromosuccinimide

NMR Nuclear Magnetic Resonance

NMP 1-methyl-2-pyrrolidone

Preparation and stability of PEPPSi-iPr pyridine-enhanced precatalyst preparation -2,6-diisopropylphenylimidazolium chloride

ppm millions

PS Polymer loading

PEAX PE-anion exchange (e.g. Isolute PE-AX column from Biotage

Pd (Ph ₃ P) ₄ Tetrakis (triphenylphosphine) palladium (0)

PdCl ₂ (dppf) [1,1-bis (diphenylphosphino) ferrocene] palladium (II) dichloride

Rt retention time

RT room temperature

s unimodal

sat. saturated

SFC Supercritical Fluid Chromatography

SCX-2 strong cation exchange (e.g. Isolute SCX-2 column from Biotage)

t triplet

TBME methyl-third butyl ether

THF tetrahydrofuran

Referring to the following examples, the compounds of the preferred embodiments are synthesized using the methods described herein or other methods known in the art. The various starting materials, intermediates, and compounds of the preferred embodiments may be separated and purified using, for example, the following conventional techniques if appropriate: precipitation, filtration, crystallization, evaporation, distillation, and chromatography. Unless otherwise stated, all starting materials were obtained from commercial suppliers and used without further purification. Salts can be prepared from compounds by known salt formation procedures.

It should be understood that organic compounds according to the preferred embodiments may exhibit tautomerism. Since the chemical structure in this specification can represent only one of the possible tautomeric forms, it should be understood that the preferred embodiment encompasses any tautomeric form of the structure shown.

Unless otherwise specified, analytical HPLC conditions are as follows:

Method 2minLC_v001

Column: Waters BEH C18 100 × 2.1 mm, 1.7 μm

Column temperature 50 ℃

Eluent A: H ₂ O, B: Acetonitrile, both contain 0.1% TFA

Flow rate 0.7 ml / min

Gradient: 0.25 min 5% B; 5% to 95% B within 1.00 min, 95% B within 0.25 min

Method 2minLC_v002

Column: Waters BEH C18 50 × 2.1 mm, 1.7 μm

Column temperature 50 ℃

Eluent A: H ₂ O, B: Methanol, both contain 0.1% TFA

Flow rate 0.8 ml / min

Gradient: 0.20 min 5% B; 5% to 95% B in 1.30 min, 95% B in 0.25 min

Method 2minLC_v003

Column: Waters BEH C18 50 × 2.1 mm, 1.7 μm

Column temperature 50 ℃

Eluent A: H ₂ O, B: Acetonitrile, both contain 0.1% TFA

Flow rate 0.8 ml / min

Gradient: 0.20 min 5% B; 5% to 95% B in 1.30 min, 95% B in 0.25 min

Method low pH_30_v001

Column: Phenomenex Gemini C18 50 × 4.6 mm, 3.0 μm

Column temperature 40 ℃

Eluent A: H ₂ O, B: Acetonitrile, both contain 0.1% TFA

Flow rate 1.2 ml / min

Gradient: 30% to 95% B in 2.0 min, 95% B in 0.2 min

Method 2minLC_30_v003

Column: Waters BEH C18 50 × 2.1 mm, 1.7 μm

Column temperature 50 ℃

Eluent A: H ₂ O, B: Acetonitrile, both contain 0.1% TFA

Flow rate 0.8 ml / min

Gradient 0.25 min 30% B; 30% to 95% B within 1.00 min, 0.25 min 95% B

2min low pH

Column: Waters Acquity CSH 1.7 μm, 2.1 × 50 mm

Temperature: 50 ℃

Mobile phase: A: water + 0.1% formic acid B: acetonitrile + 0.1% formic acid

Flow rate: 1.0 mL / min

Gradient: 0.0 min 5% B, 0.2-1.3 min 5-98% B, 1.3-1.55 min 98% B, 1.55-1.6 min 98-5% B

Method 10minLC_v003

Column: Waters BEH C18 50 × 2.1 mm, 1.7 μm

Column temperature 50 ℃

Eluent A: H ₂ O, B: Acetonitrile, both contain 0.1% TFA

Flow rate 0.8 ml / min

Gradient: 0.20 min 5% B; 5% to 95% B in 7.80 min, 95% B in 1.00 min

Method A

Column: HSS T3 1.8 μm 2.1 × 50 mm

Column temperature: 50 ℃

Eluent: A: H ₂ O + 0.05% formic acid + 3.75 mM ammonium acetate, B: acetonitrile + 0.04% formic acid

Flow rate: 1.2 ml / min

Gradient: 0.0% 2% B, 1.98 min 2-98% B, 1.40 min-2.15 min 98% B

Method OJ20MEOH

Column: Chiralcel OJ-H 250 × 10 mm, 5 μm

Mobile phase: 20% methanol / 80% CO ₂

Flow rate: 10 ml / min

Detection: UV at 220 nm

Method AS25IPA

Column: Chirapak AS-H 250 × 10 mm, 5 μm

Mobile phase: 25% IPA / 75% CO ₂

Flow rate: 10 ml / min

Detection: UV at 220 nm

Method AD40IPA

Column Chirapak AD-H 250 × 10 mm id, 5 μm

Mobile phase: 10% methanol / 90% CO ₂

Flow rate 10 ml / min

Detection: UV at 220 nm

Method B

Column: Zorbax Eclipse XDB-C18 4.6 × 50 mm, 1.8 μm

Column temperature 35 ℃

Eluent A: H ₂ O + 0.1% TFA, B: Acetonitrile + 0.1% TFA

Flow rate 1 ml / min

Gradient: 5-100% MeCN (6 min), 100 MeCN (1.5 min), 100-5% MeCN

(0.5 min)

Method C

Column: Chiralcel OJ-H 250 × 10 mm, 5 μm

Mobile phase: 15% methanol / 85% CO ₂

Flow rate: 10 ml / min

Detection: UV at 220 nm

Exemplary compounds of the invention include:

Preparation of final compounds Example 1.1 7- (6,7-diphenyl-3,4-dihydro-1,8-naphthyridin-1 (2H) -yl) heptanoic acid

Step 1: Ethyl 7- (6,7-diphenyl-3,4-dihydro-1,8-naphthyridin-1 (2H) -yl) heptanoate

Treatment of 6,7-diphenyl-1,2,3,4-tetrahydro- [with cesium carbonate (910 mg, 2.79 mmol) and ethyl 7-bromoheptanoate (0.544 ml, 2.79 mmol) in N ₂ A solution of 1,8] naphthyridine (Intermediate B) (200 mg, 0.698 mmol) in anhydrous NMP (1 ml). The reaction mixture was stirred at 120 ° C for 1 h and further stirred at 140 ° C for 3 h. After cooling to room temperature, the mixture was partitioned between EtOAc and water. , Dried over MgSO ₄ organic portions are washed with brine, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica with 4: 1 isohexane / EtOAc to give a pink oily residue.

The residue was loaded onto a column Isolute ^TM SCX-2, and washed successively with MeOH and stored in 2 M NH ₃ in the MeOH elution. The methanolic ammonia portion was concentrated in vacuo and dried in vacuo at 40 ° C to give the title compound as a colorless oil.

LC-MS Rt = 1.54 min; [M + H] ⁺ 443.4, method 2min LC_v001.

¹ H NMR (400 MHz, DMSO-d6) δ 7.3 (9H, m), 7.0 (2H, m), 4.0 (2H, q), 3.6 (2H, m), 3.4 (2H, m), 2.75 (2H , m), 2.2 (2H, t), 1.9 (2H, m), 1.6 (2H, m), 1.45 (2H, m), 1.3 (4H, m), 1.1 (3H, t).

Step 2: 7- (6,7-Diphenyl-3,4-dihydro-1,8-naphthyridin-1 (2H) -yl) heptanoic acid

Ethyl 7- (6,7-diphenyl-3,4-dihydro-1,8-naphthyridin-1 (2H) -yl) heptanoate (step 1) (100 mg, 0.226 mmol) and lithium hydroxide (37.9 mg, 0.904 mmol) in THF (2 ml) were heated for 6 h. The reaction was quenched with water and the pH was adjusted to pH 3-4 by adding 1 M HCl. Partition the mixture between EtOA _c and water. , Dried over MgSO ₄ organic portion is separated and washed with brine, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica with 3: 2 isohexane / EtOAc to obtain the title compound.

LC-MS Rt = 1.98 min; [M + H] +415.5, method low pH_30_v001.

¹ H NMR (400 MHz, DMSO-d6) δ 12.03 (1H, br s), 7.2 (9H, m), 7.05 (2H, m), 3.6 (2H, t), 3.4 (2H, m), 2.8 ( 2H, m), 2.15 (2H, t), 1.9 (2H, m), 1.6 (2H, m), 1.4 (2H, m), 1.3 (4H, m).

The compounds of the examples listed below were prepared by a method similar to Example 1.1 by replacing the 7-bromoheptanoate with the appropriate bromoester (Table 2).

Examples 2.1 and 2.2 Enantiomer 1 and enantiomer of 6- (1-methyl-6,7-diphenyl-1,2,3,4-tetrahydro-1,8-naphthyridin-2-yl) hexanoic acid Isomer 2

Step 1: 7-Chloro-2,3-diphenyl-1,8-naphthyridine

POCI ₃ (10 ml, 107 mmol) was added dropwise to 6,7-diphenyl-1,8-naphthyridine 1-oxide and 2,3-diphenyl-1,8-naphthalene at 0 ° C. Pyridine 1-oxide (Intermediate C) (3 g, 10.06 mmol). The reaction mixture was warmed at room temperature and heated at 100 ° C for 2 h. The mixture was carefully poured onto ice / water and by added portionwise Na ₂ CO ₃ (solid) and the pH was adjusted to pH 8-9. The aqueous layer was separated and extracted with DCM (3 x 150 ml). The organic portions were combined and washed with brine, dried over MgSO _4, filtered and concentrated in vacuo to give a brown oil. The crude oil was purified by chromatography on silica with 0-50% EtOAc in isohexane to obtain 7-chloro-2,3-diphenyl-1,8-naphthyridine and 5-chloro-2,3-diphenyl-1,8-naphthyridine:

7-chloro-2,3-diphenyl-1,8-naphthyridine: yellow solid

LC-MS Rt = 1.58 min, [M + H] ⁺ 317.1, method 2 min LC_v002.

¹ H NMR (400 MHz, DMSO-d6) δ 8.63 (1H, d), 8.6 (1H, s), 7.78 (1Hd), 7.28-7.7.43 (10H, m).

5-chloro-2,3-diphenyl-1,8-naphthyridine: light brown solid

LC-MS Rt = 1.64 min, [M + H] ⁺ 317.1, method 2 min LC_v002

¹ H NMR (400 MHz, DMSO-d6) δ 9.09 (1H, d), 8.52 (1H, S), 7.93 (1H, d), 7.37-7.5 (10H, m).

The desired product 7-chloro-2,3-diphenyl-1,8-naphthyridine was used in the next step.

Step 2: Ethyl 6- (6,7-diphenyl-1,8-naphthyridin-2-yl) hexanoate will contain lithium bromide (307 mg, 3.54) in THF (2 ml) at room temperature. mmol) and PEPPSi-iPr catalyst (75 mg, 0.110 mmol) were stirred for 15 minutes until a solution was formed. (6-Ethoxy-6-oxohexyl) zinc (II) bromide (13.26 ml of a 0.5 M solution in THF, 6.62 mmol) was added and the mixture was cooled to 0 ° C. Add a solution of 7-chloro-2,3-diphenyl-1,8-naphthyridine (step 1) (350 mg, 1.105 mmol) in THF (3 ml) / DMI (1 ml) and at room temperature The resulting mixture was stirred for 24 h. Partitioned between EtOAc and water, the reaction mixture and the organic portion was washed with brine, dried over MgSO _4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica with 0-50% EtOAc in isohexane to give the title product as a yellow oil;

LC-MSRt = 1.54 min; [M + H] ⁺ 425.3, method 2 min LC_v002

Step 3: Racemic ethyl-6- (6,7-diphenyl-1,2,3,4-tetrahydro-1,8-naphthyridin-2-yl) hexanoate

Ethyl 6- (6,7-diphenyl-1,8-naphthyridin-2-yl) hexanoate (step 2) (280 mg, 0.660) with 10% palladium on carbon (70.2 mg) in an argon atmosphere mmol) of a stirred solution in EtOH (10 ml), purged 3 times with nitrogen and placed under a hydrogen atmosphere overnight. With Celite (Filter material) The mixture was filtered and the catalyst was washed with EtOAc (100 ml). The filtrate was concentrated in vacuo to give the title compound as an off-white solid. The crude product was purified by chromatography on silica with 0-100% EtOAc in isohexane to give the title compound as a yellow oil.

LC-MSRt = 1.46 min; [M + H] ⁺ 429.3, method 2 min LC_v002.

¹ H NMR (400 MHz, DMSO-d6) δ 7.25-7.15 (9H, m), 7.04 (2H, m), 6.54 (1H, s, NH), 4.04 (2H, q), 3.36 (1H, m) , 2.74 (2H, m), 2.29 (2H, t), 1.99 (1H, m), 1.57 (4H, m), 1.3-1.4 (5H, m), 1.17 (3H, t)

Step 4: Enantiomers of methyl 6- (1-methyl-6,7-diphenyl-1,2,3,4-tetrahydro-1,8-naphthyridin-2-yl) hexanoate Isomer 1 and enantiomer 2

Use racemic-6- (6,7-diphenyl-1,2,3,4-tetrahydro-1,8-naphthyridin-2-yl) hexanoate in N ₂ (step 3) (131 mg, 0.306 mmol) in DMF (5 ml) was treated with a suspension of sodium hydride (61.1 mg in a 60% mixture in mineral oil, 1.528 mmol) in anhydrous DMF (5 ml). After 30 min at room temperature, iodomethane (0.096 ml, 1.528 mmol) was added and stirring was continued for 5 h. The mixture was partitioned between DCM (50 ml) and water (50 ml) and the aqueous portion was separated and extracted with DCM (3x). , Dried over MgSO ₄ washed with brine and the organic extracts were combined, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica with 0-30% EtOAc in isohexane to give the title product mixture as a colorless oil;

LC-MS Rt = 1.43 min; [M + H] ⁺ 429.3, method 2 min LC_v002.

¹ H NMR (400 MHz, DMSO-d6) δ 7.2-7.3 (9H, m), 7.04 (2H, m), 3.6 (3H, s), 3.43 (1H, m), 3.12 (3H, s), 2.75 (2H, m), 2.31 (2H, t), 1.92 (1H, m), 1.81 (1H, m), 1.63 (1H, m), 1.52 (2H, m), 1.4-1.5 (5H, m).

Separation of mixtures using supercritical fluid chromatography to obtain individual enantiomers:

First elution peak; Rt = 6.89 min 6- (1-methyl-6,7-diphenyl-1,2,3,4-tetrahydro-1,8-naphthyridin-2-yl) hexanoic acid Enantiomers of methyl esters 1

LC-MS Rt = 1.43 min; [M + H] ⁺ 429.3, method 2 min LC_v002.

¹ H NMR (400 MHz, DMSO-d6) δ 7.27 (2H, m), 7.23 (7H, m), 7.18 (2H, m), 3.58 (3H, s), 3.44 (1H, m), 3.12 (3H , s), 2.73 (2H, m), 2.31 (2H, t), 1.92 (1H, m), 1.78 (1H, m), 1.68 (1H, m), 1.56 (2H, m), 1.34 (5H, m)

Second elution peak; Rt = 8.72 min 6- (1-methyl-6,7-diphenyl-1,2,3,4-tetrahydro-1,8-naphthyridin-2-yl) hexanoic acid Enantiomers of methyl esters 2:

LC-MS Rt = 1.43 min; [M + H] ⁺ 429.3, method 2 min LC_v002.

¹ H NMR (400 MHz, DMSO-d6) δ 7.27 (2H, m), 7.23 (7H, m), 7.09 (2H, m), 3.58 (3H, s), 3.44 (1H, m), 3.12 (3H , s), 2.73 (2H, m), 2.31 (2H, t), 1.92 (1H, m), 1.78 (1H, m), 1.68 (1H, m), 1.56 (2H, m), 1.34 (5H, m)

Step 5: Example 2.1-6- (1-Methyl-6,7-diphenyl-1,2,3,4-tetrahydro-1,8-naphthyridin-2-yl) caproic acid Construct 1

Methyl 6- (1-methyl-6,7-diphenyl-1,2,3,4-tetrahydro-1,8-naphthyridin-2-yl) hexanoate (34 mg, 0.079 mmol) Enantiomer 2 was dissolved in THF / water (2: 1) and lithium hydroxide (9.99 mg, 0.238 mmol) was added. The reaction mixture was stirred vigorously at room temperature for 48 h and then diluted with water (20 ml). The pH was adjusted to pH 3-4 by adding 2 M HCl. The aqueous portion was extracted with DCM (3 × 30 ml) and the combined organic extracts were washed with brine, dried over MgSO ₄ , filtered and concentrated in vacuo to give the title compound as a yellow oil;

LCMS Rt = 1.36 min, [M + H] ⁺ 415.3, method 2 min LC_v002.

¹ H NMR (400 MHz, DMSO-d6) δ 12.03 (1H, s), 7.35-7.2 (9H, m), 7.14 (2H, m), 3.51 (1H, m), 3.18 (3H, s), 2.8 (2H, m), 2.27 (2H, t), 2.01 (1H, m), 1.82 (1H, m), 1.72 (1H, m), 1.59 (2H, m), 1.4-1.5 (5H, m).

Example 2.2 -Preparation of 6- (1-methyl-6,7-diphenyl-1,2,3,4-tetrahydro-1, in a similar manner to enantiomer 1 from a suitable starting compound, Enantiomer 2 of 8-naphthyridin-2-yl) hexanoic acid:

LCMS Rt = 1.36 min, [M + H] ⁺ 415.3, method 2 min LC_v002.

¹ H NMR (400 MHz, DMSO-d6) δ 12.03 (1H, s), 7.35-7.2 (9H, m), 7.14 (2H, m), 3.51 (1H, m), 3.18 (3H, s), 2.8 (2H, m), 2.27 (2H, t), 2.01 (1H, m), 1.82 (1H, m), 1.72 (1H, m), 1.59 (2H, m), 1.4-1.5 (5H, m).

The compounds of the examples listed below were prepared by a method similar to Examples 2.1 and 2.2 by replacing (6-ethoxy-6-oxohexyl) zinc bromide (II) with an appropriate organozinc derivative (Table 3 ).

Examples 3.1 and 3.2 Enantiomer 1 and enantiomers of 7- (2-methyl-6,7-diphenyl-3,4-dihydro-1,8-naphthyridin-1 (2H) -yl) heptanoic acid Construct 2

Step 1: 7-methyl-2,3-diphenyl-1,8-naphthyridine was treated with methyl magnesium chloride (1.676 ml, 5.03 mmol) dropwise in a N ₂ atmosphere of 6,7-diphenyl-1 1,8-naphthyridine 1-oxide and 2,3-diphenyl-1,8-naphthyridine 1-oxide (Intermediate C) (1 g, 3.35 mmol) in anhydrous THF (10 ml) The mixture was cooled (0 ° C). The resulting mixture was stirred at room temperature for 45 minutes and then partitioned between EtOAc and water. (2 × 100 ml) and extracted with EtOAc and the aqueous portion was washed with brine and the combined organic extracts were dried over MgSO _4, filtered and concentrated in vacuo. The crude residue was dissolved in acetic anhydride (5 ml) and heated at 120 ° C for 10 min using microwave radiation. The resulting mixture was partitioned between DCM (150 ml) and water. , Dried over MgSO ₄ organic portions are washed with brine, filtered and concentrated in vacuo. The crude product was loaded onto an Isolute ^™ SCX-2 column and eluted with MeOH followed by 2 M NH ₃ in MeOH. The methanolic ammonia fraction was concentrated in vacuo to obtain a brown oil, which was purified by chromatography on silica with 0-50% EtOAc in isohexane to give the title product;

LC-MS Rt = 1.33 mins; [M + H] ⁺ 297.2, Method 2 min LC_v002

¹ H NMR (400 MHz, DMSO-d6) δ 8.44 (1H, s), 8.41 (1H, d), 7.57 (1H, d), 7.42 (1H, m), 7.40 (1H, m), 7.33 (8H , m), 2.74 (3H, s).

Step 2: Racemic -2-methyl-6,7-diphenyl-1,2,3,4-tetrahydro-1,8-naphthyridine

Treat 7-methyl-2,3-diphenyl-1,8-naphthyridine (step 1) (352 mg, 1.188 mmol) with 10% palladium on carbon (126 mg) in an argon atmosphere at room temperature. The solution was stirred in ethanol (10 ml). The reaction mixture was purged 3 times with nitrogen and placed under a hydrogen atmosphere overnight. With Celite (Filter material) The mixture was filtered and the catalyst was washed with EtOAc (200 ml). The solvent was removed in vacuo to obtain the title compound as a yellow foam.

LC-MS Rt = 1.32 min; [M + H] ⁺ 301.2, method 2 min LC_v002

¹ H NMR (400 MHz, DMSO-d6) δ 7.4-7.3 (9H, m), 7.12 (2H, m), 6.66 (1H, s), 3.57 (1H, m), 2.81 (2H, m), 1.98 (1H, m), 1.54 (1H, m), 1.25 (3H, d).

Step 3: Enantiomer of 7- (2-methyl-6,7-diphenyl-3,4-dihydro-1,8-naphthyridin-1 (2H) -yl) heptanoate 1 and enantiomer 2

Add 2-methyl-6,7-diphenyl-1,2,3,4-tetrahydro-1,8-naphthyridine stored in NMP (1 ml) to the microwave vial in sequence (step 2) ( 345 mg, 1.148 mmol), ethyl 7-bromoheptanoate (0.671 ml, 3.45 mmol) and cesium carbonate (748 mg, 2.297 mmol). The resulting mixture was heated at 160 ° C. for 2 h using microwave radiation. Ethyl 7-bromoheptanoate (0.671 ml, 3.45 mmol) was added and heating was continued for another 2 h. Partitioned between EtOAc and water, the reaction mixture and the organic portion was washed with brine, dried over MgSO _4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica with 0-20% EtOAc in isohexane to obtain a yellow oil, which was loaded onto an Isolute ^TM SCX-2 column and sequentially with MeOH And 2 M NH ₃ in MeOH was eluted. The methanolic ammonia portion was concentrated in vacuo to obtain the racemic isomer 7- (2-methyl-6,7-diphenyl-3,4-dihydro-1,8-naphthyridine-1 (2H)- Ethyl) heptanoate. The mixture was subjected to a palm separation using supercritical fluid chromatography to obtain individual enantiomers.

Preparative chromatography conditions:

Instrument: Gilson Prep HPLC system

Injection volume: 4 ml

Mobile phase: heptane / 2-methyl-2-butanol (98.5: 1.5)

Flow rate: 7 ml / min

Column: Chiralpak IC 5 μm 1 × 20 × 250 mm + 1 × 30 × 250 mm

UV detection: 220 nm

Analysis conditions:

Instrument: Shimadzu Prominence

Injection volume: 15 μl

Mobile phase: heptane / 2-methyl-2-butanol (98.5: 1.5)

Flow rate: 0.500 ml / min

Column: Chiralpak IC 5 μm 4.6 × 250 mm

UV detection: 220 nm

First elution peak; Rt = 22.827 min : 7- (2-methyl-6,7-diphenyl-3,4-dihydro-1,8-naphthyridin-1 (2H) -yl) heptanoic acid Enantiomers of ethyl ester 1

LC-MS Rt = 1.49 min; [M + H] ⁺ 457.5, method 2 min LC_v002

¹ H NMR (400 MHz, DMSO-d6) δ 7.21-7.18 (9H, m), 7.08 (2H, m), 4.02 (2H, m), 3.94 (1H, m), 3.68 (1H, m), 3.16 (1H, m), 2.82 (1H, m), 2.70 (1H, m), 2.22 (2H, m), 1.80 (2H, m), 1.72 (2H, m), 1.51 (2H, m), 1.31 ( 4H, m), 1.24 (6H, m).

Second dissolution peak. (Rt = 25.184 min) : 7- (2-methyl-6,7-diphenyl-3,4-dihydro-1,8-naphthyridin-1 (2H) -yl) heptanoic acid ethyl ester pair Enantiomer 2

LC-MS Rt = 1.49 min; [M + H] ⁺ 457.5, method 2 min LC_v002

1H NMR (400 MHz, DMSO-d6) δ 7.21-7.18 (9H, m), 7.08 (2H, m), 4.02 (2H, m), 3.94 (1H, m), 3.68 (1H, m), 3.16 ( 1H, m), 2.82 (1H, m), 2.70 (1H, m), 2.22 (2H, m), 1.80 (2H, m), 1.72 (2H, m), 1.51 (2H, m), 1.31 (4H , m), 1.24 (6H, m).

Step 4: Example 3.1 Enantiomers of 7- (2-methyl-6,7-diphenyl-3,4-dihydro-1,8-naphthyridin-1 (2H) -yl) heptanoic acid 1;

Ethyl 7- (2-methyl-6,7-diphenyl-3,4-dihydro-1,8-naphthyridin-1 (2H) -yl) heptanoate (37 mg, 0.081 mmol) Enantiomer 2 was dissolved in THF / water (1 ml / 2: 1) and lithium hydroxide (9.70 mg, 0.405 mmol) was added. The mixture was stirred at room temperature for 4 days and then diluted with water (25 ml). The pH was adjusted to pH 5-6 using 1 M HCl. With EtOAc (2x 20 ml) were combined washed with brine and the aqueous portion was extracted organic extracts were dried over MgSO _4, filtered and evaporated to give 7- (2-methyl-6,7-diphenyl-3,4 Enantiomer 1 of dihydro-1,8-naphthyridin-1 (2H) -yl) heptanoic acid;

LC-MS Rt = 1.41 min; [M + H] ⁺ 429.3, method 2 min LC_v002

¹ H NMR (400 MHz, DMSO-d6) δ 12.08 (1H, s), 7.21-7.18 (9H, m), 7.08 (2H, m), 4.02 (1H, m), 3.73 (1H, m), 3.22 (1H, m), 2.83 (1H, m), 2.70 (1H, m), 2.22 (2H, m), 1.84 (2H, m), 1.72 (2H, m), 1.53 (2H, m), 1.43- 1.32 (4H, m), 1.24 (3H, d).

Example 3.2 Enantiomer 2 of 7- (2-methyl-6,7-diphenyl-3,4-dihydro-1,8-naphthyridin-1 (2H) -yl) heptanoic acid;

Preparation of 7- (2-methyl-6,7-diphenyl-3,4-dihydro-1,8-naphthyridine-1 (2H) in a similar manner to enantiomer 1 using appropriate starting compounds ) -Yl) Enantiomer 2 of heptanoic acid;

LC-MS Rt = 1.41 min; [M + H] ⁺ 429.3, method 2 min LC_v002

¹ H NMR (400 MHz, DMSO-d6) δ 12.08 (1H, s), 7.21-7.18 (9H, m), 7.08 (2H, m), 4.02 (1H, m), 3.73 (1H, m), 3.22 (1H, m), 2.83 (1H, m), 2.70 (1H, m), 2.22 (2H, m), 1.84 (2H, m), 1.72 (2H, m), 1.53 (2H, m), 1.45- 1.31 (4H, m), 1.23 (3H, d).

real Example 4.1 7- (2,3-diphenyl-7,8-dihydropyrido [3,2-b] pyrazine-5 (6H) -yl) heptanoic acid

Step 1: 2,3-Diphenyl-5,6,7,8-tetrahydropyrido [3,2-b] pyrazine

Add 2,3-diphenylpyrido [3,2-b] pyrazine (Intermediate D) (49.1 g, 143 mmol), triethylamine (20 ml, 143 mmol) and 10% carbon at room temperature A suspension of palladium (19.5 g) in anhydrous THF (410 ml) was placed in a hydrogen atmosphere (100 mbar) for 61 h. After 24 h and 48 h, additional palladium catalyst (2 x 4.9 g) was added. The reaction mixture was filtered and the catalyst was washed with THF. The filtrate was concentrated in vacuo and the crude product was dissolved in hot EtOAc (1500 ml) and washed with saturated Na ₂ CO ₃ solution (400 ml). The aqueous portion was extracted with EtOAc (200 ml) and the combined organic extracts were washed with water (150 ml), brine (300 ml), dried over sodium sulfate and concentrated in vacuo. This crude product was purified by chromatography on silica in order to elute with pure DCM and then DCM (1% MeOH) to obtain the title product;

LC-MS Rt = 1.13 min; [M + H] +288, method A

Step 2: 7- (2,3-Diphenyl-7,8-dihydropyrido [3,2-b] pyrazine-5 (6H) -yl) heptanoate

The 2,3-diphenyl-5,6,7,8-tetrahydropyrido [3,2-b] pyrazine (step 1) (6.6) in DCM (120 ml) was stirred at room temperature. g, 23.0 mmol), a mixture of ethyl 7-oxoheptanoate (4.0 g, 23.0 mmol), sodium triacetoxyborohydride (7.3 g, 34.5 mmol), and acetic acid (1.4 g, 23.0 mmol). After 2 h, a further portion of ethyl 7-oxoheptanoate (1.9 g, 11.0 mmol) was added and stirring was continued for 4 h. The reaction mixture was diluted with water and extracted with EtOAc (3x). The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica with EtOAc / heptane to remove unreacted starting material. The resulting yellow oil was dissolved in EtOH (80 ml) and treated with a suspension of sodium borohydride (0.5 g) in EtOH (10 g) at <5 ° C. The reaction mixture was stirred for 10 min and then quenched with acetone (30 ml). After stirring at room temperature for 15 min, the reaction mixture was poured into water (100 ml) and concentrated to a volume of 30 ml. The solution was extracted with EtOAc (3x) and the combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound, which was used in the next step without further purification. _Rf = 0.39 at EtOAc / heptane 1: 4.

Step 3: 7- (2,3-Diphenyl-7,8-dihydropyrido [3,2-b] pyrazine-5 (6H) -yl) heptanoic acid

Treat 7- (2,3-diphenyl-) in THF (300 ml) and MeOH (100 ml) with a solution of lithium hydroxide monohydrate (3.5 g, 83 mmol) in water (100 ml). Ethyl 7,8-dihydropyrido [3,2-b] pyrazine-5 (6H) -yl) heptanoate (step 2) (6.1 g, 13.8 mmol). The reaction mixture was heated at reflux for 5 h and cooled to room temperature. The pH of the mixture was adjusted to <pH 5 using 2 M HCl. The volatile solvents were removed in vacuo and the remaining residue was diluted with water (50 ml) and extracted with EtOAc (3x). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to give a green-gray solid. The crude material was dissolved in MeOH (30 ml) and divided into 2 portions filled with 113 g LiChroprep RP-18 column (40-63 μm, supplier Merck, reversed-phase column) was purified by elution with 10-100% MeCN in water. The solid obtained was recrystallized from a hot mixture of EtOH (120 ml) and water (90 ml). After seeding at 5 ° C and stirring for 1 h, the crystals were filtered off and the product was dried at 40 ° C for 2 days in a vacuum oven to obtain the title compound;

LC-MS Rt = 1.32 min; [M + H] +416, method A

¹ H NMR (400 MHz, DMSO-d6) δ 11.95 (1H, br s), 7.32-7.16 (10H, m), 3.59 (2H, t), 3.47 (2H, t), 2.91 (2H, m), 2.16 (2H, m), 2.01 (2H, m), 1.64 (2H, m), 1.52 (2H, m), 1.35 (4H, m).

By a method similar to Example 4.1, by replacing 2,3-diphenyl-5,6,7,8-tetrahydropyrido [3, with a suitable pyrido [3,2-b] pyrazine derivative 2-b] pyrazine to prepare compounds of the examples listed below (Table 4). Some compounds were obtained by purification by SFC.

* The second hydrolysis step using LiOH is performed after the palm separation.

Example 4.3 7- (2,3-Di-p-tolyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -yl) heptanoic acid

Step 1: Ethyl 7- (2,3-di-p-tolyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -yl) heptanoate

2,3-Di-p-tolyl-5,6,7,8-tetrahydropyrido [2,3-b] pyrazine (Intermediate E) (10 g, 31.7 mmol) in DCE (300 ml) To this solution were added DIPEA (6.09 ml, 34.9 mmol) and ethyl 7-oxoheptanoate (10.92 g, 63.4 mmol) in this order. The mixture was stirred at RT for 10 minutes and sodium triacetoxyborohydride (16.80 g, 79 mmol) was added in portions. The reaction mixture was heated at 40 ° C overnight and then slowly added to water (500 ml) and stirred at RT for 10 minutes. The organic layer was separated and the aqueous layer was extracted with dichloromethane (2 x 200 ml). The combined organics were washed with brine (200 ml), dried over anhydrous sodium sulfate and concentrated in vacuo to give a pale yellow oil. Isolute Separtis SCX-2 (capture / release super cation exchange resin) (222 g, 127 mmol) was added to the column and the product was loaded with MeOH (50 ml). The column was washed with MeOH (750 L) followed by 2 N NH ₃ / MeOH (1000 ml, prepared from 280 ml 7 N + 720 ml MeOH) to obtain the title compound. No further purification was performed;

HPLC (Agilent 1200) Rt 6.38 min, method B

Step 2: 7- (2,3-Di-p-tolyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -yl) heptanoic acid

Dissolve 7- (2,3-di-p-tolyl-7,8-dihydropyrido [2,3-b] pyrazin-5 (6H) -yl) heptanoate (step 1) in THF ( 94 ml) and lithium hydroxide monohydrate (7.79 g, 186 mmol) in water (94 ml) was added in portions. The reaction mixture was warmed to 50 ° C and stirred for 7.5 hours.

The reaction mixture was concentrated in vacuo to remove THF and diluted with water (500 ml). The pH of the aqueous layer was adjusted to pH 2 with 1 N HCl (100 ml) and extracted with EtOAc (3 x 500 ml). The combined organic layers were washed with brine (200 ml), dried over anhydrous sodium sulfate and concentrated in vacuo. The crude solid was suspended in TBME / heptane (1: 1, 100 ml) and spun on a rotary evaporator (non-vacuum) at RT until crystals formed. The solid was removed by filtration, washed with heptane (50 ml) and dried overnight at RT. The solid was recrystallized from a hot mixture of EtOH (211 ml) and water (159 ml). After seeding at 5 ° C and stirring for 1 h, the crystals were filtered off and the product was dried in a vacuum oven at 40 ° C overnight to obtain the title compound; see Table 4 for characterization data.

Step 3: 7- (2,3-Di-p-tolyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -yl) heptanoic acid mesylate

7- (2,3-Di-p-tolyl-7,8-dihydropyrido [2,3-b] pyrazin-5 (6H) -yl) heptanoic acid in anhydrous acetone (40 ml) (1.97 g, 4.44 mmol) was added methanesulfonic acid (0.288 ml, 4.44 mmol). A clear yellow solution was obtained and a yellow precipitate was observed almost immediately. The reaction mixture was stirred at room temperature for 2 hr and then filtered. The filter bed was washed with acetone and the yellow precipitate was dried under vacuum at room temperature overnight.

¹ H NMR (400 MHz, DMSO-d6) δ 12.25-8.77 (2H, broad peak), 7.21 (2H, d), 7.15 (2H, d), 7.08 (2H, d), 7.08 (2H, d), 3.59 (2H, m), 3.48 (2H, m), 2.94 (2H, t), 2.37 (3H, s), 2.28 (3H, s), 2.28 (3H, s), 2.15 (2H, t), 2.00 (2H, m), 1.60 (2H, m), 1.47 (2H, m), 1.36-1.25 (4H, complex multiplet).

mp (DSC onset) 206.59 ° C.

Example 4.8 6- (2,3-diphenyl-7,8-dihydropyrido [3,2-b] pyrazine-5 (6H) -yl) hexanoic acid

From 2,3-diphenyl-5, in a similar manner to 7- (6,7-diphenyl-3,4-dihydro-1,8-naphthyridin-1 (2H) -yl) heptanoic acid, This compound was prepared from 6,7,8-tetrahydropyrido [3,2-b] pyrazine (Example 4.1, Step 1) and ethyl 6-bromohexanoate (Example 1 Step 1 and Step 2 using microwave radiation. Step 1).

LC-MS Rt = 1.59 min; [M + H] ⁺ 402.3, method 2 min LC_v002.

¹ H NMR (400 MHz, DMSO-d6) δ 12.03 (1H, s), 7.4-7.2 (10H, m), 3.64 (2H, m), 3.52 (2H, m), 2.97 (2H, t), 2.25 (2H, t), 2.04 (2H, m), 1.74-1.56 (4H, m), 1.39 (2H, m).

Example 4.9 5- (2,3-diphenyl-7,8-dihydropyrido [3,2-b] pyrazine-5 (6H) -yl) pentanoic acid

From 2,3-diphenyl-5, in a similar manner to 7- (6,7-diphenyl-3,4-dihydro-1,8-naphthyridin-1 (2H) -yl) heptanoic acid, This compound was prepared from 6,7,8-tetrahydropyrido [3,2-b] pyrazine (Example 4.1, step 1) and ethyl 5-bromovalerate (step 1 and step 2 of Example 1 using microwave radiation 1).

LC-MS Rt = 1.57 min; [M + H] +388.3, method 2 min LC_v002.

¹ H NMR (400 MHz, DMSO-d6) δ 7.33 (2H, m), 7.27 (4H, m), 7.22 (4H, m), 3.6 (2H, m), 3.46 (2H, m), 2.91 (2H , m), 2.23 (2H, t), 2.00 (2H, m), 1.63 (2H, m), 1.54 (2H, m).

Example 5.1 7- (3-phenyl-2-p-tolyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -yl) heptanoic acid

Step 1: Ethyl 7- (3-phenyl-2-p-tolyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -yl) heptanoate

Treat 3-phenyl-2-p-tolyl-5 in anhydrous DCE (1 ml) with DIPEA (0.103 ml, 0.591 mmol) and ethyl 7-oxoheptanoate (185 mg, 1.075 mmol) in that order. , 6,7,8-tetrahydropyrido [2,3-b] pyrazine (Intermediate F) (162 mg, 0.538 mmol). The reaction mixture was stirred at RT for 10 minutes and sodium triacetoxyborohydride (570 mg, 2.69 mmol) was added. The resulting mixture was stirred at 60 ° C for 16 hours. After cooling to RT, the mixture was slowly added to water (50 ml) and extracted with DCM (3x). The combined organic extracts were passed through a phase separation column and concentrated in vacuo. The resulting crude product was purified by chromatography on silica with 0-10% EtOAc / isohexane to obtain the title product;

LCMS; Rt 1.38 min MS m / z 458 [M + H] +; method 2 min LC_v003

Step 2: 7- (3-phenyl-2-p-tolyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -yl) heptanoic acid

Treat 7- (3-phenyl-2-p-tolyl-7,8-dihydrogen) in THF (4 ml) and water (1 ml) with LiOH monohydrate (43.5 mg, 1.036 mmol) at RT Ethyl pyrido [2,3-b] pyrazine-5 (6H) -yl) heptanoate (158 mg, 0.345 mmol) and stirred at RT for 16 hours. The organic solvent was removed in vacuo and the residue was diluted with water (20 ml). The pH was adjusted to pH 4 with a 10% aqueous citric acid solution. The mixture was extracted with DCM (x3) and the organic extract was passed through a phase separation column and concentrated in vacuo. The resulting crude product was purified by chromatography on silica with 0-40% EtOAc / isohexane, followed by palladium separation using supercritical fluid chromatography to obtain the title compound;

LCMS Rt 1.19 min MS m / z 430 [M + H] +; method 2 min LC_v003

¹ H NMR (400MHz, DMSO-d6) δ 7.35 (2H, m), 7.3 (3H, m), 7.15 (2H, d), 7.05 (2H, d), 3.6 (2H, t), 3.45 (2H, m), 2.9 (2H, t), 2.25 (3H, s), 2.15 (2H, t), 2.0 (2H, m), 1.6 (2H, m), 1.45 (2H, m), 1.3 (4H, m ).

Example 5.2 7- (2-phenyl-3-p-tolyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -yl) heptanoic acid

Step 1: Ethyl 7- (2-phenyl-3-p-tolyl-7,8-dihydropyrido [2,3-b] pyrazin-5 (6H) -yl) heptanoate

Treating 2-phenyl-3-p-tolyl-5,6 with ethyl 7-oxoheptanoate (1.776 g, 10.25 mmol) and sodium triethoxyalkoxyborohydride (3.62 g, 17.09 mmol), A solution of 7,8-tetrahydropyrido [2,3-b] pyrazine (Intermediate FA) (1.03 g, 3.42 mmol) in 1,2-dichloroethane (15 ml). The reaction mixture was stirred at room temperature overnight. Diluted with saturated NaHCO ₃ (70 ml) and the mixture was extracted with DCM (x3). The combined organics were dried (MgSO _4), filtered and concentrated in vacuo. The resulting crude product was purified by chromatography on silica with 0-60% EtOAc / isohexane to obtain an oil. The product was loaded onto an Isolute ^™ SCX-2 column, washed with MeOH and eluted with 2 M NH ₃ in MeOH. The methanolic ammonia portion was concentrated in vacuo to obtain the title compound;

LCMS; Rt 5.36 min MS m / z 458.5 [M + H] +; method 10 min LC_v003

Step 2: 7- (2-phenyl-3-p-tolyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -yl) heptanoic acid

7- (2-phenyl-3-p-tolyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -yl) heptane with LiOH (0.560 g, 23.38 mmol) A solution of ethyl acetate (1.07 g, 2.338 mmol) in THF (12 ml) and water (6 ml) and stirred at 70 ° C for 18 hours. After cooling to RT, the reaction mixture was concentrated in vacuo. The residue was diluted with water (20 ml) and the pH was adjusted to pH 4 using 2 M HCl. The aqueous portion was extracted with EtOAc (2 x 20 ml). The organic extracts were washed with brine, dried (MgSO ₄₎ and evaporated in vacuo. The residue was dissolved in hot (about 80 ° C) ethanol (20 ml) and water (about 15 ml) was added until the solution became cloudy. After cooling, a solid was precipitated. The mixture was left to cool for 72 hours.

The solid was collected by filtration, washed with water and dried at 40 ° C for 5 hours to obtain the title compound;

LCMS Rt 4.36 min MS m / z 430 [M + H] +; method 10 min LC_v003

¹ H NMR (400MHz, DMSO-d6) δ 11.94 (1H, s), 7.26-7.15 (5H, m), 7.21 (2H, d), 7.06 (2H, d), 3.57 (2H, m), 3.45 ( 2H, m), 2.89 (2H, m), 2.27 (3H, s), 2.14 (2H, t), 2.0 (2H, m), 1.6 (2H, m), 1.47 (2H, m), 1.37-1.23 (4H, m).

Example 5.3 7- (2-m-tolyl-3-p-tolyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -yl) heptanoic acid

Step 1: Ethyl 7- (2-m-tolyl-3-p-tolyl-7,8-dihydropyrido [2,3-b] pyrazin-5 (6H) -yl) heptanoate

Treat 2-m-tolyl-3-pair in anhydrous DCE (1 ml) with DIPEA (0.037 ml, 0.213 mmol) and ethyl 7-oxoheptanoate (66.6 mg, 0.387 mmol) in order at RT Tolyl-5,6,7,8-tetrahydropyrido [2,3-b] pyrazine (Intermediate FB) (61 mg, 0.193 mmol). The reaction mixture was stirred at RT for 10 minutes and sodium triacetoxyborohydride (205 mg, 0.967 mmol) was added. The resulting mixture was stirred at 60 ° C overnight. After cooling to RT, the mixture was slowly added to water (50 ml) and extracted with DCM (3x). The combined organic extracts were passed through a phase separation column and concentrated in vacuo. The resulting crude product was purified by chromatography on silica with 0-5% EtOAc / isohexane to obtain the title product;

LCMS Rt 1.61 min MS m / z 473.4 [M + H] +; method 2 min LC_v003

Step 2: 7- (2-M-tolyl-3-p-tolyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -yl) heptanoic acid

Treat 7- (2-m-tolyl-3-p-tolyl-7,8-di) in THF (1 ml) and water (0.5 ml) with LiOH monohydrate (18.42 mg, 0.439 mmol) at RT Hydropyrido [2,3-b] pyrazine-5 (6H) -yl) heptanoic acid ethyl ester (step 1) (69 mg, 0.146 mmol) and stirred at RT for 4 hours. MeOH (1 ml) and 2 M NaOH (1 ml) were added and the mixture was stirred at RT overnight. The resulting mixture was added to water (20 ml) and the pH was adjusted to pH 1 with 2 M HCl. The aqueous portion was extracted with DCM (x3) and the organic extract was passed through a phase separation column. The organic solvent was concentrated in vacuo. The crude product was purified by preparative LC-MS (low pH). The appropriate fractions were collected and extracted with DCM (x3) and the organics were passed through a phase separation column. Removal of the solvent in vacuo gave the title compound;

LCMS: Rt 1.25 min MS m / z 444 [M + H] +; method 2 min LC_v003

¹ H NMR (400MHz, DMSO-d6) δ 11.94 (1H, br s), 7.21 (2H, d), 7.18 (1H, dd), 7.07 (2H, d), 7.05 (1H, dd), 7.00 (1H , ddd), 6.88 (1H, ddd), 3.57 (2H, m), 3.44 (2H, m), 2.88 (2H, t), 2.27 (3H, s), 2.23 (3H, s), 2.14 (2H, t), 2.0 (2H, m), 1.59 (2H, m), 1.47 (2H, m), 1.36-1.25 (4H, m).

By a method similar to Example 5.1 by replacing 3-phenyl-2-p-tolyl-5,6,7,8-tetrahydropyrido [2,3 with an appropriate pyrazine derivative (prepared below) -b] Pyrazine (Intermediate F) to prepare compounds of the examples listed below (Table 5).

* Example 5.7: No hydrolysis step required

Example 6.1 7- (2,3-bis (3-fluoro-4-methylphenyl) -7.8-dihydropyrido [2,3-b] pyrazine-5 (6H) -yl) heptanoic acid

Step 1: 7- (2,3-bis (3-fluoro-4-methylphenyl) -7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -yl) heptane Ethyl acetate

Treat 2,3-bis (3-fluoro-4-) in DCE (10 ml) with 7-oxoheptanoic acid ethyl ester (125 mg, 0.729 mmol) and triethylamine (0.112 ml, 0.801 mmol) (Methylphenyl) -5,6,7,8-tetrahydropyrido [2,3-b] pyrazine (Intermediate G) (256 mg, 0.729 mmol) and stirred at RT for 15 min. Sodium triacetoxyborohydride (772 mg, 3.64 mmol) was added and stirring was continued for 18 h at 60 ° C. The reaction mixture was diluted with water and DCM and the organic portion was separated. The aqueous portion was extracted with DCM and the combined organic extracts were dried (sodium sulfate), filtered and concentrated in vacuo to give a yellow gum. The crude product was purified by chromatography on silica with 0-20% EtOAc in isohexane to give the title compound;

LCMS: Rt 1.5 6min MS m / z 508 [M + H] +; method 2 min LC_v003

Step 2: 7- (2,3-bis (3-fluoro-4-methylphenyl) -7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -yl) heptane acid

Treat 7- (2,3-bis (3-fluoro-4-methylphenyl) -7,8- in THF (2 ml) and water (2 ml) with LiOH (45.7 mg, 1.907 mmol) Dihydropyrido [2,3-b] pyrazine-5 (6H) -yl) heptanoic acid ethyl ester (121 mg, 0.238 mmol) and the resulting mixture was stirred at RT for 18 h. The mixture was acidified to pH 4 with HCl and extracted with DCM. The organic extracts were combined, dried (sodium sulfate), filtered and concentrated in vacuo. The residue was azeotroped with ether to obtain the title compound;

LCMS: Rt 5.19 min MS m / z 480.3 [M + H] +; method 10 min LC_v003

¹ H NMR (400 MHz, MeOH- d ₄ ) δ 7.15-6.91 (6H, m), 3.69 (2H, t), 3.53 (2H, t), 2.97 (2H, t), 2.29-2.20 (8H, m ), 2.11 (2H, m), 1.72 (2H, m), 1.59 (2H, m), 1.47-1.36 (4H, m).

By a method similar to Example 6.1, by replacing 2,3-bis (3-fluoro-4-methylphenyl) -5,6,7,8-tetranium with an appropriate pyrazine derivative (prepared below) Hydropyrido [2,3-b] pyrazine (Intermediate G) to prepare compounds of the examples listed below (Table 6).

* Example 6.5: No hydrolysis step required

Example 7.1 Racemization -7- (8-ethyl-2,3-diphenyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -yl) heptanoic acid

Step 1: Racemic -7- (8-ethyl-2,3-diphenyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -yl) heptanoic acid Ethyl ester

Meso-8-ethyl-2,3-diphenyl-5,6,7,8-tetrahydro-pyridine and the outer [2,3-b] pyrazine (Intermediate HC) (13 mg, 0.041 mmol ) To a solution in DCE (2 ml) was added ethyl 7-oxoheptanoate (24.84 mg, 0.144 mmol), and sodium triacetoxyborohydride (69.9 mg, 0.330 mmol) in this order. The reaction mixture was stirred at room temperature under a nitrogen atmosphere. Water (10 ml) was added and the resulting mixture was extracted with EtOAc (3 x 10 ml). MgSO ₄ was combined organic extracts were dried, filtered and concentrated in vacuo. The crude product was passed through a pre-treated Isolute SCX-2 SPE column loaded with MeOH and eluted with 1 M ammonia in MeOH (10 ml) to obtain the title product; LC-MS Rt = 1.52 min; [M + H ] +472, method 2 min LC_v003.

Step 2: Racemic -7- (8-ethyl-2,3-diphenyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -yl) heptanoic acid

Rac-7 to the outside (8-ethyl-2,3-diphenyl-7,8-dihydro-pyrido [2,3-b] pyrazin -5 (6H) - yl) heptanoate (Step 1) To a solution of (15 mg, 0.032 mmol) in THF (4.5 ml) and water (1.5 ml) was added LiOH (4.57 mg, 0.191 mmol). The reaction mixture was heated to reflux for 3.5 hours and stirred at RT overnight. The pH of the reaction mixture was adjusted to pH <5 by adding 2 M HCl. The volatile solvents were removed in vacuo and the crude residue was dissolved in water (10 ml) and extracted with EtOAc (3 x 10 ml). Dried over MgSO ₄ The combined organic extracts were filtered and concentrated in vacuo to give the title compound;

LC-MS Rt = 1.48 min; [M + H] +444.5, method 2 min LC_v003.

¹ H NMR (400 MHz, DMSO-d6) δ 7.49-7.41 (2H, dd), 7.40-7.38 (2H, d), 7.30-7.21 (6H, m) 3.75-3.61 (2H, m), 3.57-3.49 (2H, m), 2.98-2.89 (1H, m), 2.33-2.28 (2H, m), 2.19-2.08 (2H, m), 1.98-1.87 (1H, m), 1.75-1.56 (4H, m) , 1.48-1.39 (4H, m), 1.29-1.23 (1H, m), 1.12-1.05 (3H, t)

By a method similar to Example 7.1 by replacing racemic-8-ethyl-2,3-di with an appropriate pyrazine derivative (prepared with an appropriate alkylmagnesium bromide reagent in a manner similar to intermediate HC) Phenyl-5,6,7,8-tetrahydropyrido [2,3-b] pyrazine (intermediate HC) was used to prepare compounds of the examples listed below (Table 7).

Examples 8.1, 8.1a and 8.1b Isomerization of 7- (7,8-dihydroxy-2,3-diphenyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -yl) heptanoic acid Isomer 1 and isomer 2

Cis-diol 1 cis-diol

(From peak 2) (from peak 1)

Step 1: Racemic -diacetic acid 5- (7-ethoxy-7- pendant heptyl) -2,3-diphenyl-5,6,7,8-tetrahydropyrido [2, 3-b] pyrazine-7,8-diyl ester

The rac - diacetic acid 2,3-phenyl-5,6,7,8-tetrahydro-pyrido [2,3-b] pyrazine-7,8-diyl diacetate (Intermediate the I) ( (69 mg, 0.171 mmol) in DCE (3 ml) was added in order of ethyl 7-oxoheptanoate (88 mg, 0.513 mmol), and sodium triacetoxyoxyborohydride (109 mg, 0.513 mmol) ). The reaction was stirred at room temperature under a nitrogen atmosphere overnight. To the reaction mixture were further added ethyl 7-oxoheptanoate (88 mg, 0.513 mmol) and sodium triacetoxyoxyborohydride (109 mg, 0.513 mmol) in this order. The reaction mixture was stirred under a nitrogen atmosphere at RT for 4 days. The mixture was diluted with water and extracted with EtOAc (3x20 ml). MgSO ₄ was combined organic extracts were dried, filtered and concentrated in vacuo. The resulting crude product was purified by chromatography on silica with 0-70% EtOAc / isohexane to obtain the title product;

LC-MS Rt = 1.46 min; [M + H] +560, method 2 min LC-v003.

Step 2: Example 8.1 Racemic -7- (7,8-dihydroxy-2,3-diphenyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H)- ) Heptanoic acid

The rac - diacetic acid 5- (7-ethoxy-7-oxo-hept-yl) -2,3-diphenyl-5,6,7,8-tetrahydro-pyrido [2,3- b] A solution of pyrazine-7,8-diyl ester (step 1) (30 mg, 0.054 mmol) in THF (3 ml) and water (1.0 ml) was added with LiOH (7.70 mg, 0.322 mmol). The suspension was heated to reflux for 1 hour and allowed to stand overnight at RT. The mixture was heated under reflux for an additional 30 minutes and after cooling to RT, 1 M HCl was added to adjust the pH to below pH 5. The volatile solvent was evaporated and the resulting mixture was extracted with EtOAc (10 ml). The organic extract was washed with water, dried over MgSO _4, filtered and concentrated in vacuo to give the title product mixture;

LC-MS Rt = 1.10 min; [M + H] +448, method 2 min LC-v003.

The mixture was subjected to a palm separation using supercritical fluid chromatography to obtain individual isomers:

Detailed method:

Column: Phenomenex LUX C2 250 × 10 mm, 5 μm

Mobile phase: 50% methanol / 50% CO ₂

Flow rate: 10 ml / min

Detection: UV at 220 nm

Example 8.1a

First elution peak; Rt = 6.21 min 7- (7,8-dihydroxy-2,3-diphenyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -Yl) Heptanoic acid isomer 1

LC-MS Rt = 1.12 min; [M + H] ⁺ 448.3, method 2 min LC_v003

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.45-7.41 (2H, m), 7.37-7.34 (2H, m), 7.29-7.27 (6H, m), 4.81 (1H, d), 4.39 (1H, br d), 3.74-3.58 (4H, m), 2.29 (2H, t), 1.74-1.63 (4H, m), 1.41 (4H, m)

Example 8.1b

Second elution peak; Rt = 9.74 min 7- (7,8-dihydroxy-2,3-diphenyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -Yl) heptanoic acid isomer 2

LC-MS Rt = 1.10 min; [M + H] ⁺ 448.0, method 2 min LC_v003

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.45-7.41 (2H, m), 7.37-7.34 (2H, m), 7.29-7.27 (6H, m), 4.81 (1H, d), 4.39 (1H, width (Double peak), 3.74-3.58 (4H, m), 2.29 (2H, t), 1.74-1.63 (4H, m), 1.41 (4H, m)

Examples 8.2a and 8.2b Isolation of 7- (7,8-dihydroxy-2,3-di-p-tolyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -yl) heptanoate Structure 1 and isomer 2

Step 1: 2,3-Di-p-tolyl-5,6-dihydropyrido [2,3-b] pyrazine

To 2,3-di-p-tolylpyrido [2,3-b] pyrazine (Intermediate E, Step 1) (6.74 g, 21.65 mmol) in THF (130 ml) at room temperature 2.4 M LiAlH4 in THF (4.51 ml, 10.82 mmol) was added dropwise. To the reaction mixture cooled to 0 ° C was added water (0.409 ml), 15% aqueous NaOH (0.409 ml) and water (1.227 ml) in portions and continuously. The mixture was stirred at 0 ° C for 15 min and warmed to RT. Anhydrous MgSO ₄ and 15 min of stirring the mixture and filtered. The residue was washed with EtOAc (x5) and the filtrate was concentrated in vacuo to obtain the title compound: LC-MS Rt = 1.12 min; [M + H] ⁺ 314, method 2 min LC_v003.

Step 2: 2,3-Di-p-tolylpyrido [2,3-b] pyrazine-5 (6H) -formic acid third butyl ester

2.5-M BuLi in hexane (7.40 ml, 18.51 mmol) dropwise treated with 2,3-di-p-tolyl-5,6 in anhydrous Et ₂ O (150 ml) cooled to -78 ° C -Dihydropyrido [2,3-b] pyrazine (step 1) (2.9 g, 9.25 mmol). After stirring at -78 ° C for 10 minutes, di-third-butyl dicarbonate (2.79 ml, 12.03 mmol) was added and the mixture was stirred and allowed to warm to RT. After 2 days stirring, with NH ₄ Cl (sat.) The reaction mixture was quenched. The phases were separated and the organics were washed with water and brine, dried (sodium sulfate), filtered and concentrated in vacuo. The crude product was purified by chromatography on silica with 0-50% EtOAc in isohexane to obtain the title compound: LC-MS Rt = 1.54 min; [M + H] ⁺ 414, [M + H-tBu] 358; method 2 min LC_v003.

Step 3: Racemic -7,8-dihydroxy-2,3-di-p-tolyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -formic acid tert-butyl Ester

To a solution of tributylmethylammonium chloride (0.970 g, 4.11 mmol) in DCM (15 ml) at RT under nitrogen was added potassium permanganate (0.650 g, 4.11 mmol) in portions over 10 minutes. The mixture was cooled to 0 ° C and treated with 2,3-di-p-tolylpyrido [2,3-b] pyrazine-5 (6H) -carboxylic acid third butyl ester (step 2) (1 g, 2.418 mmol) The solution in DCM (10 ml) was treated dropwise. Add a solution of sodium bisulfite (1.510 g, 14.51 mmol) in water (12.5 ml) and keep the temperature <10 ° C. With Celite (Filter material) The mixture was filtered and washed with DCM. The phases were separated and the organic portion was washed with brine, dried (sodium sulfate), filtered and the solvent was removed in vacuo. The crude product was dissolved in DCM and purified by chromatography on silica with 30-50% EtOAc in isohexane to give the title compound;

LC-MS Rt = 1.31 min; [M + H] ⁺ 448, [M + H-tBu] 392; method 2 min LC_v003.

Step 4: Racemic -diacetic acid 5- (third butoxycarbonyl) -2,3-di-p-tolyl-5,6,7,8-tetrahydropyrido [2,3-b] pyrazine -7,8-diyl ester

Add acetic anhydride (260 μl, 2.76 mmol) to racemic -7,8-dihydroxy-2,3-di-p-tolyl-7,8-dihydropyrido [2,3-b] pyrazine- A solution of 5 (6H) -tributyl butyl ester (step 3) (411 mg, 0.918 mmol) in pyridine (1783 μl, 22.04 mmol) was stirred at RT for 18 h. The resulting mixture was diluted with DCM and washed with saturated NaHCO _3. The organic portion was dried (sodium sulfate), filtered and concentrated in vacuo. The crude product was purified by eluting on silica with 0-65% EtOAc in isohexane to give the title compound;

LC-MS Rt = 1.47 min; [M + H] ⁺ 532, [M + H-tBu] 476; method 2 min LC_v003.

Step 5: Racemic -diacetic acid 2,3-di-p-tolyl-5,6,7,8-tetrahydropyrido [2,3-b] pyrazine-7,8-diyl ester

At RT Racemic - acid diethyl 5- (tertiary-butoxycarbonyl) -2,3-p-tolyl-5,6,7,8-tetrahydro-pyrido [2,3-b] A solution of pyrazine-7,8-diyl ester (step 4) (430 mg, 0.809 mmol) in 4 M HCl in dioxane (4.044 ml, 16.18 mmoO) was stirred for 20 minutes. The mixture was washed with a saturated sodium bicarbonate solution and extracted with ethyl acetate (2 × 20 ml). The combined organic extracts were dried over MgSO _4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica with 10-100% ethyl acetate in isohexane to obtain the title compound;

LC-MS Rt = 1.29 min; [M + H] ⁺ 432; method 2 min LC_v003.

Step 6: Racemic -diacetic acid 5- (7-ethoxy-7- pendant oxyheptyl) -2,3-di-p-tolyl-5,6,7,8-tetrahydropyrido [2 , 3-b] pyrazine-7,8-diyl ester

The racemic -diacetic acid 2,3-di-p-tolyl- was treated with ethyl 7-oxoheptanoate (257 mg, 1.495 mmol) followed by sodium triacetoxyborohydride (634 mg, 2.99 mmol). 5,6,7,8-tetrahydropyrido [2,3-b] pyrazine-7,8-diyl ester (step 5) (215 mg, 0.498 mmol) in 1,2-dichloroethane (20 ml). The resulting suspension was stirred at RT for 18 h. Further portions of ethyl 7-oxoheptanoate (517 mg, 3.386 mmol) were added over a 2 day time course. The mixture was diluted with NaHCO ₃ (saturated 50 ml) and extracted with DCM (3 × 40 ml). Dried (MgSO ₄₎ organic extracts were combined and concentrated in vacuo. The crude product was purified by chromatography on silica with 0-1% THF / DCM to obtain the title compound:

LC-MS Rt = 6.62 min; [M + H] ⁺ 588. Method 10 min LC_v003

Step 7: 7- (7,8-Dihydroxy-2,3-di-p-tolyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -yl) heptanoic acid Isomers 1 and 2

The rac - diacetic acid 5- (7-ethoxy-7-oxo-heptyl) -2,3-p-tolyl-5,6,7,8-tetrahydropyridine [2,3 -b] Pyrazine-7,8-diyl ester (step 6) (117 mg, 0.199 mmol) in THF (3 ml) and water (1 ml) was added with LiOH (28.6 mg, 1.194 mmol) . The mixture was stirred at RT for 18 h, and then heated at 60 ° C for 1 h. After cooling to RT, the mixture was acidified to pH 4/5 with 2 M HCl and extracted with EtOAc. The combined organic extracts were dried (sodium sulfate), filtered and concentrated in vacuo to obtain the title product mixture;

The mixture was subjected to a palm separation using supercritical fluid chromatography to obtain individual isomers:

Detailed method:

Column: Phenomenex LUX C2 250 × 10 mm, 5 μm

Mobile phase: 40% methanol / 60% CO ₂

Flow rate: 10 ml / min

Detection: UV at 220 nm

real Example 8.2a

First elution peak; Rt = 6.58 min 7- (7,8-dihydroxy-2,3-di-p-tolyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H ) -Yl) Heptanoic acid isomers 1

LC-MS Rt = 4.34min; [M + H] ⁺ 476, method 10 min LC_v003

¹ H NMR (400 MHz, MeOH- d ₄ ) δ 7.26 (2H, d), 7.21 (2H, d), 7.07 (4H, m), 4.77 (1H, m), 4.22-4.17 (1H, m), 3.71 (2H, t), 3.63-3.56 (1H, m), 3.53-3.47 (1H, m), 2.33 (6H, s), 2.21 (2H, t) 1.77-1.67 (2H, m), 1.65-1.51 (2H, m) 1.48-1.37 (4H, m)

Example 8.2b

Second elution peak; Rt = 10.23 min 7- (7,8-dihydroxy-2,3-di-p-tolyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H ) -Yl) Heptanoic acid isomers 2

LC-MS Rt = 4.28 min; [M + H] +476, method 10 min LC_v003

¹ H NMR (400 MHz, MeOH-d4) δ 7.26 (2 H, d), 7.21 (2 H, d), 7.07 (4 H, m), 4.77 (1 H, m), 4.24-4.15 (1 H , m), 3.71 (2 H, t), 3.64-3.56 (1 H, m), 3.54-3.46 (1 H, m), 2.33 (6 H, s), 2.21 (2 H, t), 1.78- 1.67 (2 H, m), 1.64-1.53 (2 H, m), 1.49-1.27 (4 H, m)

Example 9.1 (R) -7- (8-hydroxy-2,3-diphenyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -yl) heptanoic acid

Step 1: (R) -7- (8-Ethyloxy-2,3-diphenyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -yl) Ethyl heptanoate

(R) -acetic acid 2,3-diphenyl-5,6,7,8-tetrahydropyrido [2,3-b] pyrazine-8-yl ester (intermediate HBR) is stored in DCE (7 To the solution in ml) were added ethyl 7-oxoheptanoate (71.8 mg, 0.417 mmol), and sodium triethylhexyloxyborohydride (236 mg, 1.112 mmol) in this order. The reaction mixture was stirred at room temperature under a nitrogen atmosphere overnight. A further portion of ethyl 7-oxoheptanoate (6 equivalents) was added and the reaction mixture was stirred at RT for 4 days. The mixture was diluted with water (20 ml) and extracted with EtOAc (3x20 ml). MgSO ₄ was combined organic extracts were dried, filtered and concentrated in vacuo. The resulting crude product was purified by chromatography on silica with 0-40% EtOAc / isohexane to obtain the title compound;

LC-MS Rt = 1.42 min; [M + H] +503, method 2 min LC_v003.

Step 2: (R) -7- (8-Hydroxy-2,3-diphenyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -yl) heptanoic acid

(R) -7- (8-Ethyloxy-2,3-diphenyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -yl) heptanoic acid To a solution of ethyl acetate (step 1) (24.4 mg, 0.049 mmol) in THF (3 ml) and water (1 ml) was added LiOH (6.99 mg, 0.292 mmol). The reaction mixture was heated to reflux for 1.5 h. An additional 6 equivalents of LiOH were added and heating was continued for 1 h at reflux. After cooling to RT, the pH of the mixture was adjusted to a pH below 5 by adding 2 M HCl. The volatile solvents were removed in vacuo. To the residue was added water (10 ml) and the mixture was extracted with ethyl acetate (3 x 10 ml). The combined organic phases were dried over MgSO _4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica with eluting with 0-100% EtOAc / isohexane followed by 0-100% MeOH / DCM. The residue was passed through a pre-treated Isolute SCX-2 SPE column loaded with MeOH and eluted with 1 M ammonia in MeOH. The basic portion was concentrated in vacuo and the residue was dissolved in THF (3 ml) and water (1.0 ml) and treated with LiOH (6.99 mg, 0.292 mmol). After stirring for 1.5 h at reflux, the mixture was cooled to RT and acidified with 2 M HCl to a pH below 5. The volatile solvents were removed in vacuo. To the residue was added water (10 ml) and the mixture was extracted with ethyl acetate (3 x 10 ml). The combined organic phases were dried over MgSO _4, filtered and concentrated in vacuo to give the title compound;

LC-MS Rt = 1.15 mins; [M + H] +432, method 2 min LC_v003.

¹ H NMR (400 MHz CDCl3) δ 7.32 (2H, dd), 7.28 (2H, m), 7.21-7.12 (6H, m) 4.75 (1H, dd), 3.60 (2H, t), 3.43 (2H, t ), 2.29-2.18 (3H, m), 2.01 (1H, m), 1.61-1.50 (4H, m), 1.35-1.26 (4H, m).

Example 9.2 (S) -7- (8-hydroxy-2,3-diphenyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -yl) heptanoic acid

Step 1: (S) -7- (8-Ethyloxy-2,3-diphenyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -yl) Ethyl heptanoate

(S) -acetic acid 2,3-diphenyl-5,6,7,8-tetrahydropyrido [2,3-b] pyrazine-8-yl ester (intermediate HBS) (46 mg, 0.133 To a solution in DCE (7 ml) was added ethyl 7-oxoheptanoate (68.8 mg, 0.4 mmol) and sodium triacetoxyborohydride (226 mg, 1.065 mmol) in this order. The reaction mixture was stirred at room temperature under a nitrogen atmosphere overnight.

Another portion of ethyl 7-oxoheptanoate (71.8 mg, 0.417 mmol) was added. The reaction mixture was stirred for an additional 5 hours under a nitrogen atmosphere. Water (20 ml) was added and the resulting mixture was extracted with EtOAc (3 x 20 ml). MgSO ₄ was combined organic extracts were dried, filtered and concentrated to give a crude oil. The resulting crude product was purified by chromatography on silica with 0-40% EtOAc / isohexane to obtain an oil. Pass the compound through a pre-treated Isolute SCX-2SPE column loaded with MeOH and eluted with 1M ammonia in MeOH (20 ml) to obtain the title compound;

LC-MS Rt = 1.40 min; [M + H] +502, method 2 min LC_v003.

Step 2: (S) -7- (8-Hydroxy-2,3-diphenyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -yl) heptanoic acid

In a similar manner to Example 9.1 from (S) -7- (8-Ethyloxy-2,3-diphenyl-7,8-dihydropyrido [2,3-b] pyrazine-5 ( 6H) -Ethyl) heptanoate (step 1) and LiOH to prepare the title compound;

LC-MS Rt = 1.16 min; [M + H] +432, method 2 min LC_v003.

¹ H NMR (400 MHz CDCl3) δ 7.32 (2H, dd), 7.28 (2H, m), 7.21-7.12 (6H, m) 4.75 (1H, dd), 3.60 (2H, t), 3.43 (2H, t ), 2.29-2.18 (3H, m), 2.01 (1H, m), 1.61-1.50 (4H, m), 1.35-1.26 (4H, m)

Examples 9.8, 9.8a, and 9.8b Enantiomer of 7- (8-hydroxy-2,3-di-p-tolyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -yl) heptanoic acid 1 And enantiomer 2

Step 1: Racemic -7- (8-ethoxymethyl-2,3-di-p-tolyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -yl Ethyl heptanoate

In 1,2-dichloroethane to deposit racemic (3 ml) in the - acetic acid 2,3-dimethyl-5,6,7,8-tetrahydropyridin-p and [2,3-b] To pyrazine-8-yl ester (Intermediate HF) (70 mg, 0.187 mmol) was added ethyl 7-oxoheptanoate (97 mg, 0.562 mmol). The reaction mixture was stirred at room temperature for 20 minutes and sodium triacetoxyborohydride (119 mg, 0.562 mmol) was added. The solution was stirred at room temperature overnight. Water (5 ml) was added and the reaction mixture was stirred vigorously for 15 minutes. The resulting mixture was extracted with DCM (x3). MgSO ₄ was combined organic extracts were dried, filtered and concentrated. The residue was passed through a pre-treated Isolute SCX-2 SPE column loaded with MeOH and eluted with 1 M ammonia in MeOH (20 ml). The solvent was removed in vacuo and the resulting crude was purified by chromatography on silica with 0-100% EtOAc / isohexane to give the title compound

LC-MS Rt = 1.58 min; [M + H] +530.4, method 2 min LC_v003.

Step 2: Example 9.8 Racemic -7- (8-hydroxy-2,3-di-p-tolyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -yl) Heptanoic acid

Rac-7 (8-acetyl-2,3-dihydro-7,8-toluenediamine yl and [2,3-b] pyrazine in ethanol (2 ml) in the outer -5 (6H) -yl) heptanoic acid ethyl ester To step 1) (75 mg, 0.142 mmol) was added 2 M sodium hydroxide (0.283 ml, 0.566 mmol). The reaction mixture was stirred at room temperature for 18 hours. The mixture was acidified with 2 M HCl (0.283 ml) and the solvent was removed in vacuo. To the residue were added DCM and water. The organic portion was separated, dried (MgSO _4), filtered and concentrated in vacuo to give the title compound;

LC-MS Rt = 1.27 min; [M + H] +460.4, method 2 min LC_v003.

¹ H NMR (400MHz, CDCl3) δ 7.33 (2H, d), 7.24 (2H, d), 7.08 (4H, m), 4.86 (1H, m), 3.67 (2H, m), 3.51 (2H, m) , 2.36 (3H, s), 2.35 (3H, s) 2.31 (3H, m), 2.09 (1H, m), 1.66 (4H, m), 1.41 (4H, m).

Step 3: Enantiomers of 7- (8-hydroxy-2,3-di-p-tolyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -yl) heptanoic acid Structure 1 and Enantiomer 2

Using supercritical fluid chromatography racemic 7- (8-hydroxy-2,3-p-tolyl-7,8-dihydro-pyrido [2,3-b] pyrazin -5 (6H) - Carboxy) heptanoic acid (step 2) to perform a palm separation to obtain individual enantiomers:

Detailed method:

Column: Phenomenex LUX C2 250 × 10 mm, 5 μm

Mobile phase: 45% methanol / 55% CO ₂

Flow rate: 10 ml / min

Detection: UV at 220 nm

System: Berger Minigram SFC2

Column temperature: 35 ℃

Example 9.8a

First elution peak; Rt = 7.14 min: 7- (8-hydroxy-2,3-di-p-tolyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H)- Enantiomer of heptanoic acid 1

LC-MS Rt = 1.25 min; [M + H] +460.4, method 2 min LC_v003

¹ H NMR (400 MHz, CDCl3) δ 7.34 (2H, d), 7.27 (2H, d), 7.08 (4H, m), 4.84 (1H, m), 3.68 (2H, m), 3.51 (2H, m ), 2.36 (3H, s), 2.35 (3H, s) 2.33 (3H, m), 2.09 (1H, m), 1.66 (4H, m), 1.41 (4H, m).

Example 9.8b

Second elution peak; Rt = 8.16 min: 7- (8-hydroxy-2,3-di-p-tolyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H)- Enantiomer of heptanoic acid 2

LC-MS Rt = 1.25 min; [M + H] +460.4, method 2 min LC_v003

¹ H NMR (400MHz, CDCl3) δ 7.34 (2H, d), 7.27 (2H, d), 7.08 (4H, m), 4.83 (1H, m), 3.67 (2H, m), 3.51 (2H, m) , 2.36 (3H, s), 2.35 (3H, s) 2.32 (3H, m), 2.07 (1H, m), 1.66 (4H, m), 1.41 (4H, m).

By replacing the (R) -acetic acid 2,3-diphenyl-5,6,7,8-tetrahydropyrido [2,3-b] with a suitable pyrazine derivative in a similar manner to Example 9.1 Pyrazine-8-yl ester (intermediate HBR) to prepare compounds of the examples listed below (Table 8). Some compounds were obtained by performing purification using SFC.

Example 10.1

(E) -7- (2,3-diphenyl-7,8-dihydropyrido [3,2-b] pyrazine-5 (6H) -yl) hept-3-enoic acid

Step 1: 5- (pent-4-enyl) -2,3-diphenyl-5,6,7,8-tetrahydropyrido [3,2-b] pyrazine

To 2,3-diphenyl-5,6,7,8-tetrahydropyrido [3,2-b] pyrazine (Example 4.1, step 1) (2 g, 6.96 mmol) in DCE (35 ml) To the solution was added pent-4-enal (2.061 ml, 20.88 mmol) and the mixture was stirred at RT overnight. An additional portion of sodium triacetoxyborohydride (4.43 g, 20.88 mmol) was added and the mixture was stirred at RT under a nitrogen atmosphere for 2.5 hours. Water was added and the mixture was extracted with EtOAc (3 x 60 ml). MgSO ₄ was combined organic extracts were dried, filtered and concentrated in vacuo. The crude material was purified by chromatography on silica with EtOAc / isohexane to give the title compound;

LC-MS Rt = 1.54 min; [M + H] ⁺ 357, method 2 min LC_v003.

Step 2: (E) -7- (2,3-Diphenyl-7,8-dihydropyrido [3,2-b] pyrazine-5 (6H) -yl) hept-3-enoic acid ester

5- (pent-4-enyl) -2,3-diphenyl-5,6,7,8-tetrahydropyrido [3,2-b] pyrazine (step 1) (200 mg, 0.563 mmol) and methyl but-3-enoate (225 mg, 2.251 mmol) in DCM (300 ml) were added with the second-generation Grubbs catalyst (5 mol%, 23.88 mg, 0.028 mmol). The reaction was stirred under a nitrogen atmosphere at RT overnight. Add another second-generation Grubbs catalyst (5 mol%, 23.88 mg, 0.028 mmol) and keep stirring for 2.5 h. The solvent was removed in vacuo and the resulting crude was purified by chromatography on silica with EtOAc / isohexane to give the title compound;

LC-MS Rt = 1.42 min; [M + H] ⁺ 428, method 2 min LC_v003.

Step 3: (E) -7- (2,3-Diphenyl-7,8-dihydropyrido [3,2-b] pyrazine-5 (6H) -yl) hept-3-enoic acid

To (E) -7- (2,3-diphenyl-7,8-dihydropyrido [3,2-b] pyrazine-5 (6H) -yl) hept-3-enoic acid methyl ester ( Step 2) To a solution of (30 mg, 0.070 mmol) in THF (3 ml): MeOH (1 ml) was added LiOH (10.08 mg, 0.421 mmol) in water (1 ml). The reaction mixture was heated at reflux for 1.5 h. After cooling to RT, 2 M HCl was added until the pH of the mixture was below pH 5. The volatile solvents were removed in vacuo and the resulting mixture was extracted with EtOAc (2 x 15 ml). The combined organic extracts were washed with water was over MgSO ₄ dried and concentrated in vacuo to give the title compound;

LC-MS Rt = 1.15 min; [M + H] ⁺ 414, method 2 min LC_v003.

Example 10.2 8- (2,3-Di-p-tolyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -yl) caprylic acid

Step 1: 5- (Heptan-6-alkenyl) -2,3-di-p-tolyl-5,6,7,8-tetrahydropyrido [2,3-b] pyrazine

Similar to 5- (pent-4-enyl) -2,3-diphenyl-5,6,7,8-tetrahydropyrido [3,2-b] pyrazine (Example 10.1, Step 1) The title compound was prepared from 2,3-di-p-tolyl-5,6,7,8-tetrahydropyrido [2,3-b] pyrazine (intermediate E) and hept-6-enal.

LC-MS Rt = 1.47 min; [M + H] ⁺ 412.7, method 2 min LC_v003.

Step 2: (E) -8- (2,3-Di-p-tolyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -yl) oct-2-enoic acid Ethyl ester

With (E) -7- (2,3-diphenyl-7,8-dihydropyrido [3,2-b] pyrazine-5 (6H) -yl) hept-3-enoate (Example 10.1 Step 2) In a similar manner from 5- (hept-6-alkenyl) -2,3-di-p-tolyl-5,6,7,8-tetrahydropyrido [2,3-b] py Azine (step 1) and ethyl acrylate prepared the title compound.

LC-MS Rt = 1.42 min; [M + H] ⁺ 484.4, method 2 min LC_v003.

Step 3: Ethyl 8- (2,3-di-p-tolyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -yl) octanoate (2,3-Di-p-tolyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -yl) oct-2-enoate (step 1) (60 mg , 0.124 mmol) and 10% Pd / C (66.0 mg, 0.062 mmol) in MeOH (10 ml) was placed under a hydrogen atmosphere at a pressure of 0.35 bar and stirred overnight at room temperature. With Celite (Filter material) The mixture was filtered and washed with MeOH. The filtrate was concentrated in vacuo and the crude product was purified by chromatography on silica with isohexane / EtOAc to give the title compound as a pale yellow oil;

LC-MS Rt = 1.41 min; [M + H] ⁺ 486.2, method 2 min LC_v003.

Step 4: 8- (2,3-Di-p-tolyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -yl) caprylic acid

With (E) -7- (2,3-diphenyl-7,8-dihydropyrido [3,2-b] pyrazine-5 (6H) -yl) hept-3-enoic acid (example 10.1 Step 3) In a similar manner from 8- (2,3-Di-p-tolyl-7,8-dihydropyrido [2,3-b] pyrazin-5 (6H) -yl) octanoate 1) preparing the title compound;

LC-MS Rt = 1.27 min; [M + H] ⁺ 458.1, method 2 min LC_v003.

¹ H NMR (400 MHz, CDCl3) δ 7.34-7.32 (2H, d), 7.25-7.23 (2H, d) 7.07-7.04 (4H, m), 3.67 (2H, t), 3.46 (2H, t), 3.02 (2H, t), 2.34 (3H, s), 2.32 (3H, s), 2.32-2.29 (2H, t), 2.12-2.07 (2H, m), 1.72-1.57 (4H, m), 1.41- 1.26 (6H, m)

Example 11.1 2- (4- (2,3-diphenyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -yl) butoxy) acetic acid

Step 1: 4- (2,3-Diphenyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -yl) butanoic acid methyl ester

From 2,3-diphenyl-5,6,7,8-tetrahydropyrido [3,2-b] pyrazine (Example 4.1 step 1) and 4-lane oxygen in a similar manner to step 10 of Example 10 Methyl butyrate to prepare the title compound;

LC-MS Rt = 1.39 min; [M + H] ⁺ 388, method 2 min LC_v003.

Step 2: 4- (2,3-diphenyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -yl) butyl acetate

To 4- (2,3-diphenyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -yl) butanoate at 0 ° C (step 1) ( 500 mg, 1.290 mmol) in THF (5 ml) was added to 1 M lithium aluminum hydride in THF (1.290 ml, 1.290 mmol). The reaction was warmed to RT and stirred for 1 h. The mixture was cooled in an ice bath and the reaction was quenched by the addition of MeOH. After warming to RT, the solvent was removed in vacuo and the residue was dissolved in EtOAc. With Celite (Filter material) and the mixture was filtered and the filtrate washed with water (3x), dried (MgSO ₄₎ and concentrated in vacuo to give the title compound;

LC-MS Rt = 1.24 min; [M + H] ⁺ 402, method 2 min LC_v003.

Step 3: 4- (2,3-Diphenyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -yl) but-1-ol

4- (2,3-diphenyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -yl) butyl acetate (step 2) (410 mg, 1.021 mmol) ) To a solution in THF (6 ml) and water (3 ml) was added lithium hydroxide (56.9 mg, 2.375 mmol) and the mixture was heated under reflux for 18 h. The reaction mixture was diluted with EtOAc and washed with water (2x), the combined organic extracts were washed with brine, dried (MgSO _4), filtered and concentrated in vacuo to give the title compound;

LC-MS Rt = 1.07 min; [M + H] ⁺ 360.5, method 2 min LC_v003.

Step 4: 2- (4- (2,3-diphenyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -yl) butoxy) acetic acid tert-butyl Ester

To 4- (2,3-diphenyl-7,8-dihydropyrido [2,3-b] pyrazin-5 (6H) -yl) but-1-ol (step 3) (50 mg, 0.139 mmol) in a stirred solution of toluene (1 ml) was added KOH (40% aqueous solution, 1 ml, 0.139 mmol) and tetrabutylammonium hydrogen sulfate (47.2 mg, 0.139 mmol). After 5 min at RT, Add tert-butyl bromoacetate (90 μL). The reaction mixture was stirred at RT for 24 h. The mixture was diluted with ether and the phases were separated. The aqueous portion was extracted with ether (x2), the combined organics were dried (sodium sulfate), filtered and the solvent was removed in vacuo. The residue was dissolved in THF (1 ml), followed by the addition of KOH (40% aqueous solution, 1 ml, 0.139 mmol), tetrabutylammonium hydrogen sulfate (47.2 mg, 0.139 mmol) and third butyl bromoacetate (88 μL). The reaction mixture was stirred at RT for 6 h. The mixture was diluted with ether and stirred for 12 h at RT. The phases were separated, the aqueous phase was extracted with ether (x2), the combined organics were dried (sodium sulfate), filtered and the solvent was removed in vacuo. The crude material was purified by eluting on silica with 0-100% EtOAc / DCM to obtain the title compound:

LC-MS Rt = 1.36 min; [M + H] ⁺ 474, method 2 min LC_v003.

Step 5: 2- (4- (2,3-diphenyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -yl) butoxy) acetic acid

Treat 2- (4- (2,3-diphenyl-7,8-dihydropyrido [2,3-b] pyrazine) in DCM (0.5 ml) with TFA (0.5 ml, 6.49 mmol) -5 (6H) -yl) butoxy) acetic acid tert-butyl ester (step 4) (20 mg, 0.042 mmol) and stirred at RT for 1 h. The solvent was removed in vacuo and the crude product was dissolved in DCM (<10% MeOH) and basified with a saturated sodium bicarbonate solution. The organic portion was separated and the aqueous portion was extracted with 10% MeOH / DCM. The combined organic extracts were washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to obtain the title compound;

LC-MS Rt = 3.82 min; [M + H] ⁺ 418, method 10 min LC_v003.

¹ H NMR (MeOD) δ 7.40-7.20 (10H, m), 3.90 (2H, s), 3.72 (2H, t), 3.60-3.47 (4H, m), 2.98 (2H, t), 2.13 (2H, m), 1.81 (2H, m), 1.70 (2H, m).

Example 11.2 2- (3-((2,3-diphenyl-7,8-dihydropyrido [3,2-b] pyrazine-5 (6H) -yl) methyl) phenoxy) acetic acid

Step 1: 3-((2,3-Diphenyl-7,8-dihydropyrido [3,2-b] pyrazine-5 (6H) -yl) methyl) phenol

2,3-diphenyl-5,6,7,8-tetrahydropyrido [3, 2-b] A solution of pyrazine (Example 4.1, step 1) (287 mg, 0.999 mmol) and 3-hydroxybenzaldehyde (244 mg, 1.998 mmol) in toluene (3 ml). The resulting suspension was stirred at RT for 3 h. Add water and continue stirring for 30 min. EtOAc was added and the aqueous portion was acidified to pH 1 with 2M HCl. The organic layer was separated and concentrated in vacuo. The crude product was purified by chromatography on silica with EtOAc / isohexane. The second purification was carried out by leaching with water / MeCN on silica to obtain the title compound;

¹ H NMR (400MHz, DMSO-d6) δ 9.32 (1H, s), 7.30 (2H, m), 7.24 (8H, m), 7.12 (1H, t), 6.73 (2H, m), 6.64 (1H, d), 4.80 (2H, s), 3.42 (2H, t), 2.96 (2H, t), 2.03 (2H, m)

Step 2: 2- (3-((2,3-Diphenyl-7,8-dihydropyrido [3,2-b] pyrazine-5 (6H) -yl) methyl) phenoxy) Ethyl acetate

The 3-((2,3-diphenyl-7,8-dihydropyrido [3,2-b] pyrazine-5 (6H) -yl) methyl group contained in acetone (3 ml) A mixture of phenol (140 mg, 0.356 mmol), potassium carbonate (98 mg, 0.712 mmol) and ethyl 2-bromoacetate (119 mg, 0.712 mmol) was heated at reflux overnight. The suspension was cooled to room temperature and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica with EtOAc / isohexane to give the title compound.

Step 3: 2- (3-((2,3-Diphenyl-7,8-dihydropyrido [3,2-b] pyrazine-5 (6H) -yl) methyl) phenoxy) Acetic acid

Treat 2- (3-((2,3-diphenyl-7,8-dihydropyrido [3,2-) in EtOH (2 ml) dropwise with 2M NaOH (0.340 ml, 0.680 mmol) b] Pyrazin-5 (6H) -yl) methyl) phenoxy) ethyl acetate (step 2) (163 mg, 0.340 mmol). The solution was stirred at room temperature for 1 h. The resulting white suspension was collected by filtration, washed with water and dried in a 40 ° C vacuum oven to obtain the title compound;

LC-MS Rt = 1.18 min; [M + H] +452, method 2 min LC_v003.

¹ H NMR (400 MHz, DMSO-d6) δ 7.31 (2H, m), 7.26 (8H, m), 7.16 (1H, t), 6.79 (2H, m), 6.67 (1H, dd), 4.81 (2H , s), 4.04 (2H, s), 3.44 (2H, t), 2.96 (2H, t), 2.03 (2H, m)

Example 11.3 4- (2- (2,3-Di-p-tolyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -yl) ethylamino) -4-oxo Butyric acid

Step 1: 2- (2,3-Di-p-tolyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -yl) ethylaminocarboxylic acid third butyl ester

Add 2,3-di-p-tolyl-5,6,7,8-tetrahydropyrido [2,3-b] pyrazine (Intermediate E) (150 mg, 0.476 mmol) and N-Boc-2- Aminoacetaldehyde (151 mg, 0.951 mmol) was suspended in 1,2-dichloroethane (3 ml). After 20 minutes at room temperature, sodium triethoxylate borohydride (252 mg, 1.189 mmol) was added and stirring was continued at room temperature for 2 days. An additional portion of N-Boc-2-aminoacetaldehyde (100 mg) was added, followed by sodium triacetoxyborohydride (252 mg, 1.189 mmol) and the reaction mixture was stirred at room temperature for 3 days. The mixture was partitioned between water and EtOAc and stirring was continued for 30 minutes. The organic layer was separated and concentrated in vacuo. The residue was purified by chromatography on silica to elute with 20-60% EtOAc in isohexane to obtain the title compound;

LC-MS Rt = 1.33 min; [M + H] +460, method 2 min LC_v003

Step 2: 2- (2,3-Di-p-tolyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -yl) ethylamine

2- (2,3-Di-p-tolyl-7,8-dihydropyrido [2,3-b] pyrazine- in 4 M HCl in dioxane (1 ml, 4.00 mmol) 5 (6H) -yl) ethylaminocarboxylic acid third butyl ester (step 1) (171 mg, 0.373 mmol) was stirred for 2 h. The suspension was added to EtOAc and saturated sodium carbonate. The organic layer was separated, dried (MgSO ₄₎ sulfate, filtered and concentrated in vacuo to give the title compound;

LC-MS Rt = 1.00 min; [M + H] +359, method 2 min LC_v003.

Step 3: 4- (2- (2,3-Di-p-tolyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -yl) ethylamino) -4 -Ethyl oxybutyrate

Ethyl succinic chloride (74.4 mg, 0.452 mmol) was treated dropwise at RT to contain 2- (2,3-diethyl ether) in ethyl acetate (5 ml) and triethylamine (0.084 ml, 0.603 mmol). A mixture of p-tolyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -yl) ethylamine (step 2) (108 mg, 0.301 mmol) and the resulting suspension was Stir at RT for 30 minutes. The mixture was poured into water and extracted with ethyl acetate. The organic layer was separated, dried and concentrated in vacuo to obtain the title compound;

LC-MS Rt = 1.15 min; [M + H] +486.8, method 2 min LC_v003

Step 4: 4- (2- (2,3-Di-p-tolyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -yl) ethylamino) -4 -Pendant oxybutyric acid

4- (2- (2,3-Di-p-tolyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -yl) ethylamino) -4- side Ethyl oxybutyrate (step 3) (168 mg, 0.345 mmol) was dissolved in EtOH (3 ml). 2 M sodium hydroxide (0.345 ml, 0.690 mmol) was added and the solution was stirred at room temperature for 30 minutes.

The reaction mixture was concentrated in vacuo and the residue was partitioned between EtOAc and 0.1 M HCl solution. The organic layer was separated and washed with saturated brine, dried (MgSO ₄₎ and concentrated to a volume of 5 ml in vacuo. The suspension was filtered and washed with EtOAc to obtain the title compound;

LC-MS Rt = 1.04 min; [M + H] +459, method 2 min LC_v003

Example 12.1 7- (6-Pentoxy-2,3-di-p-tolyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -yl) heptanoic acid

Step 1: 2,3-Di-p-tolyl-7,8-dihydropyrido [2,3-b] pyrazine-6 (5H) -one

To ₂ -bromo-3-chloro-7,8-dihydropyrido [2,3-b] pyrazine-6 (5H) -one (Intermediate J) (10 g, 38.1 mmol) under N ₂ supply P-tolyl To a stirred suspension of acid (11.39 g, 84 mmol) in MeCN (400 ml) and water (100 ml) was added solid K ₂ CO ₃ (thick mesh) (7.90 g, 57.1 mmol), Pd (PPh ₃ ) ₂ Cl ₂ (1.337 g, 1.905 mmol). The yellow RM was heated to 80 ° C and stirred for 66 hours. The RM is slowly cooled to RT and then placed in the refrigerator for 3 to 4 hours. The yellow fine needles were filtered under suction and washed with a small amount of acetonitrile and water in that order. After air-drying for 10 min, the solid was transferred and dried under vacuum at 40 ° C for 2 hours to obtain the finely crystalline needle-shaped title compound;

LC-MS Rt = 1.24 min; [M + H] +330.3, method 2 min LC_v003.

Step 2: 7- (6-Pentoxy-2,3-di-p-tolyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -yl) heptanoate

Treatment of 2,3-di-p-tolyl-7,8-dihydropyrido [2,3-b] pyrazine-6 (5H) -one with potassium carbonate (2.098 g, 15.18 mmol) under a nitrogen atmosphere (step 1) (1.0 g, 3.04 mmol) and ethyl 7-bromoheptanoate (1.440 g, 6.07 mmol) in a yellow solution in DMF (20 ml) and the resulting suspension was stirred at room temperature for 16 hours. The mixture was diluted with water and extracted with EtOAc (x2). Water (x2) and the extracts were washed with brine, dried (MgSO ₄₎ and evaporated to a brown oil in vacuo. The crude material was purified by chromatography on silica with 0-100% EtOAc / isohexane to obtain the title compound as a light solid;

LC-MS Rt = 1.52 min; [M + H] +486.5, method 2 min LC_v003.

Step 3: 7- (6-Pendoxy-2,3-di-p-tolyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -yl) heptanoic acid

Treatment of 7- (6-oxo-2,3-di-p-tolyl-7,8-dihydropyrido [2,3-b] pyrazine-5 with 1M sodium hydroxide (3.40 ml, 3.40 mmol) A solution of (6H) -yl) heptanoic acid ethyl ester (550 mg, 1.133 mmol) in methanol (10 ml) and the resulting solution was stirred at 50 ° C for 1 hour. The solution was cooled to room temperature and concentrated in vacuo. The residue was diluted with water and acidified with 1N HCl to a pH of about 2 to give a white solid, which was extracted with DCM (x3). Dried (MgSO ₄₎ and the extracts were evaporated in vacuo to give the title compound as a white solid;

LC-MS Rt = 1.28 mins; [M + H] +458, method 2 min low pH

¹ H NMR (400 MHz, CDCl3) δ 7.41-7.35 (4H, m), 7.39-7.30 (4H, m), 4.22-4.14 (2H, m), 3.24 (2H, t), 2.90 (2H, t) , 2.40-2.29 (8H, m), 1.79-1.69 (2H, m), 1.68-1.60 (2H, m), 1.48-1.35 (4H, m).

Example 13.1 7- (2- (pyridin-4-yl) -3-p-tolyl-7,8-dihydropyrido [2,3-b] pyrazin-5 (6H) -yl) heptanoic acid

Step 1: Ethyl 7- (2-bromo-3-chloro-6-oxo-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -yl) heptanoate

2-Bromo-3-chloro-7,8-dihydro-5H-pyrido [2,3-b] pyrazin-6-one (Intermediate J with potassium carbonate (10.27 g, 74.3 mmol) under nitrogen ) (3.9 g, 14.86 mmol) and ethyl 7-bromoheptanoate (7.05 g, 29.7 mmol) in DMF (75 ml) and the resulting solution was stirred at room temperature for 96 hours. The mixture was diluted with water and extracted with EtOAc (x2). Washed with water, brine, the combined organic extracts were dried (MgSO ₄₎ and concentrated in vacuo. The crude product was purified by chromatography on silica with 0-60% EtOAc / isohexane 0-60% to obtain the title compound;

LC-MS Rt = 4.91 min; [M + H] +418/420, method 10 min LC_v003.

Step 2: 7- (2-Bromo-3-chloro-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -yl) heptanoate

Slowly treat 7- (2-bromo-3-chloro-6- pendantoxy-7,8-dihydropyrido [ A solution of 2,3-b] pyrazine-5 (6H) -yl) heptanoate (step 1) (1.0 g, 2.388 mmol) in tetrahydrofuran (10 ml) and the resulting solution was stirred at 0 ° C 30 minutes and then warmed to room temperature. The mixture was cooled to 0 ° C and treated with borane tetrahydrofuran complex borane (2.4 ml, 2.4 mmol). After the addition was complete, the mixture was stirred at 0 ° C and subsequently at RT for 30 minutes. The mixture was cooled in ice and treated carefully with MeOH. The mixture was stirred at room temperature for 1 hour and then evaporated in vacuo to obtain an oil, which was purified by chromatography on silica with 0-100% EtOAc / isohexane to obtain Title compound

LC-MS Rt = 4.91 min; [M + H] +418/420, method 10 min LC_v003.

Step 3: Ethyl 7- (3-chloro-2- (pyridin-4-yl) -7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -yl) heptanoate

7- (2-Bromo-3-chloro-7,8-dihydropyrido [2,3-b] pyrazin-5 (6H) -yl) heptanoate was ethylated by bubbling nitrogen through (x3) A mixture of the ester (step 2) (100 mg, 0.247 mmol) and potassium carbonate (102 mg, 0.741 mmol) in dioxane (2 ml) was degassed. Pd (Ph ₃ P) ₄ (28.6 mg, 0.025 mmol) was added and the mixture was degassed by bubbling nitrogen through (x3). The mixture was heated at 150 ° C for 2 hours using microwave irradiation. The mixture was diluted with water and extracted with EtOAc (x2). The organics were washed with brine, dried (MgSO ₄₎ and evaporated to a pale oil in vacuo. The crude was purified by chromatography on silica with 20-100% EtOAc / isohexane to obtain the title compound as a clear oil; LC-MS Rt = 1.08 min; [M + H] +403, method 10 min LC_v003.

Step 4 : 7- (2- (Pyridin-4-yl) -3-p-tolyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -yl) heptanoate ethyl ester

7- (3-Chloro-2- (pyridin-4-yl) -7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) by bubbling nitrogen through (x3) -Yl) ethyl heptanoate (step 3) (58 mg, 0.144 mmol), p-tolyl A mixture of acid (39.1 mg, 0.288 mmol) and potassium carbonate (59.7 mg, 0.432 mmol) in dioxane (2 ml) was degassed. Pd (Ph ₃ P) ₄ (33.3 mg, 0.029 mmol) was added and the mixture was degassed by bubbling nitrogen through (x3). The mixture was heated at 150 ° C for 2 hours using microwave irradiation. The mixture was diluted with water and extracted with EtOAc (x2). The combined extracts were washed with brine, dried (MgSO ₄₎ and evaporated in vacuo. The crude product was purified by chromatography on silica in order to elute with 50-100% EtOAc in isohexane and 5-10% THF in DCM. The fractions were evaporated in vacuo and the residue was purified by ion exchange using an Isolute SCX-2 column, loaded with methanol and washed with 2M NH ₃ in MeOH to elute the title compound;

LC-MS Rt = 4.27 min; [M + H] +459, method 10 min LC_v003.

Step 5: 7- (2- (pyridin-4-yl) -3-p-tolyl.yl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -yl) heptanoic acid

Treatment of 7- (2- (pyridin-4-yl) -3-p-tolyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H with LiOH (33.9 mg, 1.417 mmol) A solution of ethyl) -yl) heptanoate (step 4) (65 mg, 0.142 mmol) in THF (3 ml) and water (1 ml) and the mixture was stirred at room temperature for 16 hours.

The mixture was concentrated in vacuo and the residue was diluted with water and washed with EtOAc (x2). The aqueous portion was acidified (1N HCl, pH ~ 5) and extracted with EtOAc. The combined extracts were washed with brine, dried (MgSO ₄₎ and evaporated to a yellow gum in vacuo, triturated with ether to give the title compound;

LC-MS Rt = 3.48 min; [M + H] +431, method 10 min LC_v003.

¹ H NMR (400 MHz, CDCl ₃ - d ) δ 8.41 (2 H, d), 7.42 (2 H, m), 7.30 (2 H, d), 7.12 (2 H, d), 3.69 (2 H, t), 3.50 (2 H, t), 3.01 (2 H, t), 2.39-2.29 (5 H, m), 2.11 (2 H, m), 1.71-1.60 (4 H, m), 1.43-1.35 (4 H, m).

Example 13.2 7- (3- (pyridin-4-yl) -2-p-tolyl-7,8-dihydropyrido [2,3-b] pyrazin-5 (6H) -yl) heptanoic acid

Step 1: Ethyl 7- (3-chloro-2-p-tolyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -yl) heptanoate

7- (2-Bromo-3-chloro-7,8-dihydropyrido [2,3-b] pyrazin-5 (6H) -yl) heptanoate was ethylated by bubbling nitrogen through (x3) Esters (Example 13.1, Step 2) (50 mg, 0.124 mmol), p-tolyl A mixture of acid (16.80 mg, 0.124 mmol) and potassium carbonate (51.2 mg, 0.371 mmol) in dioxane (2 ml) was degassed. Pd (Ph ₃ P) ₄ (14.28 mg, 0.012 mmol) was added and the mixture was degassed by bubbling nitrogen through (x3). The reaction mixture was heated at 150 ° C for 3 hours using microwave radiation. The mixture was diluted with water and extracted with EtOAc (x2). The organic extracts were combined and washed with brine, dried (MgSO ₄₎ and evaporated in vacuo. The crude product was purified by chromatography on silica with 10-50% EtOAc in isohexane to obtain 7- (3-chloro-2-p-tolyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -yl) heptanoic acid ethyl ester with 7- (2-bromo-3-chloro-7,8-dihydropyrido [2,3-b] pyrazine (3: 1) mixture of -5 (6H) -yl) heptanoic acid ethyl ester (Example 13.1, step 2).

LC-MS Rt = 6.05 min; [M + H] +416/418, method 10 min LC-v003.

Step 2: 7- (3- (Pyridin-4-yl) -2-p-tolyl-7,8-dihydropyrido [2,3-b] pyrazin-5 (6H) -yl) heptanoate ester

7- (3-Chloro-2-p-tolyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -yl) heptane by bubbling nitrogen through (x3) Ethyl Ester (Example 13.2, Step 1) (30 mg, 0.072 mmol) and 7- (2-bromo-3-chloro-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H ) -Yl) ethyl heptanoate (Example 13.1, step 2) (10 mg, 0.025 mmol), 4- (4,4,5,5-tetramethyl-1,3,2-dioxane A (3: 1) mixture of diyl-2-yl) pyridine (39.4 mg, 0.192 mmol) and potassium carbonate (39.9 mg, 0.288 mmol) in dioxane (2 ml) was degassed. Pd (Ph ₃ P) ₄ (22.22 mg, 0.019 mmol) was added and the mixture was degassed by bubbling nitrogen through (x3). The reaction mixture was heated at 150 ° C for 2 hours using microwave radiation. The mixture was diluted with water and extracted with EtOAc (x2). The combined extracts were washed with brine, dried (MgSO ₄₎ and evaporated in vacuo. The crude material was purified by ion exchange [Isolute SCX-2, washed with MeOH and eluted with 2 M NH ₃ in MeOH] to obtain a brown residue. The crude residue was purified by chromatography on silica in order to elute with 0-100% EtOAc and 10% MeOH / DCM in isohexane to obtain the title compound;

LC-MS Rt = 1.18 min; [M + H] +459, method 2 min LC-v003.

Step 3: 7- (3- (Pyridin-4-yl) -2-p-tolyl-7,8-dihydropyrido [2,3-b] pyrazin-5 (6H) -yl) heptanoic acid

Treatment of 7- (3- (pyridin-4-yl) -2-p-tolyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H with LiOH (7.83 mg, 0.327 mmol) A solution of ethyl) -yl) heptanoate (step 2) (15 mg, 0.033 mmol) in THF (2 ml) and water (1 ml) and stirred at 70 ° C for 4 hours. The mixture was cooled to room temperature and concentrated in vacuo. The residue was acidified (1N HCl, pH ~ 5) and extracted with DCM (x3). The combined extracts were washed with brine, dried (MgSO ₄₎ and evaporated to a yellow gum in vacuo, and triturated with ether at 40 ℃ was dried in vacuo for 2.5 hours to obtain the title compound;

LC-MS Rt = 1.03 min; [M + H] +431, method 2 min LC_v003.

¹ H NMR (400 MHz, CDCl ₃ - d ) δ 8.53 (2 H, d), 7.53 (2 H, d), 7.21 (2 H, d), 7.10 (2 H, d), 3.66-3.60 (2 H, m), 3.52-3.46 (2 H, m), 3.03 (2 H, t), 2.36-2.28 (5 H, m), 2.15-2.08 (2 H, m), 1.73-1.60 (4 H, m), 1.42 (4 H, m).

Examples 14.1 and 14.2 Enantiomer 1 of 7- (7-hydroxy-2,3-di-p-tolyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -yl) heptanoic acid 1 And enantiomer 2

Step 1: 7- (2,3-Di-p-tolylpyrido [2,3-b] pyrazine-5 (6H) -yl) heptanoate

A solution of 2,3-di-p-tolyl-5,6-dihydropyrido [2,3-b] pyrazine (Example 8.2, step 1) (3.88 g, 12.38 mmol) in DCE (70 ml) To this was added ethyl 7-oxoheptanoate (6.40 g, 37.1 mmol) and sodium triacetoxyborohydride (10.4 g, 49.1 mmol) in this order. The reaction mixture was stirred at room temperature under a nitrogen atmosphere for 2 days. The reaction mixture was diluted with water (70 ml) and extracted with EtOAc (3 x 70 ml). MgSO ₄ was combined organic extracts were dried, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica with EtOAc / isohexane, followed by further purification using reverse phase chromatography with MeCN / water (0.1% TFA) to obtain the title compound;

LC-MS Rt = 1.46 min; [M + H] +470.5, method 2 min LC_v003.

Step 2: Racemic -7- (7-hydroxy-2,3-di-p-tolyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -yl) heptanoic acid Ethyl ester

A solution of 1M BH ₃ .THF in THF (3.66 ml, 3.66 mmol) was added portionwise to 7- (2,3-di-p-tolylpyrido [2,3-b] pyrazine- 5 (6H) -yl) heptanoate (step 1) (1.145 g, 2.438 mmol). The reaction mixture was stirred at room temperature for 1 hour and then cooled to 0-5 ° C using an ice bath. The mixture was treated with 35% H ₂ O ₂ (1.067 ml, 12.19 mmol) followed by 2M NaOH (6.10 ml, 12.19 mmol). The mixture was warmed to room temperature and stirred overnight under a nitrogen atmosphere. The reaction mixture was washed with water (25 ml) and extracted with ethyl acetate (2 x 25 ml). The combined organic extracts were dried over MgSO _4, filtered and the filtrate was concentrated in vacuo to give an orange oil. The crude product was purified by chromatography on silica with EtOAc / isohexane, followed by further purification by chromatography on silica with DCM / MeOH to obtain the title compound;

LC-MS Rt = 1.37min; [M + H] +488.6, method 2 min LC_v003.

Step 3: Pair of 7- (7-hydroxy-2,3-di-p-tolyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -yl) heptanoate Enantiomer 1 and enantiomer 2

Using supercritical fluid chromatography racemic 7- (7-hydroxy-2,3-p-tolyl-7,8-dihydro-pyrido [2,3-b] pyrazin -5 (6H) - Ethyl) heptanoate (step 2) was subjected to a palladium separation to obtain individual enantiomers:

Detailed method:

Column: Phenomenex LUX C2 250 × 10 mm, 5 μm

Mobile phase: 45% methanol + 0.1% DEA / 55% CO ₂

Flow rate: 10 ml / min

Detection: UV at 220 nm

System: Berger Minigram SFC2

Column temperature: 35 ℃

First elution peak; Rt = 3.73 min: 7- (7-hydroxy-2,3-di-p-tolyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H)- Enantiomer of ethyl) heptanoate 1 LC-MS Rt = 1.31 min; [M + H] +488.7, method 2 min LC_v003

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.35-7.33 (2H, m), 7.26-7.24 (2H, m), 7.09-7.07 (4H, m), 4.44 (1H, broad m), 4.17-4.11 ( 2H, m), 3.79-3.61 (2H, br m), 3.61 (1H, complex multiplet), 3.43 (1H, complex multiplet), 3.28 (1H, m), 3.11 (1H, m), 2.36 (3H , s), 2.33 (3H, s), 2.28 (2H, m), 2.01 (1H, br m), 1.70-1.51 (4H, m), 1.41 (4H, m), 1.27 (3H, m)

Second elution peak; Rt = 4.71 min: 7- (7-hydroxy-2,3-di-p-tolyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H)- Enantiomer of ethyl) heptanoate 2 LC-MS Rt = 1.32 min; [M + H] +488.6, method 2 min LC_v003

¹ H NMR (400 MHz, CDCl3) δ 7.34 (2H, d), 7.25 (2H, d), 7.09-7.06 (4H, m), 4.44 (1H, brm), 4.14 (2H, q), 3.78-3.61 (2H, complex multiplet), 3.61 (1H, complex multiplet), 3.43 (1H, complex multiplet), 3.27 (1H, m), 3.11 (1H, m), 2.35 (3H, s), 2.33 (3H , s), 2.28 (2H, t), 2.02 (1H, brm), 1.74-1.53 (4H, m), 1.41 (4H, m), 1.27 (3H, t)

Example 14.1 Enantiomer 1 of 7- (7-hydroxy-2,3-di-p-tolyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -yl) heptanoic acid 1

7- (7-Hydroxy-2,3-di-p-tolyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -yl) heptanoic acid ethyl ester (step 3) (5.6 mg, 0.011 mmol) of enantiomer 1 was dissolved in ethanol (0.5 ml) and 2 M NaOH (0.023 ml, 0.046 mmol) was added. The solution was stirred at room temperature under a nitrogen atmosphere overnight. 2 M HCl was added to the reaction mixture until the pH was below pH 5. The volatile solvents were removed by distillation. To the residue was added water (10 ml) and the mixture was extracted with ethyl acetate (3 x 10 ml). The organic extracts were combined, dried over MgSO ₄ , filtered and concentrated in vacuo to obtain the title compound as an oil, which was dried in a vacuum oven at 40 ° C. overnight;

LC-MS Rt = 1.15 min; [M + H] +460.5, method 2 min LC_v003

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.24 (2H, d), 7.15 (2H, d), 7.01-6.93 (4H, m), 4.33 (1H, br m), 3.66-3.54 (2H, m) , 3.51 (1H, complex multiplet), 3.43 (1H, complex multiplet), 3.17 (1H, m), 3.01 (1H, m), 2.25 (3H, s), 2.27 (3H, s), 2.23 (2H , m), 1.63-1.52 (4H, m), 1.36-1.29 (4H, m)

Example 14.2 Enantiomer 2 of 7- (7-hydroxy-2,3-di-p-tolyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -yl) heptanoic acid 2

7- (7-Hydroxy-2,3-di-p-tolyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -yl) heptanoic acid ethyl ester (step 3) (5.6 mg, 0.011 mmol) of enantiomer 2 was dissolved in ethanol (0.5 ml) and 2 M NaOH (0.023 ml, 0.046 mmol) was added. The solution was stirred at room temperature under a nitrogen atmosphere overnight. 2 M NaOH (0.023 ml, 0.046 mmol) was added to the mixture and the reaction was stirred for an additional hour at room temperature under a nitrogen atmosphere. 2 M HCl was added to the reaction mixture until the pH was below pH 5. The volatile solvents were removed by distillation. To the residue was added water (10 ml) and the mixture was extracted with ethyl acetate (3 x 10 ml). The organic extracts were combined, dried over MgSO ₄ , filtered and concentrated in vacuo to obtain the title compound as an oil, which was dried in a vacuum oven at 40 ° C. overnight;

LC-MS Rt = 1.15 min; [M + H] +460.4, method 2 min LC_v003

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.33 (2H, d), 7.25 (2H, d), 7.11-7.03 (4H, m), 4.42 (1H, br m), 3.77-3.62 (2H, m) , 3.59 (1H, m), 3.43 (1H, m), 3.26 (1H, m), 3.10 (1H, m), 2.35 (3H, s), 2.33 (3H, s), 2.32 (2H, m), 1.75-1.58 (4H, m), 1.48-1.35 (4H, m)

Example 15.1 Racemization -7- (2,3-Di-p-tolyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -yl) -3,4-dihydroxyheptanoic acid

Step 1: (E) -7- (2,3-Di-p-tolyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -yl) hept-3-enoic acid Methyl ester

With (E) -7- (2,3-diphenyl-7,8-dihydropyrido [3,2-b] pyrazine-5 (6H) -yl) hept-3-enoate (Example 10.1 Step 1 and Step 2) The title was prepared in a similar manner from 2,3-di-p-tolyl-5,6,7,8-tetrahydropyrido [2,3-b] pyrazine (Intermediate E). Compound.

LC-MS Rt = 1.32 min; [M + H] ⁺ 457.4, method 2 min LC_v003.

Step 2: Racemic -7- (2,3-di-p-tolyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -yl) -3,4-di Methyl hydroxyheptanoate

To methyltributylammonium chloride (141 mg, 0.597 mmol) (hygroscopic) in dichloromethane (5 ml) was added potassium permanganate (94 mg, 0.597 mmol) and at room temperature The purple solution was stirred for 45 minutes. The solution was cooled to 0 ° C with an ice bath and (E) -7- (2,3-di-p-tolyl-7,8-dihydropyrido [2] stored in dichloromethane (1 ml) was added in portions. , 3-b] pyrazine-5 (6H) -yl) hept-3-enoic acid methyl ester (step 1) (160 mg, 0.351 mmol). The solution was stirred at 0-5 ° C for 2h. Sodium metabisulfite (500 mg, 2.63 mmol) in water (5 ml) was added dropwise to the reaction mixture at 0-5 ° C. After 15 minutes, the purple suspension became a white suspension. The organic layer was separated from the suspension using a phase separator column. The organic layer was evaporated to dryness. The crude product was purified by chromatography on silica with 0-100% EtOAc / isohexane to obtain the title compound;

LC-MS Rt = 1.12 min; [M + H] ⁺ 490.5, method 2 min LC-v003.

Step 3: Racemic -7- (2,3-di-p-tolyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -yl) -3,4-di Hydroxyheptanoic acid

Rac to in methanol (1 ml) in the outer-7- (2,3-di-p-tolyl-7,8-dihydro-pyrido [2,3-b] pyrazin -5 (6H) - yl ) -3,4-Dihydroxyheptanoic acid methyl ester (step 2) (30 mg, 0.061 mmol) was added with 2 M NaOH (0.061 ml, 0.123 mmol). The solution was stirred at room temperature for 3 h. 2 M HCl (0.061 ml) was added and the solution was evaporated to dryness. The crude product was purified by chromatography on silica with 0-15% DCM / MeOH to obtain the title compound;

LC-MS Rt = 1.04 min; [M + H] ⁺ 476.5, method 2 min LC_v003.

¹ H NMR (400MHz, DMSO-d6) δ 7.23 (2H, d), 7.13 (2H, d), 7.08 (2H, d), 7.03 (2H, d), 3.32 (1H, obs m), 3.68 (1H , m), 3.58 (2H, m), 3.46 (2H, m), 2.89 (2H, t), 2.28 (3H, s), 2.27 (3H, s), 2.25 (1H, m), 2.12 (1H, m), 2.01 (2H, m), 1.76 (1H, br m), 1.59 (1H, br m), 1.47 (1H, br m), 1.29 (1H, br m).

Example 16.1 7- (7-hydroxy-6- pendantoxy-2,3-di-p-tolyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -yl) heptanoic acid

7- (6-Panoxy-2,3-di) was treated dropwise with 1 M lithium bistrimethylsilazamide in THF (0.5 ml, 0.500 mmol) at -78 ° C under a nitrogen atmosphere. P-Tolyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -yl) heptanoic acid (Example 12.1) (100 mg, 0.219 mmol) in THF (2 ml) Its solution. After the addition was completed, the mixture was stirred at -78 ° C for 1 hour, and then (+)-(8,8-dichlorocamphorylsulfonyl) oxaziridine (78 mg, 0.262 mmol) was added in THF ( 2 ml). The resulting solution was stirred at -78 ° C for 60 minutes. The cooling conditions were removed and the mixture was warmed to about -10 ° C. The mixture was slowly warmed to room temperature overnight. The mixture was cooled to -78 ℃, (3 ml) was quenched with saturated NH ₄ Cl and allowed to warm slowly to room temperature. The yellow solution was diluted with water and extracted with EtOAc (x2). The aqueous layer (pH about 9) was acidified to pH about 2 with 1 M HCl and extracted with DCM (x2). Dried (MgSO ₄₎ organic extracts were combined and evaporated in vacuo to give a yellow gum. The residue was purified by chromatography on silica in order to elute with 1% MeOH / DCM followed by 10% MeOH / DCM to obtain the title compound;

LC-MS Rt = 0.84 min; [M + H] ⁺ 474, low pH at method 2 min.

¹ H NMR (400MHz, CDCl ₃ ) δ 7.89 (1H, d), 7.26 (2H, d), 7.24 (2H, d), 7.03 (4H, m), 4.44 (1H, m), 4.20 (1H, d ), 4.02 (1H, m), 3.54 (1H, m), 3.10 (1H, m), 2.28 (3H, s), 2.28 (3H, s), 2.24 (2H, m), 1.66 (2H, m) , 1.56 (2H, m), 1.43-1.25 (4H, m).

Examples 17.1a and 17.1b Enantiomers of 7- (7-methoxy-2,3-di-p-tolyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -yl) heptanoic acid Isomer 1 and enantiomer 2

Step 1: Racemic -7- (7-methoxy-2,3-di-p-tolyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -yl) Ethyl heptanoate

Sequentially at RT with DIPEA (0.044 ml, 0.255 mmol) under nitrogen, 7-oxo-heptanoate (80 mg, 0.463 mmol) in anhydrous treated DCE (4 ml) of rac-7 in Methoxy-2,3-di-p-tolyl-5,6,7,8-tetrahydropyrido [2,3-b] pyrazine (Intermediate K) (80 mg, 0.232 mmol). The resulting mixture was stirred at RT for 10 minutes and treated with sodium triacetoxyborohydride (245 mg, 1.158 mmol). The mixture was heated at 60 ° C for 16 hours. An additional portion of sodium triacetoxyborohydride (245 mg, 1.158 mmol) was added and the mixture was heated at 50 ° C for 3 days. After cooling to RT, the reaction mixture was diluted with DCM (50 ml) and washed with water (x2). The organic portion was separated using a phase separation column and the solvent was removed in vacuo. The crude product was purified by chromatography on silica with 0-20% EtOAc / isohexane to obtain the title compound.

LCMS Rt 1.43 min MS m / z 502 [M + H] + method 2 min LC-v003.

Step 2: Racemic -7- (7-methoxy-2,3-di-p-tolyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -yl) Heptanoic acid

At RT with 2 M NaOH (416 μL, 0.831 mmol) rac-stored in the processing (3 ml) in the MeOH -7- (7- methoxy-2,3-7,8-di-p Dihydropyrido [2,3-b] pyrazine-5 (6H) -yl) heptanoic acid ethyl ester (step 1) (139 mg, 0.277 mmol) and the mixture was stirred at RT for 4 hours. An additional 2 M NaOH (416 μL, 0.831 mmol) was added and the reaction mixture was stirred at RT overnight. The organic solvent was removed in vacuo and the resulting aqueous portion was diluted with water (20 ml). The pH was adjusted to pH 1 using 2 M HCl and the mixture was extracted with DCM (x3). The combined organic extracts were separated using a phase separation column and the solvent was removed in vacuo. The crude product was purified by chromatography on silica in order to elute with 0-30% EtOAc / isohexane and 10% MeOH in EtOAc to obtain the title compound;

LCMS: Rt 1.30 min MS m / z 474/475 [M + H] + method 2 min low pH.

Separation of mixtures using supercritical fluid chromatography to obtain individual enantiomers:

Detailed method:

Column: Chiralcel OJ-H 250 × 10 mm, 5 μm

Mobile phase: 25% methanol / 75% CO ₂

Flow rate: 10 ml / min

Column temperature: 35 ℃

Detection: UV at 220 nm

System: Berger Minigram SFC2

Example 17.1a

First elution peak; Rt = 3.51 min 7- (7-methoxy-2,3-di-p-tolyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -Yl) enantiomer 1 of heptanoic acid

LCMS: Rt 1.29 min MS m / z 474 [M + H] +; method 2 min low pH

1H NMR (400 MHz, CDCl3) δ 7.32 (2H, d), 7.24 (2H, d), 7.06 (4H, m), 3.91 (1H, m), 3.74-3.62 (2H, m), 3.58 (1H, m), 3.47 (3H, s), 3.43 (1H, m), 3.24 (1H, m), 3.13 (1H, m), 2.34 (3H, s), 2.32 (3H, s), 2.29 (2H, m ), 1.70-1.55 (4H, m), 1.41 (4H, m).

Example 17.1b

Second elution peak; Rt = 4.69 min 7- (7-methoxy-2,3-di-p-tolyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -Yl) enantiomer 2 of heptanoic acid

LCMS: Rt 1.29 min MS m / z 474 [M + H] +; method 2 min low pH

1H NMR (400 MHz, CDCl3) δ 7.32 (2H, d), 7.24 (2H, d), 7.06 (4H, m), 3.91 (1H, m), 3.73-3.62 (2H, m), 3.58 (1H, m), 3.47 (3H, s), 3.43 (1H, m), 3.24 (1H, m), 3.13 (1H, m), 2.34 (3H, s), 2.32 (3H, s), 2.29 (2H, m ), 1.71-1.55 (4H, m), 1.40 (4H, m)

Preparation of intermediate compounds Intermediate A 2,3-diphenyl- [1,8] naphthyridine

2-amino-pyridine-3-carboxaldehyde (5 g, 40.9 mmol) and deoxybenzoin (8.03 g, 40.9 mmol) in hexahydropyridine (4.46 ml, 45.0 mmol) stored at 120 ° C The suspension was heated overnight. The resulting solution was partitioned between DCM (200 ml) and water (200 ml). The organic layer was separated and washed with water (2 x 150 ml), washed with brine, dried over MgSO _4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica with 0-50% EtOAc in isohexane to give the title product as a yellow solid;

LC-MS Rt = 1.41 min; [M + H] ⁺ 283.1, method 2 min LC_v002.

¹ H NMR (400 MHz, DMSO-d6) δ 9.12 (1H, dd), 8.56 (2H, dd), 7.68 (1H, dd), 7.44 (2H, m), 7.34 (8H, m).

Intermediate B 6,7-diphenyl-1,2,3,4-tetrahydro- [1,81naphthyridine

A solution of 2,3-diphenyl- [1,8] naphthyridine (Intermediate A) (2 g, 7.08 mmol) in EtOH (50 ml) was purged with N ₂ and 10% palladium on carbon ( 0.754 g, 0.708 mmol). The reaction mixture was placed under a hydrogen atmosphere overnight. With Celite (Filter material) The mixture was filtered and the catalyst was washed with EtOAc (400 ml). The filtrate was concentrated in vacuo to obtain the title compound as an off-white solid;

LC-MS: Rt = 1.33 min; [M + H ₂ O] ⁺ = 303.3, method 2 min LC_v001

¹ H NMR (400 MHz, DMSO-d6) δ 7.3 (9H, m), 7.1 (2H, m), 6.7 (1H, s), 3.4 (2H, m), 2.7 (2H, t), 1.8 (2H , m)

in Interstitial C

Treatment of 2,3-diphenyl- [1,8] naphthyridine (Intermediate A) (5.3 with hydrogen peroxide (6.58 ml, 75 mmol) and methylphosphonium trioxide (VII) (0.468 g, 1.878 mmol) g, 18.77 mmol) in DCM (60 ml) and the resulting mixture was stirred at room temperature overnight. , Dried over MgSO ₄ in DCM (250 ml) and water (250 ml) and the mixture was partitioned between organic portion was washed with brine, filtered and concentrated in vacuo. The resulting yellow foam was dried overnight at 40 ° C in vacuo to obtain the title compound mixture. This crude mixture was used without further purification;

LC-MS 2 peak: Rt = 1.31 min, 18%, [M + H] ⁺ 299.2; Rt = 1.36 min, 82%, [M + H] ⁺ 299.2, method 2 min LC_v002.

Intermediate D 2,3-diphenylpyrido [3,2-b] pyrazine

Diphenylethylenedione (45.7 g, 217 mmol) and pyridine-2,3-diamine (23.7 g, 217 mmol) were stored in methanol (514 ml) and acetic acid (57 ml) at 160 ° C using microwave radiation. The solution was heated for 10 min. The reaction mixture was concentrated in vacuo. To the crude residue in methanol (510 ml) was added activated carbon (25 g) and the suspension was stirred at 60 ° C for 1 h. The suspension was filtered hot, cooled and then stirred in an ice bath. The solid was filtered, washed with cold methanol (50 ml) and dried under vacuum at 40 ° C overnight to obtain the title compound as light brown crystals.

LC-MS Rt = 1.07 min; [M + H] +284, method A

Intermediate E 2,3-Di-p-tolyl-5,6,7,8-tetrahydropyrido [2,3-b] pyrazine

Step 1: 2,3-Di-p-tolylpyrido [2,3-b] pyrazine

Store 1,2-di-p-tolylethane-1,2-dione (commercially available) (175 g, 733 mmol) and pyridine-2,3-diamine (80 g, 733 mmol) in EtOH (1609 ml) and AcOH (179 ml) were heated to reflux (bath at 85 ° C) and held for 1.5 h. The mixture was cooled and concentrated in vacuo.

The crude material was dissolved in DCM (500 ml) and filtered through silica to remove baseline impurities. The silica was washed with EtOAc (2 L). The combined filtrate layers were concentrated in vacuo to obtain a brown solid. The material was ground at 1: 1 TBME / heptane (300 ml). The solid was removed by filtration and washed with 1: 1 TBME / heptane (200 ml), followed by drying at RT for 2 days to obtain the title compound (1 equivalent) as an AcOH salt.

HPLC (Agilent 1200), Rt 5.37 min, method B.

Step 2: 2,3-Di-p-tolyl-5,6,7,8-tetrahydropyrido [2,3-b] pyrazine

Treat 2,3-di-p-tolylpyrido [2,3-b] pyrazine with 10% palladium on carbon (30 g, 28.8 mmol) (step 1) (181 g, 487 mmol) in EtOH / THF ( 1: 2, 2100 ml) and the reaction mixture was placed in 0.1 bar hydrogen at RT. After 2 and 4 days, additional batches of 10% palladium on carbon (10 g, 9.6 mmol, twice) and Et ₃ N (85 ml, 706 mmol, twice) were added. After a total of 7 days, the reaction mixture was filtered by Hyflo (filter material) and washed with THF (2.5 L, portions). The filtrate was concentrated in vacuo to obtain a green / yellow solid. The solid was triturated with 1: 1 TBME / heptane (500 ml) and filtered. The solid was washed with 1: 1 TBME / heptane (200 ml) to give a pale yellow solid, which was dried overnight to obtain the title compound;

HPLC (Agilent 1200), Rt 4.73 min, method B.

Intermediate EA 7-methyl-2,3-diphenyl-5,6,7,8-tetrahydropyrido [2,3-b] pyrazine

Prepared the title compound from 5-methyl-pyridine-2,3-diamine and diphenylethylenedione in a similar manner to intermediate E;

LC-MS Rt = 1.21 min; [M + H] +302, method 2 min LC_v003

Intermediate EB 6-methyl-2,3-diphenyl-5,6,7,8-tetrahydropyrido [2,3-b] pyrazine

Prepared the title compound from 6-methyl-pyridine-2,3-diaminediphenylethylenedione in a similar manner to intermediate E;

LC-MS Rt = 1.12 min; [M + H] +302 method 2 min LC_v003

Intermediate EC 2,3-bis (4-fluorophenyl) -7-methyl-5,6,7,8-tetrahydropyrido [2,3-b] pyrazine

Prepared the title compound from 5-methylpyridine-2,3-diamine and 1,2-bis (4-fluorophenyl) ethane-1,2-dione in a similar manner to intermediate E;

LC-MS Rt = 1.15 min; [M + H] +338, method 2 min LC_v003.

Intermediate ED 2,3-bis (4-fluorophenyl) -6-methyl-5,6,7,8-tetrahydropyrido [2,3-b] pyrazine

Prepared the title compound from 6-methylpyridine-2,3-diamine and 1,2-bis (4-fluorophenyl) ethane-1,2-dione in a similar manner to intermediate E;

LC-MS Rt = 1.17 min; [M + H] +338, method 2 min LC_v003.

in Interstitial EE 2,3-bis (4- (trifluoromethyl) phenyl) -5,6,7,8-tetrahydropyrido [2,3-b] pyrazine

From 1,2-bis (4- (trifluoromethyl) phenyl) ethane-1,2-dione in a similar manner to Intermediate E (this can be according to Bioorganic & Medicinal Chemistry Letters (2007), 17 ( 21), 5825-5830) and pyridine-2,3-diamine to prepare the title compound;

LC-MS Rt = 1.39 min; [M + H] +424, method 2 min LC_v003.

Intermediate EF 6-methyl-2,3-di-p-tolyl-5,6,7,8-tetrahydropyrido [2,3-b] pyrazine

The title compound was prepared in a similar manner to intermediate E by replacing 6-methyl-pyridine-2,3-diamine with pyridine-2,3-diamine;

LC-MS Rt = 1.17 min; [M + H] +330, method 2 min LC_v003

Intermediate F 3-phenyl-2-p-tolyl-5,6,7,8-tetrahydropyrido [2,3-b] pyrazine

Step 1: Pyrido [3,2-b] pyrazine-2,3 (1H, 4H) -dione

A stirred suspension of 2,3-diaminopyridine (75 g, 687 mmol) in diethyl oxalate (291 ml, 2131 mmol) was heated to 120 ° C. under N ₂ . After 1 h, ethanol was distilled off from the reaction mixture and the temperature was raised to 160 ° C. and held for another 2 hours. The reaction mixture was cooled to RT and diluted with diethyl ether (200 ml). The resulting suspension was stirred for 1 hour and the solid was isolated by filtration and dried in a vacuum oven. The solid was suspended in ethanol (500 ml) and ultrasonicated for 1 hour. The suspension was filtered and dried (vacuum oven overnight) to obtain the title compound;

LCMS: Rt 0.29 min MS m / z 164 [M + H] +; method 2 min LC_v003

Step 2: 2,3-Dichloropyrido [3,2-b] pyrazine

POCl ₃ (57.1 ml, 613 mmol) was added to pyrido [3,2-b] pyrazine-2,3 (1H, 4H) -dione (step 1) (20 g, 123 mmol) and at 110 The suspension was heated at for 8 hours. After cooling to RT, the reaction mixture was added portionwise to the stirring water at RT, and ice-cooled if necessary. With cooling was added a saturated NaHCO ₃ solution (about 4 L) was basified aqueous phase. And the aqueous portion was extracted and concentrated in vacuo with EtOAc (2 x 2.5 L) dried over MgSO ₄ organic extracts were combined to give a solid. The crude product was purified by chromatography on silica with 5% -70% EtOAc in isohexane to give the title compound as a yellow solid;

LCMS: Rt 0.53 min MS m / z 200 [M + H] +; method 2 min LC_30_v003

Step 3: 2-Chloro-3-phenylpyrido [2,3-b] pyrazine

Phenyl in water (0.5 ml) in nitrogen Acid (305 mg, 2.5 mmol), potassium carbonate (691 mg, 5 mmol) and tetrakis (triphenylphosphine) palladium (0) (144 mg, 0.125 mmol) treated in anhydrous dioxane (10 ml) 2,3-dichloropyrido [2,3-b] pyrazine (step 2) (500 mg, 2.5 mmol). The resulting mixture was heated at 100 ° C for 1 hour using microwave radiation.

After cooling to RT, the mixture was diluted with water (100 ml) and extracted with DCM (x3). Washed with brine and the organic extracts were combined, dried over MgSO ₄ and filtered. The solvent was removed in vacuo and the crude product was purified by chromatography on silica with 0-30% EtOAc / isohexane to obtain the title compound as a solid;

LCMS: Rt 1.03 min MS m / z 242/244 [M + H] +; method 2 min LC_v003.

1H NMR (400MHz, DMSO-d6) δ 9.2 (1H, m), 8.6 (1H, dd), 8.0 (1H, m), 7.9 (2H, m), 7.6 (3H, m)

Step 4: 3-Phenyl-2-p-tolylpyrido [2,3-b] pyrazine

P-tolyl in water (0.5 ml) under nitrogen Acid (108 mg, 0.797 mmol), potassium carbonate (200 mg, 1.448 mmol), and tetrakis (triphenylphosphine) palladium (0) (41.8 mg, 0.036 mmol) treated in anhydrous dioxane (4 ml) 2-chloro-3-phenylpyrido [2,3-b] pyrazine (step 3) (175 mg, 0.724 mmol). The resulting mixture was heated at 150 ° C. for 1 hour using microwave radiation. After cooling to RT, the mixture was diluted with water (100 ml) and extracted with DCM (x3). Washed with brine and the organic extracts were combined, dried over MgSO ₄ and filtered. The solvent was removed in vacuo and the crude product was purified by chromatography on silica with 0-30% EtOAc / isohexane to give the title compound as a yellow solid;

LC-MS Rt 1.19 min; MS m / z 298 [M + H] +; method 2 min LC_v003

¹ H NMR (400MHz, DMSO-d6) δ 9.2 (1H, m), 8.6 (1H, dd), 7.9 (1H, m), 7.55 (2H, d), 7.4 (5H, m) 7.2 (2H, d ), 2.3 (3H, s).

Step 5: 3 -Phenyl-2-p-tolyl-5,6,7,8-tetrahydropyrido [2,3-b] pyrazine

Treatment of 3-phenyl-2-p-tolylpyrido [2, with nitrogen ammonium formate (190 mg, 3.01 mmol) and 10% palladium on carbon (64.1 mg, 0.060 mmol) in anhydrous MeOH (5 ml) 3-b] pyrazine (step 4) (179 mg, 0.602 mmol). The resulting mixture was heated under reflux for 16 hours. After cooling to RT, use Celite (Filter material) The mixture was filtered and the catalyst was washed with MeOH and MeOH / DCM (1: 1). The filtrate was concentrated in vacuo and dissolved in DCM (50 ml). The solution was washed with water (x2) and brine (x1). The resulting organic portion was passed through a phase separation column and concentrated in vacuo to obtain the title compound;

LCMS; Rt 1.08 min MS m / z 303 [M + H] + method 2 min LC_v003

Intermediate FA 2-phenyl-3-p-tolyl-5,6,7,8-tetrahydropyrido [2,3-b] pyrazine

Step 1: 2-Chloro-3-p-tolyl-pyrido [2,3-b] pyrazine

2,3-Dichloropyrido [2,3-b] pyrazine (Intermediate F Step 2) (5 g, 25 mmol), p-tolyl by bubbling nitrogen through (x3) A mixture of acid (4.08 g, 30.0 mmol), tricyclohexylphosphine (1.682 g, 6.00 mmol) and cesium carbonate (16.29 g, 50.0 mmol) in anhydrous dioxane (60 ml) was degassed. Tris (dibenzylideneacetone) dipalladium (0) (2.289 g, 2.5 mmol) was added and the reaction mixture was degassed by bubbling nitrogen through (x3). The resulting mixture was stirred at 70 ° C for 16 hours and at room temperature for 2 days. The mixture was diluted with water and EtOAc and with the aid of Celite (Filter material) Filter. The phases were separated and the aqueous phase was extracted with EtOAc. Washed with brine and the organic extracts were combined, dried over MgSO ₄ and concentrated in vacuo. The crude product was purified by chromatography on silica with 0-2% THF / DCM to obtain a mixture of mono- and di-arylated products. The material was repurified by chromatography on silica with 0-2% THF / DCM to obtain the title compound;

LCMS; Rt 1.13 min MS m / z 256/258 [M + H] + method 2 min LC_v003

Step 2: 2-Phenyl-3-p-tolyl-pyrido [2,3-b] pyrazine

2-Chloro-3-p-tolyl-pyrido [2,3-b] pyrazine (800 mg, 3.13 mmol), phenyl by bubbling nitrogen through (x3) A mixture of acid (572 mg, 4.69 mmol) and K ₂ CO ₃ (1297 mg, 9.39 mmol) in dioxane (10 ml) was degassed. PdCl ₂ (dppf) (229 mg, 0.313 mmol) was added and the reaction mixture was degassed by bubbling nitrogen through (x3). The resulting mixture was heated at 150 ° C for 2 hours using microwave radiation. PdCl ₂ (dppf) (229 mg, 0.313 mmol) was added and the mixture was heated at 150 ° C. for 2 hours using microwave radiation. After cooling to RT, the mixture was diluted with water and EtOAc, and with the aid of Celite (Filter material) Filter.

The phases were separated and the aqueous phase was extracted with EtOAc. Washed with brine and the organic extracts were combined, dried over MgSO ₄ and concentrated in vacuo. The crude product was purified by chromatography on silica with 2-5% THF / DCM to obtain a contaminated gum. The material was repurified by chromatography on silica with 0-60% EtOAc / isohexane to obtain the title compound;

LCMS; Rt 3.93 min MS m / z 298 [M + H] + method 10 min LC_v003

Step 3: 2-phenyl-3-p-tolyl-5,6,7,8-tetrahydro-pyrido [2,3-b] pyrazine

Treatment of 2-phenyl-3-p-tolyl-pyridino with ammonium formate (2.269 g, 36.0 mmol) and 10% palladium hydroxide on carbon (200 mg, 0.142 mmol) in anhydrous MeOH (10 ml) under nitrogen. [2,3-b] pyrazine (1.07 g, 3.60 mmol). The resulting mixture was heated under reflux for 1 hour. After cooling to RT, use Celite (Filter material) The mixture was filtered and the catalyst was washed with MeOH, then DCM. The filtrate was concentrated in vacuo to obtain a solid, which was triturated with MeOH. Drying the resulting solid in vacuo to obtain the title compound;

LCMS; Rt 1.04 min MS m / z 302 [M + H] + method 2 min LC_v003

Intermediate FB 2-m-tolyl-3-p-tolyl-5,6,7,8-tetrahydropyrido [2,3-b] pyrazine

In a similar manner to intermediate FA by using m-tolyl Acid replaces phenyl Acid to prepare the title compound;

LCMS; Rt 1.10 min MS m / z 316 [M + H] + method 2 min LC_v003 ¹ H NMR (400MHz, DMSO-d6) δ 7.2 (3H, m), 7.05-7.0 (5H, br m), 6.9 ( 1H, m), 3.35 (2H, m), 2.9 (2H, m), 2.3 (3H, s), 2.25 (3H, s), 1.95 (2H, m).

In a similar manner to intermediate F from 2,3-dichloropyrido [2,3-b] pyrazine (intermediate F step 2) and appropriately Acid to prepare intermediates in the following table (Table 9)

Intermediate G 2,3-bis (3-fluoro-4-methylphenyl) -5,6,7,8-tetrahydropyrido [2,3-b] pyrazine

Step 1: 2,3-Bis (3-fluoro-4-methylphenyl) pyrido [2,3-b] pyrazine

2,3-Dichloropyrido [2,3-b] pyrazine (Intermediate F Step 2) (500 mg, 2.500 mmol), 3-fluoro-4-methyl by bubbling nitrogen through (x3) Phenyl Slurry removal of acid (847 mg, 5.50 mmol), tetrakis (triphenylphosphine) palladium (0) (173 mg, 0.150 mmol) and potassium carbonate (1520 mg, 11.00 mmol) in dioxane (20 ml) gas. The reaction mixture was heated under nitrogen at 150 ° C for 4 h using microwave radiation. The resulting mixture was partitioned between EtOAc and water. The organic portion was separated, dried (sodium sulfate), filtered and concentrated in vacuo. The crude product was purified by chromatography on silica to elute with 0-3% THF in DCM to obtain the title compound;

LCMS; Rt 1.28 min MS m / z 348 [M + H] + method 2 min LC_v003

Step 2: 2,3-Bis (3-fluoro-4-methylphenyl) -5,6,7,8-tetrahydropyrido [2,3-b] pyrazine

Add 2,3-bis (3-fluoro-4) to Pd (OH) ₂ (20% on carbon, 50% water wet) (30 mg, 0.214 mmol) and ammonium formate (557 mg, 8.84 mmol) -Methylphenyl) pyrido [2,3-b] pyrazine (step 1) (307 mg, 0.884 mmol) in MeOH (3 ml) and the reaction mixture was heated to reflux for 5 h. An additional portion of Pd (OH) ₂ (20% on carbon, 50% water wet) (30 mg, 0.214 mmol) was added and the mixture was heated to reflux and held for 6 h. With Celite (Filter material) The reaction mixture was filtered and washed with MeOH and EtOAc. The filtrate was concentrated in vacuo to obtain the title compound as a yellow solid.

LCMS; Rt 1.07 min MS m / z 352 [M + H] + method 2 min LC_v003

In a similar manner to intermediate G from 2,3-dichloropyrido [2,3-b] pyrazine (Intermediate F step 2) and appropriate The acid prepares the intermediates in the following table (Table 10).

in Interstitial H 8-bromo-2,3-diphenyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -carboxylic acid third butyl ester

Step 1: 2,3-Diphenyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -formic acid third butyl ester

Treat 2,3-diphenyl-5,6,7,8 in THF (75 ml) with di-tert-butyl dicarbonate (4.85 ml, 20.88 mmol) and DMAP (0.425 g, 3.48 mmol) -Tetrahydropyrido [3,2-b] pyrazine (Example 4.1 step 1) (5 g, 17.40 mmol) and stirred at RT for 5 h. An additional 0.2 equivalent of DMAP was added and the mixture was stirred at RT for 5 days. The mixture was added to water and extracted with EtOAc (x2). Washed with brine and the organic extracts were combined, dried over MgSO ₄ and concentrated in vacuo. The product was washed with 0.1 M HCl and extracted with EtOAc. Washed with brine and the combined organic extracts over MgSO ₄ dried and concentrated in vacuo to give the title compound;

LC-MS Rt = 1.43 min; [M + H] +389, method 2 min LC_v003.

Step 2: 8-Bromo-2,3-diphenyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -carboxylic acid third butyl ester

At RT dihydro-pyrido [2,3-b] pyrazin -5 (6H) solution of 2,3-diphenyl-7,8 in N ₂ - carboxylic acid tert-butyl ester (Step 1) ( 25 g, 64.5 mmol) in a stirred solution in carbon tetrachloride (645 ml) was added NBS (13.78 g, 77 mmol), and immediately afterwards Laurel Peroxide (0.257 g, 0.645 mmol) was added at 60 ° C. The solution was heated for 4 h 15 min. The mixture was filtered by means of filter paper _{and, 2 M Na 2 SO 3 (} 300 ml) and saturated brine (300 ml) and the filtrate was washed with saturated NaHCO ₃ (300 ml). The solution was dried over MgSO ₄ and filtered, and the MgSO ₄ bed was washed with DCM (100 ml). The solvent was removed in vacuo. The crude product was dissolved in ether (300 ml) and left at RT and placed in the refrigerator overnight. The resulting crystalline solid was separated by decanting the mother liquor. The crystals were washed with diethyl ether to obtain the title compound. Other products were obtained by eluting the mother liquor with isohexane / EtOAc to obtain the title product;

LC-MS Rt = 1.50 min; [M + H] +468, method 2 min LC_v003.

in Interstitial HA 2,3-diphenyl-5,6,7,8-tetrahydropyrido [2,3-b] pyrazine-8-yl acetate

Step 1: 8-Ethyloxy-2,3-diphenyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -carboxylic acid third butyl ester

8-Bromo-2,3-diphenyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -carboxylic acid third butyl ester (Intermediate H) (200 mg (0.429 mmol) in DCM (8 ml) was added silver acetate (143 mg, 0.858 mmol). The reaction mixture was stirred at room temperature under a nitrogen atmosphere overnight. With Celite (Filter material) The reaction mixture was filtered and washed with DCM (20 ml). The filtrate was then concentrated in vacuo to obtain the title compound;

LC-MS Rt = 1.54 min; [M + H] +446, method 2 min LC_v003.

Step 2: 2,3-Diphenyl-5,6,7,8-tetrahydropyrido [2,3-b] pyrazine-8-yl acetate

8-Ethyloxy-2,3-diphenyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -formic acid third butyl ester ( Step 1) (190 mg, 0.426 mmol) in 4 M HCl in dioxane (anhydrous) (2.665 ml, 10.66 mmol) was stirred at room temperature for 1 hour. The mixture was concentrated in vacuo and the crude product was purified by chromatography on silica with EtOAc / isohexane to give the title compound;

LC-MS Rt = 1.32 min; [M + H] +346, method 2 min LC_v003.

Intermediate HBR and HBS (R) -acetic acid 2,3-diphenyl-5,6,7,8-tetrahydropyrido [2,3-b] pyrazine-8-yl ester (intermediate HBR) and (S) -acetic acid 2,3-diphenyl-5,6,7,8-tetrahydropyrido [2,3-b] pyrazine-8-yl ester (intermediate HBS)

Step 1: (R) -8-Ethyloxy-2,3-diphenyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -formic acid third butyl Esters and (S) -8-Ethyloxy-2,3-diphenyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -carboxylic acid third butyl ester

Purification of 8-Ethyloxy-2,3-diphenyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) by performing SFC under conditions detailed below -Third butyl formate (Intermediate HA step 1) to obtain the following compound:

Column: Chiralcel OJ-H 250 × 10 mm, 5 μm

Mobile phase: 10% isopropanol / 90% CO ₂

Flow rate: 10 ml / min

Detect UV at 220 nm

First elution peak: Rt 4.36 min: (R) -8-acetamido-2,3-diphenyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H ) -Tert-butyl formate

Second eluting peak: Rt 6.76 min (S) -8-acetamido-2,3-diphenyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -Third butyl formate

Step 2: (R) -acetic acid 2,3-diphenyl-5,6,7,8-tetrahydropyrido [2,3-b] pyrazine-8-yl ester and (S) -acetic acid 2, 3-diphenyl-5,6,7,8-tetrahydropyrido [2,3-b] pyrazine-8-yl ester

(R) -8-Ethyloxy-2,3-diphenyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -formic acid in a nitrogen atmosphere A solution of butyl ester (62 mg, 0.139 mmol) in 4 M HCl in dioxane (1.252 ml, 5.01 mmol) was stirred for 1 hour. The reaction mixture was concentrated in vacuo to obtain (R) -acetic acid 2,3-diphenyl-5,6,7,8-tetrahydropyrido [2,3-b] pyrazine-8-yl ester (intermediate HBR), which was used without further purification.

LC-MS Rt = 0.94 min; [M + H] +346, method 2 min LC_v003.

Similarly, from (S) -8-Ethyloxy-2,3-diphenyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -carboxylic acid tert-butyl Ester preparation (S) -acetic acid 2,3-diphenyl-5,6,7,8-tetrahydropyrido [2,3-b] pyrazine-8-yl ester (intermediate HBS);

LC-MS Rt = 0.94 min; [M + H] +346, method 2 min LC_v003.

Intermediate HC Racemization -8-ethyl-2,3-diphenyl-5,6,7,8-tetrahydropyrido [2,3-b] pyrazine

In diethyl ether under nitrogen to deposit at RT (4 ml) contained in the 8-bromo-2,3-diphenyl-7,8-dihydro-pyrido [2,3-b] pyrazin -5 (6H ) -A mixture of tert-butyl formate (Intermediate H) (200 mg, 0.429 mmol) and nitrate (0.728 mg, 4.29 μmol) was added with 1 M ethyl bromide in THF (0.557 ml, 0.557 mmol) Of magnesium. The reaction mixture was stirred at RT under a nitrogen atmosphere for 3 h. The mixture was poured into a saturated ammonium chloride solution (10 ml) and extracted with EtOAc (2 x 10 ml). The combined organic extracts were dried over MgSO _4, filtered and concentrated in vacuo. The resulting crude product was purified by chromatography on silica with 0-30% EtOAc / isohexane to obtain the title compound;

LC-MS Rt = 1.15 min; [M + H] +316, method 2 min LC_v003.

Other analogs of this intermediate were prepared using methods similar to intermediate HC by replacing ethyl magnesium bromide with appropriate alkyl or cycloalkyl magnesium bromide analogs, such as 8-cyclopropyl-2,3- Diphenyl-5,6,7,8-tetrahydropyrido [2,3-b] pyrazine, 8-isopropyl-2,3-diphenyl-5,6,7,8-tetrahydro Pyrido [2,3-b] pyrazine and 8-methyl-2,3-diphenyl-5,6,7,8-tetrahydropyrido [2,3-b] pyrazine.

Intermediate HD 8-methoxy-2,3-diphenyl-5,6,7,8-tetrahydropyrido [2,3-b] pyrazine

Step 1: 8-methoxy-2,3-diphenyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -carboxylic acid third butyl ester

8-Bromo-2,3-diphenyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -carboxylic acid third butyl ester (Intermediate H) (200 mg (0.429 mmol) in anhydrous MeOH (8 ml, 198 mmol) was added silver carbonate (237 mg, 0.858 mmol). The mixture was stirred under nitrogen at RT for 2.5 hours and then with the aid of Celite (Filter material) Filter and wash with methanol (25 ml). The filtrate was concentrated in vacuo to obtain the title compound;

LC-MS Rt = 1.45 min; [M + H] +418, method 2 min LC_v003.

Step 2: 8-methoxy-2,3-diphenyl-5,6,7,8-tetrahydropyrido [2,3-b] pyrazine

From 8 in a similar manner to 2,3-diphenyl-5,6,7,8-tetrahydropyrido [2,3-b] pyrazine-8-yl acetate (intermediate HBR, step 2) -Methoxy-2,3-diphenyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -carboxylic acid third butyl ester (step 1) to prepare the title compound;

LC-MS Rt = 1.17 min; [M + H] +318, method 2 min LC_v003.

Intermediate HE 2,3-bis (4- (trifluoromethyl) phenyl) -5,6,7,8-tetrahydropyrido [2,3-b] pyrazine-8-yl acetate

In a similar manner to intermediate H by using 2,3-bis (4- (trifluoromethyl) phenyl) -5,6,7,8-tetrahydropyrido [2,3-b] pyrazine (Intermediate EE) substituting 2,3-diphenyl-5,6,7,8-tetrahydropyrido [3,2-b] pyrazine (Example 4.1, step 1) to prepare the title compound;

LC-MS Rt = 1.40 min; [M + H] +482, method 2 min LC_v003.

Intermediate HF Racemization -2,3-di-p-tolyl-5,6,7,8-tetrahydropyrido [2,3-b] pyrazine-8-yl acetate

Step 1: 2,3-Di-p-tolyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -formic acid third butyl ester

To di-tert-butyl dicarbonate (1.104 ml, 4.76 mmol) in THF (50 ml), 2,3-di-p-tolyl-5,6,7,8-tetrahydropyrido was added sequentially. [2,3-b] pyrazine (Intermediate E) (1 g, 3.17 mmol), 4-dimethylaminopyridine (0.039 g, 0.317 mmol). The suspension was stirred at room temperature for 48 hours. The solvent was concentrated in vacuo. The crude product was purified by chromatography on silica to elute with 0-50% EtOAc in isohexane to give the title compound;

LC-MS Rt = 1.49 min; [M + H] +416.3, method 2 min LC_v003.

Step 2: Racemic -8-bromo-2,3-di-p-tolyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -formic acid third butyl ester

To 2,3-di-p-tolyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -carboxylic acid third butyl ester (step 1) (530 mg, 1.275 mmol) To the stirred solution in chloroform (10 ml) was added N-bromosuccinimide (272 mg, 1.531 mmol), lauryl peroxide (50.8 mg, 0.128 mmol) in this order, and the mixture was heated to reflux and held for 1 hour. . The solvent was concentrated in vacuo. The crude product was purified by chromatography on silica with 0-50% EtOAc in isohexane to obtain the title compound, which was used directly in the next step.

Step 3: Racemic -8-ethoxyl-2,3-di-p-tolyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -formic acid Ester

Racemic-8-bromo-2,3-di-p-tolyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) in dichloromethane (10 ml) ) -Third-butyl formate (step 2) (220 mg, 0.445 mmol) was added with silver acetate (149 mg, 0.890 mmol). The reaction mixture was stirred at room temperature for 30 minutes. With Celite (Filter material) The reaction mixture was filtered and washed with DCM (20 ml). The filtrate was then concentrated in vacuo and the crude product was purified by chromatography on silica with 0-50% EtOAc in isohexane to give the title compound.

LC-MS Rt = 1.61 min; [M + H] +475.3, method 2 min LC_v003.

Step 4: 2,3-Di-p-tolyl-5,6,7,8-tetrahydropyrido [2,3-b] pyrazine-8-yl acetate

Racemic-8-acetoxy-2,3-di-p-tolyl-7,8-dihydropyrido [2,3-b] pyrazine- in dichloromethane (5 ml) To tributyl 5 (6H) -formate (step 3) (110 mg, 0.232 mmol) was added trifluoroacetic acid (0.089 ml, 1.161 mmol). The solution was stirred at room temperature for 4 h. To the reaction mixture was added a saturated aqueous sodium carbonate solution (2 ml) and the mixture was stirred vigorously for 10 minutes. The organic layer was separated and concentrated in vacuo to obtain the title compound;

LC-MS Rt = 1.60 min; [M + H] +374.6, method 2 min LC_v003.

Intermediate HG N, N-dimethyl-2,3-diphenyl-5,6,7,8-tetrahydropyrido [2,3-b] pyrazine-8-amine

Step 1: 8- (Dimethylamino) -2,3-diphenyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -carboxylic acid third butyl ester

8-Bromo-2,3-diphenyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -carboxylic acid third butyl ester (Intermediate H) (500 mg , 1.072 mmol) in ethanol (10 ml) was added 40% dimethylamine in water (0.407 ml, 3.22 mmol) and the mixture was stirred overnight under a nitrogen atmosphere. The solvent was concentrated in vacuo. The crude product was purified by chromatography on silica with EtOAc in isohexane to obtain the title compound;

LC-MS Rt = 1.13 min; [M + H] +431, method 2 min LC_v003.

Step 2: N, N-Dimethyl-2,3-diphenyl-5,6,7,8-tetrahydropyrido [2,3-b] pyrazine-8-amine

From 8- in a similar manner to 2,3-diphenyl-5,6,7,8-tetrahydropyrido [2,3-b] pyrazine-8-yl acetate (Intermediate HA step 2) (Dimethylamino) -2,3-diphenyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -formic acid third butyl ester (step 1) Title compound

LC-MS Rt = 0.93 min; [M + H] +331, method 2 min LC_v003.

Intermediate I Racemization -Diacetic acid 2,3-diphenyl-5,6,7,8-tetrahydropyrido [2,3-b] pyrazine-7,8-diyl ester

Step 1: 2,3-Diphenylpyrido [2,3-b] pyrazine-5 (6H) -formic acid third butyl ester

Treatment of 8-bromo-2,3-diphenyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -formic acid tert-butyl with DBU (1.939 ml, 12.87 mmol) A solution of the ester (Intermediate H) (5 g, 10.72 mmol) in DCM (250 ml) and stirred overnight at RT under a nitrogen atmosphere. The solvent was removed in vacuo. The resulting crude product was purified by chromatography on silica with 0-20% EtOAc / isohexane to obtain the title compound;

LC-MS Rt = 1.45 min; [M + H] +386, method 2 min LC_v003.

Step 2: Racemic -7,8-dihydroxy-2,3-diphenyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -formic acid third butyl ester

To a solution of tributylmethylammonium chloride (728 mg, 3.09 mmol) in DCM (10 ml) was added potassium permanganate (488 mg, 3.09 mmol) in portions over 10 minutes at room temperature. The reaction mixture was stirred under a nitrogen atmosphere for 30 minutes. The mixture was cooled to 0 ° C and stored with 2,3-diphenylpyrido [2,3-b] pyrazine-5 (6H) -formic acid third butyl ester (step 1) (700 mg, 1.816 mmol) The solution in DCM (8 ml) was treated dropwise. The reaction was then stirred at 0-5 ° C for another 2 hours in a nitrogen atmosphere. A solution of sodium bisulfite (1134 mg, 10.90 mmol) in water (9 ml) was added dropwise to the reaction mixture at 0-5 ° C. With Celite (Filter material) The mixture was filtered and washed with DCM (20 ml) and water (10 ml). The organic layer was separated and concentrated in vacuo to obtain a foaming solid. The crude material was purified by chromatography on silica with 0-90% EtOAc / isohexane to obtain the title compound;

LC-MS Rt = 1.19 min; [M + H] +420, method 2 min LC_v003.

Step 3: Racemic-diacetic acid 5- (third butoxycarbonyl) -2,3-diphenyl-5,6,7,8-tetrahydropyrido [2,3-b] pyrazine- 7,8-diyl ester

It will contain racemic -7,8-dihydroxy-2,3-diphenyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -formic acid in a nitrogen atmosphere. A mixture of tributyl ester (step 2) (230 mg, 0.548 mmol), acetic anhydride (155 μl, 1.645 mmol) and pyridine (1064 μl, 13.16 mmol) was stirred at RT overnight. After standing at RT for 2 days, the mixture was diluted with saturated sodium bicarbonate and extracted with DCM (2 × 20 ml). The organic extracts were combined and concentrated in vacuo. The crude material was purified by chromatography on silica with 20-100% EtOAc / isohexane to obtain the title compound;

LC-MS Rt = 1.39 min; [M + H] +504, method 2 min LC_v003.

Step 4: Racemic-diacetic acid 2,3-diphenyl-5,6,7,8-tetrahydropyrido [2,3-b] pyrazine-7,8-diyl ester

Racemic -diacetic acid 5- (third butoxycarbonyl) -2,3-diphenyl-5,6,7,8-tetrahydropyrido [2,3-b] pyrazine at RT A solution of -7,8-diyl ester (step 3) (190 mg, 0.377 mmol) in 4 M HCl in dioxane (2 ml, 8.00 mmol) was stirred for 30 min. The mixture was concentrated in vacuo and the residue was dissolved in saturated sodium bicarbonate and extracted with EtOAc (2 x 20 ml). Dried (MgSO ₄₎ organic extracts were combined, filtered and concentrated in vacuo. The crude material was purified by chromatography on silica with 0-70% EtOAc / isohexane to obtain the title compound;

LC-MS Rt = 1.21 min; [M + H] +404, method 2 min LC_v003.

Intermediate J 2-bromo-3-chloro-7,8-dihydro-5H-pyrido [2,3-b] pyrazin-6-one

Step 1: 3,5-Dibromo-6-chloro-pyrazin-2-ylamine

A solution of 6-chloropyrazine-2-amine (2 g, 15.44 mmol) and NBS (13.7 g, 77 mmol) in CHCl ₃ (100 ml) was heated under reflux for 20 hours. The resulting mixture was purified by chromatography on silica with DCM. Concentrated in vacuo and the relevant portion of the crude product was dissolved in EtOAc (about 100 ml), treated with 10% sodium thiosulfate (2 × 100 ml), washed with brine, dried (MgSO ₄₎ and concentrated in vacuo to give the title Compound

¹ H NMR (400 MHz, CDCl3) δ 5.4-5.0 (2H, br s).

Step 2: 2-Bromo-3-chloro-7,8-dihydro-5H-pyrido [2,3-b] pyrazin-6-one

Treat the inclusions in THF (15 ml) with 0.5 M (3-ethoxy-3- pendoxypropyl) zinc (II) bromide in THF (15.31 ml, 7.66 mmol) under nitrogen. A mixture of 3,5-dibromo-6-chloropyrazine-2-amine (step 1) (1.0 g, 3.48 mmol) and bistriphenylphosphine palladium (II) chloride (0.122 g, 0.174 mmol) and The mixture was stirred at room temperature for 3 hours. Add another 0.5 M (3-ethoxy-3- pendantoxypropyl) zinc (II) bromide in THF (7.5 mL, 3.8 mmol) and continue stirring for 1.5 hours. Additional 0.5 M (3-ethoxy-3- pendantoxypropyl) zinc (II) bromide in THF (3.8 mL, 1.9 mmol) was added and the mixture was stirred at RT for 65 hours. The mixture was diluted with water (10 ml) and concentrated in vacuo. The residue was diluted with EtOAc (100 ml). With Celite (Filter material) The emulsion is filtered. The phases were separated and the aqueous portion was extracted with EtOAc (50 ml). Washed with brine and the organic extracts were combined, dried (MgSO ₄₎ and concentrated in vacuo. The residue was triturated with EtOAc (ca. 10 ml) to give the title compound as a yellow solid.

¹ H NMR (400 MHz, DMSO-d6) δ 11.15 (1H, br s), 3.1-3.0, (2H, m), 2.75-2.65 (2H, m).

Intermediate K Racemization -7-methoxy-2,3-di-p-tolyl-5,6,7,8-tetrahydropyrido [2,3-b] pyrazine

Step 1: 7-Chloro-2,3-di-p-tolylpyrido [2,3-b] pyrazine

In a similar manner to 2,3-di-p-tolylpyrido [2,3-b] pyrazine (Intermediate E step 1) 5-chloro-pyridine-2,3-diamine to prepare the title compound. No acetic acid was used in this reaction.

Step 2: 7-Methoxy-2,3-di-p-tolylpyrido [2,3-b] pyrazine

Treat sodium (278 mg, 12.09 mmol) in portions bubbled through nitrogen in anhydrous MeOH (10 ml) and DCM (5 ml) containing 7-chloro-2,3-di-p-tolylpyrido [2 , 3-b] pyrazine (836 mg, 2.417 mmol). The resulting mixture was heated under reflux overnight. Add another portion of sodium (278 mg, 12.09 mmol) and keep refluxing overnight. After cooling to RT, the solvent was removed in vacuo and the resulting residue was added to water. Mixture was extracted with DCM (x3) and extracted, dried and concentrated in vacuo and washed with brine The organic extract was dried over MgSO _4. Purify by chromatography on silica with 10-40% EtOAc / isohexane to obtain the title compound;

LCMS: Rt 1.31 min MS m / z 342 [M + H] + method 2 min LC_v003

Step 3: Racemic -7-methoxy-2,3-di-p-tolyl-5,6,7,8-tetrahydropyrido [2,3-b] pyrazine

Treatment of 7-methoxy-2,3-di-p-tolylpyrido [2,3-b] in anhydrous MeOH (4 ml) with 10% carbon on Pd (58.6 mg, 0.056 mmol) in nitrogen Pyrazine (94 mg, 0.275 mmol). The suspension was stirred under a hydrogen atmosphere at RT for 32 hours. The resulting mixture was loaded into 2.5 g of Celite using MeOH On the column and rinse with 1: 1 MeOH: DCM. The filtrate was concentrated in vacuo and the residue was dissolved in DCM (30 ml) and washed with water (x2). Separating the organic portion and removing the solvent in vacuo to obtain the title compound;

LCMS Rt 1.12 min MS m / z 346 [M + H] + method 2 min LC_v003

It should be understood from the foregoing that, although specific embodiments of the present invention have been described herein for the purpose of explanation, various modifications can be made thereto without departing from the spirit and scope of the present invention. Therefore, in addition to the scope of the accompanying patent application, the present invention is not subject to other restrictions.

Supervision Clauses Example 1. A compound represented by Formula I

And pharmaceutically acceptable salts thereof, in which A is N or CR ';R' is H, C ₁ -C ₈ alkyl optionally substituted with one or more halogen atoms; R ¹ is H, optionally Or more than one halogen atom, C ₁ -C ₄ alkyl, OH, OR ', -NR ¹⁹ R ²¹ , CN or C ₃ -C ₇ cycloalkyl substituted C ₁ -C ₈ alkyl; or R ¹ is- XY; or R ¹ series -WR ⁷ -XY; or R ¹ series -S (O) ₂ -WXY; or R ¹ series -S (O) ₂ -WR ⁷ -XY; R ² series H, as appropriate Or more than one halogen atom, C ₁ -C ₄ alkyl, OH, OR ', -NR ¹⁹ R ²¹ , CN or C ₃ -C ₇ cycloalkyl substituted C ₁ -C ₈ alkyl; or R ^2- XY; or R ² series -WR ⁷ -XY; or R ² series -S (O) ₂ -WXY; R ² series -S (O) ₂ -WR ⁷ -XY; where R ¹ or R ² must be -XY , -WR ⁷ -XY, -S (O) ₂ -WXY; or -S (O) ₂ -WR ⁷ -XY; R ³ is H, optionally with one or more halogen atoms, C ₁ -C ₄ alkane Oxy, OH, -NR ¹⁹ R ²¹ , CN or C ₃ -C ₇ cycloalkyl substituted C ₁ -C ₈ alkyl; R ⁴ is H, optionally with one or more halogen atoms, C ₁ -C ₄ alkoxy, OH, -NR ¹⁹ R ²¹ , CN or C ₃ -C ₇ cycloalkyl substituted C ₁ -C ₈ alkyl; R ⁵ is optionally via one or more halogen atoms, C ₁ -C ₄ alkyl, OH, OR ', -NR ¹⁹ R ²¹ , CN or C ₃ -C ₇ cycloalkyl substituted C ₁ -C ₈ alkyl; optionally C ₁ -C ₈ alkoxy substituted with one or more halogen atoms; C _6- C ₁₄ aryl;-(C ₀ -C ₄ alkyl) -4 to 14-membered heteroaryl or-(C ₀ -C ₄ alkyl) -3 to 14-membered heterocyclic group, wherein the heteroaryl And heterocyclyl contain at least one heteroatom selected from N, O and S, wherein the aryl, heteroaryl and heterocyclyl are each optionally substituted with one or more Z substituents; R ⁶ is C ₆ -C ₁₄ aryl group ;-( C ₀ -C ₄ alkyl) -4 to 14-membered heteroaryl, - (C ₀ -C ₄ alkyl) -3 to 14-membered heterocyclic group, wherein the heteroaryl and heterocycle Contains at least one heteroatom selected from N, O, and S, wherein the aryl, heteroaryl, and heterocyclyl are each optionally substituted by one or more Z substituents; W is optionally hydroxyl, halogen, or C of ₁ -C ₄ alkyl substituted by C ₁ -C ₈ extending alkyl; X system optionally substituted with hydroxy, halogen or C ₁ -C ₄ alkyl group substituted with the C ₁ -C ₈ alkylene; the Y-based carboxy, alkoxycarbonyl Carbonyl, tetrazolyl, aminoformyl, monoalkylaminoformyl, dialkylaminoformyl, or -CONH-S (O) _q -R ^x , where R ^x is -C ₁ -C ₄ alkyl or -NR ¹⁹ R ^21; q lines 0 1 or 2; R ⁷ by the line ₆ -C ₁₄ represents a divalent moiety of the aryl group -D- -C; -3 to 14-membered heterocyclic group -D-, wherein the heterocyclic group containing at least one heteroatom selected from N, O And heteroatoms of S, where D is O, S, NH or absent; Z is independently OH, aryl, O-aryl, benzyl, O-benzyl, optionally via one or more OH groups or the group NH ₂ substituted C ₁ -C ₆ alkyl, optionally substituted with one or more of halogen atoms, C ₁ -C ₆ alkyl, optionally substituted with one or more OH groups of the C ₁ -C ₆ alkoxy, optionally substituted with one or more of halogen, C ₁ -C ₆ alkoxy, optionally substituted with one or more of C ₁ -C ₄ alkoxy-substituted C ₁ -C ₆ alkoxy, NR ¹⁸ (SO ₂ ) R ²¹ , (SO ₂ ) NR ¹⁹ R ²¹ , (SO ₂ ) R ²¹ , NR ¹⁸ C (O) R ²¹ , C (O) NR ¹⁹ R ²¹ , NR ¹⁸ C (O) NR ¹⁹ R ²¹ , NR ¹⁸ C (O) OR ¹⁹ , NR ¹⁹ R ²¹ , C (O) OR ¹⁹ , C (O) R ¹⁹ , SR ¹⁹ , OR ¹⁹ , pendant oxygen group, CN, NO ₂ , halogen or 3 To 14-membered heterocyclyl, wherein the heterocyclyl contains at least one heteroatom selected from N, O, and S; R ^{18 is} independently H or C ₁ -C ₆ alkyl; R ¹⁹ and R ^{21 are} each independently H; C ₁ -C ₈ alkyl; C ₃ -C ₈ cycloalkyl; C ₁ -C ₄ alkoxy -C ₁ -C ₄ alkyl; (C ₀ -C ₄ alkyl) -aryl, optionally one or more selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, and Halo group substitution; (C ₀ -C ₄ alkyl) -3 to 14-membered heterocyclyl, the heterocyclyl includes one or more heteroatoms selected from N, O and S, optionally by one or Multiple substituents selected from the group consisting of halogen, pendant oxygen, C ₁ -C ₆ alkyl and C (O) C ₁ -C ₆ alkyl; (C ₀ -C ₄ alkyl) -O-aryl, Optionally substituted with one or more groups selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy and halogen; and (C ₀ -C ₄ alkyl) -O-3 to 14-membered heterocyclic cycloalkyl group, the heterocyclyl group comprises one or more selected from N, O, and S heteroatoms of which is optionally substituted with one or more substituents selected from halo, C ₁ -C ₆ alkyl or C (O) C ₁ - C ₆ alkyl radical substitution; wherein the alkyl radicals are optionally substituted by one or more halogen atoms, C ₁ -C ₄ alkoxy, C (O) NH ₂ , C (O) NHC ₁ -C ₆ alkyl Or C (O) N (C ₁ -C ₆ alkyl) ₂ substitution; or R ¹⁹ and R ²¹ together with the nitrogen atom to which they are attached form a 5- to 10-membered heterocyclic group, the heterocyclic group comprising one or more selected From other heteroatoms of N, O and S, the heterocyclyl is optionally selected from one or more of the following Substituted with substituents: OH; halogen; aryl; 5-10 heterocyclyl group, which includes one or more selected from N, O, and S heteroatoms of; S (O) ₂ - aryl; S (O) ₂ -C ₁ -C ₆ alkyl; C ₁ -C ₆ alkyl, optionally substituted by one or more halogen atoms; C ₁ -C ₆ alkoxy, optionally by one or more OH groups or C ₁ -C ₄ alkoxy substitution; and C (O) OC ₁ -C ₆ alkyl, wherein the aryl and heterocyclyl are substituted by basic C ₁ -C ₆ alkyl, C ₁ -C ₆ Haloalkyl or C ₁ -C ₆ alkoxy substituted.

Example 2. A compound represented by Formula Ia

Or a pharmaceutically acceptable salt thereof, in which A is N or CR ';R' is H, optionally a C ₁ -C ₈ alkyl group substituted with one or more halogen atoms; R ¹ is H, optionally Or more than one halogen atom, C ₁ -C ₄ alkyl, OH, OR ', -NR ¹⁹ R ²¹ , CN or C ₃ -C ₇ cycloalkyl substituted C ₁ -C ₈ alkyl; or R ¹ is- XY; or R ¹ series -WR ⁷ -XY; or R ¹ series -S (O) ₂ -WXY; or R ¹ series -S (O) ₂ -WR ⁷ -XY; R ² series H, as appropriate Or more than one halogen atom, C ₁ -C ₄ alkyl, OH, OR ', -NR ¹⁹ R ²¹ , CN or C ₃ -C ₇ cycloalkyl substituted C ₁ -C ₈ alkyl; or R ^2- XY; or R ² series -WR ⁷ -XY; or R ² series -S (O) ₂ -WXY; R ² series -S (O) ₂ -WR ⁷ -XY; where R ¹ or R ² series -XY, -WR ⁷ -XY, -S (O) ₂ -WXY; or -S (O) ₂ -WR ⁷ -XY; R ^2a is hydrogen; R ² and R ^2a are pendant oxygen groups together; R ³ is H, C _1- C ₄ alkoxy, OH, -NR ¹⁹ R ²¹ , CN, halogen, C ₃ -C ₇ cycloalkyl or C ₁ -C ₈ alkyl optionally substituted with one or more halogen atoms; R ⁴ H, C ₁ -C ₄ alkoxy, OH, -NR ¹⁹ R ²¹ , CN, halogen, C ₃ -C ₇ cycloalkyl or C ₁ -C ₈ alkane optionally substituted with one or more halogen atoms group; R ⁵ based view Conditions with one or more halogen atoms, C ₁ -C ₄ alkyl, OH, OR ', - NR 19 R 21, CN or C ₃ -C ₇ substituted cycloalkyl group of C ₁ -C ₈ alkyl; optionally C ₁ -C ₈ alkoxy substituted with one or more halogen atoms; C ₆ -C ₁₄ aryl;-(C ₀ -C ₄ alkyl) -4 to 14-membered heteroaryl or-(C _0- C ₄ alkyl) -3 to 14-membered heterocyclyl, wherein the heteroaryl and heterocyclyl contain at least one heteroatom selected from N, O and S, wherein each of the aryl, heteroaryl and heterocyclyl Optionally substituted with one or more Z substituents; R ⁶ is C ₆ -C ₁₄ aryl;-(C ₀ -C ₄ alkyl) -4 to 14-membered heteroaryl,-(C ₀ -C ₄ alkane) -3) to 14-membered heterocyclyl, wherein the heteroaryl and heterocyclyl contain at least one heteroatom selected from N, O, and S, wherein the aryl, heteroaryl, and heterocyclyl are each optionally one or more substituents Z; W is optionally substituted Department of hydroxy, halogen, C ₁ -C ₄ alkyl or C ₁ -C ₈ extending alkyl; X system optionally substituted with hydroxy, halogen or C ₁ -C ₄ Alkyl substituted C ₁ -C ₈ alkylene; Y is carboxyl, alkoxycarbonyl, tetrazolyl, aminoformyl, monoalkylaminoformyl, dialkylaminoformyl or -CONH-S (O) _q -R ^x Where R ^x is -C ₁ -C ₄ alkyl or -NR ¹⁹ R ²¹ ; q is 0, 1 or 2; R ⁷ is a bivalent moiety represented by: -O-, -NHC (O)-, _{-CH 2 = CH 2 -, -} C 6 -C 14 aryl group -D -; - 3 to 14-membered heterocyclic group -D-, wherein the heterocyclic group containing at least one heteroatom selected from N, O, and S heteroatoms of atoms Where D is O, S, NH or absent; Z is independently OH, aryl, O-aryl, benzyl, O-benzyl, optionally via one or more OH groups or NH ₂ groups the C ₁ -C ₆ substituted alkyl, optionally substituted with one or more of halogen atoms, C ₁ -C ₆ alkyl, optionally substituted with one or more OH groups of the C ₁ -C ₆ alkoxy, optionally substituted with one or more of halogen, C ₁ -C ₆ alkoxy, optionally substituted with one or more of C ₁ -C ₄ alkoxy-substituted C ₁ -C ₆ alkoxy, NR ¹⁸ (SO ₂ ) R ²¹ 、 (SO ₂ ) NR ¹⁹ R ²¹ 、 (SO ₂ ) R ²¹ 、 NR ¹⁸ C (O) R ²¹ 、 C (O) NR ¹⁹ R ²¹ 、 NR ¹⁸ C (O) NR ¹⁹ R ²¹ 、 NR ¹⁸ C (O) OR ¹⁹ , NR ¹⁹ R ²¹ , C (O) OR ¹⁹ , C (O) R ¹⁹ , SR ¹⁹ , OR ¹⁹ , pendant oxygen group, CN, NO ₂ , halogen or 3 to 14 membered heterocyclic ring Wherein the heterocyclyl contains at least one heteroatom selected from N, O and S; R ^{18 is} independently H or C ₁ -C ₆ alkyl; R ¹⁹ and R ^{21 are} each independently H; C ₁ -C ₈ alkyl; C ₃ -C ₈ cycloalkyl; C ₁ -C ₄ alkoxy-C ₁ -C ₄ Alkyl; (C ₀ -C ₄ alkyl) -aryl, optionally substituted with one or more groups selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy and halogen; ( C ₀ -C ₄ alkyl) -3 to 14-membered heterocyclyl, the heterocyclyl includes one or more heteroatoms selected from N, O, and S, optionally via one or more selected from halogen, pendant Oxygen, C ₁ -C ₆ alkyl and C (O) C ₁ -C ₆ alkyl groups; (C ₀ -C ₄ alkyl) -O-aryl groups, optionally with one or more Group substitution selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy and halogen; and (C ₀ -C ₄ alkyl) -O-3 to 14-membered heterocyclyl, the heterocyclyl comprising one or more heteroatoms selected from N, O, and S heteroatoms of which is optionally substituted with one or more substituents selected from halo, C ₁ -C ₆ alkyl or C (O) C ₁ -C ₆ alkyl group of Substitution; wherein the alkyl groups are optionally substituted by one or more halogen atoms, C ₁ -C ₄ alkoxy, C (O) NH ₂ , C (O) NHC ₁ -C ₆ alkyl, or C (O) N (C ₁ -C ₆ alkyl) ₂ substitution; or R ¹⁹ and R ²¹ together with the nitrogen atom to which they are attached form a 5- to 10-membered heterocyclic group, the heterocyclic group including a Or more heteroatoms selected from N, O, and S, the heterocyclyl optionally substituted with one or more substituents selected from: OH; halogen; aryl; 5 to 10 membered heterocyclyl, Including one or more heteroatoms selected from N, O, and S; S (O) ₂ -aryl; S (O) ₂ -C ₁ -C ₆ alkyl; C ₁ -C ₆ alkyl, as appropriate Substitution with one or more halogen atoms; C ₁ -C ₆ alkoxy, optionally with one or more OH groups or C ₁ -C ₄ alkoxy; and C (O) OC ₁ -C ₆ Alkyl, in which the aryl and heterocyclyl substitution is substantially physically substituted with C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl or C ₁ -C ₆ alkoxy.

Embodiment 3. The compound of Embodiment 1 or 2, wherein R ¹ is H, and optionally C ₁ -C ₈ alkyl substituted with one or more halogen atoms, C ₁ -C ₄ alkyl, OH or OR '; Or R ¹ system -XY; or R ¹ system -WR ⁷ -XY; or R ¹ system -S (O) ₂ -XY or R ² system -S (O) ₂ -WR ⁷ -XY; R ² system H , optionally substituted with one or more 'substituents of a halogen atom, C ₁ -C ₄ alkyl, OH or oR C ₁ -C ₈ alkyl group; R ² -XY system; or R ² based -WR ⁷ -XY; or R ² is -S (O) ₂ -XY; R ² is -S (O) ₂ -WR ⁷ -XY; R ^2a is H; or R ² and R ^2a are pendant oxygen groups together; R ³ is H and C ₁ -C ₄ alkoxy, OH, -NR ¹⁹ R ²¹ , CN, halogen, C ₃ -C ₇ cycloalkyl or C ₁ -C ₄ alkyl optionally substituted with one or more halogen atoms; R ⁴ H, C ₁ -C ₄ alkoxy, OH, -NR ¹⁹ R ²¹ , CN, halogen, C ₃ -C ₇ cycloalkyl or C ₁ -C ₄ alkane optionally substituted with one or more halogen atoms Group; where R ¹ or R ² is -XY, -WR ⁷ -XY, -S (O) ₂ -WXY; or -S (O) ₂ -WR ⁷ -XY; W is optionally via hydroxyl, halogen or C of ₁ -C ₄ alkyl substituted by C ₁ -C ₆ extending alkyl; X system optionally substituted with hydroxy, halogen or C ₁ -C ₄ alkyl group substituted with the C ₁ -C ₆ alkylene; the Y-based -C (O ) OH, -C (O ) OR ^x , tetrazolyl, aminoformyl, monoalkylaminoformyl, dialkylaminoformyl, or -CONH-S (O) _q -R ^x , where R ^x is -C _1- C ₄ alkyl or -NR ¹⁹ R ²¹ ; q is 2; R 'is H, C ₁ -C ₄ alkyl optionally substituted with one or more halogen atoms; R ⁷ is -C ₆ -C ₁₄ aryl-D- represents a divalent moiety; -3 to 14-membered heterocyclyl-D-, wherein the heterocyclyl contains at least one heteroatom selected from N, O, and S, wherein D is O; ¹⁹ and R ^{21 are} each independently H; C ₁ -C ₈ alkyl.

Embodiment 4. The compound of any one of the preceding embodiments, wherein R ¹ is -XY; or -WR ⁷ -XY; R ² is H, optionally via one or more halogen atoms, C ₁ -C ₄ Alkyl, OH or OR 'substituted C ₁ -C ₈ alkyl; R ³ is H, C ₁ -C ₄ alkoxy, OH, -NR ¹⁹ R ²¹ , CN, halogen, C ₃ -C ₇ cycloalkane Or C ₁ -C ₄ alkyl, optionally substituted with one or more halogen atoms; R ⁴ is H, C ₁ -C ₄ alkoxy, OH, -NR ¹⁹ R ²¹ , CN, halogen, C _3- C ₇ cycloalkyl or C ₁ -C ₄ alkyl optionally substituted with one or more halogen atoms; W is C ₁ -C ₆ butane optionally substituted with hydroxyl, halogen or C ₁ -C ₄ alkyl group; X system optionally substituted with hydroxy, halogen or C ₁ -C ₄ alkyl group substituted with the C ₁ -C ₆ alkylene; the Y-based -C (O) OH, -C ( O) oR x, tetrazolyl, Aminoformyl, monoalkylaminoformyl, dialkylaminoformyl, or -CONH-S (O) _q -R ^x , where R ^x is -C ₁ -C ₄ alkyl or- NR ¹⁹ R ^21; q lines 2; R 'Department of H, optionally substituted by one or more of halogen atoms, C ₁ -C ₄ alkyl group; R ⁷ represents the system by a -C ₆ -C ₁₄ aryl group -D- Divalent moiety; -3 to 14-membered heterocyclyl-D-, wherein the heterocyclyl contains At least one selected from N, O, and S heteroatoms of atoms, wherein D line O; and R ¹⁹ and R ²¹ are each independently H; C ₁ -C ₈ alkyl.

Embodiment 5. The compound according to any one of the preceding embodiments, wherein R ¹ is -XY; or -WR ⁷ -XY; R ² is H, optionally C ₁ -C substituted with one or more halogen atoms. ₄ alkyl; R ³ is H, C ₁ -C ₄ alkoxy, OH, -NR ¹⁹ R ²¹ , CN, halogen, C ₃ -C ₇ cycloalkyl or optionally substituted with one or more halogen atoms C ₁ -C ₄ alkyl; R ⁴ is H, C ₁ -C ₄ alkoxy, OH, -NR ¹⁹ R ²¹ , CN, halogen, C ₃ -C ₇ cycloalkyl or optionally one or more the halogen atom-substituted C ₁ -C ₄ alkyl; W is optionally substituted Department of hydroxy, halogen, C ₁ -C ₄ alkyl or C ₁ -C ₆ extending alkyl; X system optionally substituted with hydroxy, halogen or C ₁ the -C ₄ alkyl substituted by C ₁ -C ₆ alkylene; the Y-based -C (O) OH; and R ⁷ by the line ₆ -C ₁₄ represents a divalent moiety of the aryl group -D- -C; -3 to A 14-membered heterocyclyl-D-, wherein the heterocyclyl contains at least one heteroatom selected from N, O, and S, where D is O.

Embodiment 6. The compound according to any one of the preceding embodiments, wherein R ¹ is a C ₁ -C ₄ alkyl group optionally substituted with one or more halogen atoms,-(CH ₂ ) _m -C (O) OR "or-(CH ₂ ) _m -R ^7- (CH ₂ ) _n -C (O) OR"; R ² is H, optionally a C ₁ -C ₄ alkyl group substituted with one or more halogen atoms; R ³ is H, C ₁ -C ₄ alkoxy, OH, -NR ¹⁹ R ²¹ , CN, halogen, C ₃ -C ₇ cycloalkyl or C ₁ -C optionally substituted with one or more halogen atoms ₄ alkyl; R ⁴ is H, C ₁ -C ₄ alkoxy, OH, -NR ¹⁹ R ²¹ , CN, halogen, C ₃ -C ₇ cycloalkyl or optionally substituted with one or more halogen atoms C ₁ -C ₄ alkyl; m is 1, 2, 3, ₄ , 5, 6, 7 or 8; n is 0, 1, 2 or 3; R "is H or optionally via one or more halogen atoms the substituted C ₁ -C ₄ alkyl; and R ⁷ by the line ₆ -C ₁₄ represents a divalent moiety of the aryl group -D- -C; -3 to 14-membered heterocyclic group -D-, wherein the heterocyclic group contains At least one heteroatom selected from N, O and S, wherein D is O;

Embodiment 7. The compound according to any one of the preceding embodiments, wherein R ¹ is-(CH ₂ ) _m -C (O) OR "or-(CH ₂ ) _m -R ^7- (CH ₂ ) _n- C (O) OR "; R ² is H, optionally C ₁ -C ₄ alkyl substituted with one or more halogen atoms; R ³ is H, C ₁ -C ₄ alkoxy, OH, -NR ¹⁹ R ²¹ , CN, halogen, C ₃ -C ₇ cycloalkyl or C ₁ -C ₄ alkyl optionally substituted with one or more halogen atoms; R ⁴ is H, C ₁ -C ₄ alkoxy, OH , -NR ¹⁹ R ²¹ , CN, halogen, C ₃ -C ₇ cycloalkyl or C ₁ -C ₄ alkyl optionally substituted with one or more halogen atoms; m is 1, 2, 3, 4, 5 , 6, 7, or 8; n is 0, 1, 2, or 3; R "is H or C ₁ -C ₄ alkyl optionally substituted with one or more halogen atoms; and R ⁷ is -C _6- C ₁₄ aryl-D- represents a divalent moiety; -3 to 14-membered heterocyclyl-D-, wherein the heterocyclyl contains at least one heteroatom selected from N, O and S, wherein D is O.

Embodiment 8. The compound according to any one of the preceding embodiments, wherein R ¹ is-(CH ₂ ) _m -C (O) OR "; R ² is H, optionally substituted with one or more halogen atoms C ₁ -C ₄ alkyl; R ³ is H, C ₁ -C ₄ alkoxy, OH, -NR ¹⁹ R ²¹ , CN, halogen, C ₃ -C ₇ cycloalkyl or optionally one or more C ₁ -C ₄ alkyl substituted with halogen atom; R ⁴ is H, C ₁ -C ₄ alkoxy, OH, -NR ¹⁹ R ²¹ , CN, halogen, C ₃ -C ₇ cycloalkyl or optionally C ₁ -C ₄ alkyl substituted with one or more halogen atoms; m is 1, 2, 3, 4, 5, 6, 7, or 8; and R "is H or optionally substituted with one or more halogen atoms C ₁ -C ₄ alkyl.

Embodiment 9. The compound of any one of the preceding embodiments, wherein R ¹ is-(CH ₂ ) _m -C (O) OR "; R ² is H; R ³ is H, C ₁ -C ₄ alkane Oxygen, OH, -NR ¹⁹ R ²¹ , CN, halogen, C ₃ -C ₇ cycloalkyl or C ₁ -C ₄ alkyl optionally substituted with one or more halogen atoms; R ⁴ is H, C ₁ -C ₄ alkoxy, OH, -NR ¹⁹ R ²¹ , CN, halogen, C ₃ -C ₇ cycloalkyl or C ₁ -C ₄ alkyl optionally substituted with one or more halogen atoms; R "is H; and m is 4, 5, or 6.

Embodiment 10. The compound according to embodiment 1 or 2, wherein R ¹ is XY; R ² is H or C ₁ -C ₈ alkyl optionally substituted with one or more halogen atoms; R ³ is H, C ₁ -C ₄ alkoxy, OH, -NR ¹⁹ R ²¹ , CN, halogen, C ₃ -C ₇ cycloalkyl or C ₁ -C ₄ alkyl optionally substituted with one or more halogen atoms; R ⁴ is H, C ₁ -C ₄ alkoxy, OH, -NR ¹⁹ R ²¹ , CN, halogen, C ₃ -C ₇ cycloalkyl or C ₁ -C ₄ alkyl optionally substituted with one or more halogen atoms ; X-based substituent of optionally hydroxy, halogen, C ₁ -C ₄ alkyl or C ₁ -C ₆ alkylene; the Y-based -C (O) OH, -C ( O) oR x or -CONH-S ( O) _q -R ^x , wherein R ^x is -C ₁ -C ₄ alkyl; and q is 2.

Embodiment 11. The compound of Embodiment 1 or 2 wherein R ¹ is

or ; And R ² is H, , -CH ₃ or .

Embodiment 12. The compound of Embodiment 1 or 2 wherein R ¹ is H, -CH ₃ ,

R ² series or .

Example 12.1. The compound of Example 2, wherein R ² and R ^2a are pendant oxygen together; R ¹ is XY; R ³ is H, C ₁ -C ₄ alkoxy, OH, -NR ¹⁹ R ²¹ , CN, halogen, C ₃ -C ₇ cycloalkyl or C ₁ -C ₄ alkyl optionally substituted with one or more halogen atoms; R ⁴ is H, C ₁ -C ₄ alkoxy, OH, -NR ¹⁹ R ²¹ , CN, halogen, C ₃ -C ₇ cycloalkyl or C ₁ -C ₄ alkyl optionally substituted with one or more halogen atoms; X is optionally hydroxyl, halogen or C ₁ -C ₄ Alkyl-substituted C ₁ -C ₆ alkylene; Y is -C (O) OH, -C (O) OR ^x or -CONH-S (O) _q -R ^x , where R ^x is -C _1- C ₄ alkyl; and q is 2.

Embodiment 13. The compound as in any one of the preceding embodiments, wherein R ⁵ is C ₆ -C ₁₄ aryl;-(C ₀ -C ₄ alkyl) -4 to 14-membered heteroaryl or-(C _0- C ₄ alkyl) -3 to 14-membered heterocyclyl, wherein the heteroaryl and heterocyclyl contain at least one heteroatom selected from N, O and S, wherein the aryl, heteroaryl and heterocyclic Each is optionally substituted with one or more Z substituents; and R ⁶ is a C ₆ -C ₁₄ aryl group;-(C ₀ -C ₄ alkyl) -4 to 14-membered heteroaryl group,-(C _0- C ₄ alkyl) -3 to 14-membered heterocyclyl, wherein the heteroaryl and heterocyclyl contain at least one heteroatom selected from N, O and S, wherein each of the aryl, heteroaryl and heterocyclyl It is optionally substituted with one or more Z substituents.

Embodiment 14. The compound according to any one of the preceding embodiments, wherein R ⁵ is a C ₆ -C ₁₄ aryl group; -5 to 6-membered heteroaryl or -5 to 6-membered heterocyclic group, wherein the heteroaryl And heterocyclyl contain at least one heteroatom selected from N, O and S, wherein the aryl, heteroaryl and heterocyclyl are each optionally substituted with one or more Z substituents; and R ⁶ is C ₆ -C ₁₄ aryl; -5 to 6-membered heteroaryl, -5 to 6-membered heterocyclyl, wherein the heteroaryl and heterocyclyl contain at least one heteroatom selected from N, O, and S, wherein the aryl , Heteroaryl and heterocyclyl are each optionally substituted with one or more Z substituents.

Embodiment 15. The compound according to any one of the preceding embodiments, wherein R ⁵ is phenyl; 2-pyridyl, 3-pyridyl or 4-pyridyl, and R ⁶ is phenyl; 2-pyridyl, 3-pyridyl or 4-pyridyl, wherein phenyl, 2-pyridyl, 3-pyridyl, and 4-pyridyl are each optionally substituted with one or more Z substituents.

Embodiment 16. The compound of Embodiments 1 to 14 wherein R ⁵ phenyl is optionally substituted with the following groups: OH, optionally C ₁ -substituted with one or more OH groups or NH ₂ groups C ₄ alkyl, optionally substituted with one or more of halogen atoms, C ₁ -C ₄ alkyl, optionally substituted by one or more OH groups or C ₁ -C ₄ alkoxy groups C ₁ -C ₄ Alkoxy, NR ¹⁹ R ²¹ , C (O) OR ¹⁹ , C (O) R ¹⁹ , SR ¹⁹ , OR ¹⁹ , CN, NO ₂ or halogen; and R ⁶ is phenyl, which is optionally passed through the following groups substituents: OH, optionally substituted with one or more OH groups of NH ₂ groups or C ₁ -C ₄ alkyl, optionally substituted with one or more of halogen atoms, C ₁ -C ₄ alkyl, optionally substituted with one or more of OH groups or C ₁ -C ₄ alkoxy C ₁ -C ₄ ^{alkoxy, NR 19 R 21, C (} O) oR 19, C (O) R 19, SR 19, OR ¹⁹ , CN, NO ₂ or halogen.

Embodiment 17. The compound of Embodiments 1 to 14 or 16, wherein R ⁵ is a phenyl group, optionally substituted with the following group: C ₁ substituted with one or more OH groups or NH ₂ groups as appropriate. -C ₄ alkyl, optionally substituted with one or more of halogen atoms, C ₁ -C ₄ alkyl, optionally substituted by one or more OH groups or C ₁ -C ₄ alkoxy groups C ₁ -C ₄ alkoxy or halogen; and R ⁶ is phenyl, optionally substituted with the following groups: C ₁ -C ₄ alkyl optionally substituted with one or more OH or NH ₂ groups, optionally C ₁ -C ₄ alkyl substituted with one or more halogen atoms, optionally C ₁ -C ₄ alkoxy or halogen substituted with one or more OH groups or C ₁ -C ₄ alkoxy.

Embodiment 18. The compound of Embodiments 1 to 14 or 16 to 17, wherein R ⁵ is a phenyl group, optionally substituted by the following group: C ₁ -C ₄ alkoxy, halogen, or optionally one or more C ₁ -C ₄ alkyl substituted with three halogen atoms; and R 6 is phenyl, optionally substituted with the following groups: C ₁ -C ₄ alkoxy, halogen, or optionally substituted with one or more halogen atoms C ₁ -C ₄ alkyl.

Embodiment 19. The compound of Embodiments 1 to 14 or 16 to 18, wherein R ⁵ is a phenyl group, optionally substituted by the following group: methyl, trifluoromethyl, methoxy, or halogen; and R ⁶ A phenyl group, optionally substituted by the following groups: methyl, trifluoromethyl, methoxy, or halogen.

Embodiment 20. The compound of Embodiments 1 to 13, wherein R ⁵ is

R ⁶ series

Example 21. The compound of Example 1 or 2 represented by Formula IIa

Wherein: R ¹ is H, optionally C ₁ -C ₈ alkyl substituted with one or more halogen atoms, C ₁ -C ₄ alkyl, OH or OR '; or R ¹ is -XY; or R ¹ is -WR ⁷ -XY; or R ¹ -S (O) ₂ -XY or R ² -S (O) ₂ -WR ⁷ -XY; R ² is H, optionally with one or more halogen atoms, C ₁ -C ₄ alkyl, OH, OR ', -NR ¹⁹ R ²¹ , CN or C ₃ -C ₇ cycloalkyl substituted C ₁ -C ₈ alkyl; or R ² -XY; or R ^2- WR ⁷ -XY; or R ² system -S (O) ₂ -WXY; R ² system -S (O) ₂ -WR ⁷ -XY; R ¹ or R ² system -XY, -WR ⁷ -XY,- S (O) ₂ -WXY; or -S (O) ₂ -WR ⁷ -XY; R ^2a is hydrogen; R ² and R ^2a are pendant oxygen groups together; wherein R ¹ or R ² is -XY, -WR ⁷ -XY, -S (O) ₂ -WXY; or -S (O) ₂ -WR ⁷ -XY; R ³ is H, C ₁ -C ₄ alkoxy, OH, -NR ¹⁹ R ²¹ , CN, halogen , C ₃ -C ₇ cycloalkyl or C ₁ -C ₈ alkyl optionally substituted with one or more halogen atoms; R ⁴ is H, C ₁ -C ₄ alkoxy, OH, -NR ¹⁹ R ²¹ , CN, halogen, C ₃ -C ₇ cycloalkyl or C ₁ -C ₈ alkyl optionally substituted with one or more halogen atoms; W is optionally substituted with hydroxy, halogen or C ₁ -C ₄ alkyl C ₁ -C ₆ alkylene; X is optionally via hydroxyl Group, halogen or C ₁ -C ₄ alkyl-substituted C ₁ -C ₆ alkylene; Y is -C (O) OH, -C (O) OR ^x , tetrazolyl, aminoformyl, mono Alkylaminomethylamidino, dialkylaminomethylamidino or -CONH-S (O) _q -R ^x , where R ^x is -C ₁ -C ₄ alkyl or -NR ¹⁹ R ²¹ ; p is 0, 1, 2, 3 or 4; q is 2; R 'is H, optionally a C ₁ -C ₄ alkyl group substituted with one or more halogen atoms; R ⁷ is a divalent moiety represented by:- O -, - NHC (O) -, - CH 2 = CH 2 -, - C 6 -C 14 aryl group -D -; - 3 to 14-membered heterocyclic group -D-, wherein the heterocyclic group containing at least one A heteroatom selected from N, O, and S, wherein D is O, S, NH, or is absent; and R ¹⁹ and R ^{21 are} each independently H; C ₁ -C ₈ alkyl.

Embodiment 22. The compound of Embodiment 21, wherein R ¹ is -XY; or -WR ⁷ -XY; R ² is H, optionally via one or more halogen atoms, C ₁ -C ₄ alkyl, OH, C ₁ -C ₈ alkyl substituted with pendant oxygen or OR '; R ³ is H, C ₁ -C ₄ alkoxy, OH, -NR ¹⁹ R ²¹ , CN, halogen, C ₃ -C ₇ cycloalkyl Or C ₁ -C ₄ alkyl optionally substituted with one or more halogen atoms; R ⁴ is H, C ₁ -C ₄ alkoxy, OH, -NR ¹⁹ R ²¹ , CN, halogen, C ₃ -C ₇ cycloalkyl or C ₁ -C ₄ alkyl optionally substituted with one or more halogen atoms; W is C ₁ -C ₆ alkyl, optionally substituted with hydroxyl, halogen or C ₁ -C ₄ alkyl ; X-based substituent of optionally hydroxy, halogen, C ₁ -C ₄ alkyl or C ₁ -C ₆ alkylene; the Y-based -C (O) OH, -C ( O) oR x, tetrazolyl, amine Methylformyl, monoalkylaminoformyl, dialkylaminoformyl or -CONH-S (O) _q -R ^x , where R ^x is -C ₁ -C ₄ alkyl or -NR ¹⁹ R ²¹ ; q is 2; p is 0, 1, 2, 3, or 4; R 'is H, optionally a C ₁ -C ₄ alkyl group substituted with one or more halogen atoms; and R ⁷ is composed of It represents a divalent moiety of: -O -, - NHC (O ) -, - CH 2 = CH 2 -, - C 6 -C 14 Group -D -; - 3 -D-to 14-membered heterocyclic group, wherein the heterocyclic group containing at least one heteroatom selected from N, O, and S heteroatoms of atoms, wherein D system O, S, NH2 or is absent.

Embodiment 23. The compound of Embodiment 21 or 22, wherein R ¹ is -XY; or -WR ⁷ -XY; R ² is H, and optionally C ₁ -C ₄ alkyl substituted with one or more halogen atoms ; R ³ is H, C ₁ -C ₄ alkoxy, OH, -NR ¹⁹ R ²¹ , CN, halogen, C ₃ -C ₇ cycloalkyl or C ₁ -optionally substituted with one or more halogen atoms C ₄ alkyl; R ⁴ is H, C ₁ -C ₄ alkoxy, OH, -NR ¹⁹ R ²¹ , CN, halogen, C ₃ -C ₇ cycloalkyl or optionally substituted with one or more halogen atoms the C ₁ -C ₄ alkyl; W is optionally substituted Department of hydroxy, halogen, C ₁ -C ₄ alkyl or C ₁ -C ₆ extending alkyl; X system optionally substituted with hydroxy, halogen or C ₁ -C ₄ substituted alkyl of C ₁ -C ₆ alkylene; the Y-based -C (O) OH; p lines 0,1 or 2; and R ⁷ by the Department of -C ₆ -C ₁₄ aryl group represents a divalent -D- Part; -3 to 14-membered heterocyclyl-D-, wherein the heterocyclyl contains at least one heteroatom selected from N, O and S, wherein D is O.

Embodiment 24. The compound of Embodiments 21 to 23, wherein R ¹ is-(CH ₂ ) _m -C (O) OR "or-(CH ₂ ) _m -R ^7- (CH ₂ ) _n -C (O ) OR "; R ² is H, C ₁ -C ₄ alkyl optionally substituted with one or more halogen atoms; R ³ is H, C ₁ -C ₄ alkoxy, OH, -NR ¹⁹ R ²¹ , CN, halogen, C ₃ -C ₇ cycloalkyl or C ₁ -C ₄ alkyl optionally substituted with one or more halogen atoms; R ⁴ is H, C ₁ -C ₄ alkoxy, OH, -NR ¹⁹ R ²¹ , CN, halogen, C ₃ -C ₇ cycloalkyl or C ₁ -C ₄ alkyl optionally substituted with one or more halogen atoms; m is 1, 2, 3, 4, 5, 6, 7 or 8; n is 0, 1, 2 or 3; p is 0, 1 or 2; R "is H or C ₁ -C ₄ alkyl optionally substituted with one or more halogen atoms; and R ⁷ is a ₆ -C ₁₄ represents a divalent moiety of the aryl group -D- -C; -3 -D-to 14-membered heterocyclic group, wherein the heterocyclic group containing at least one heteroatom selected from N, O, and S heteroatoms of atoms, wherein D is O; Example 25. The compound of Examples 21 to 24, wherein R ¹ is-(CH ₂ ) _m -C (O) OR "or-(CH ₂ ) _m -R ^7- (CH ₂ ) _n -C (O) oR "; R 2 Department of H, optionally substituted by one or more of halogen atoms, C ₁ -C ₄ alkyl group; R ³ Department of H, C ₁ -C ₄ alkoxy ^{Group, OH, -NR 19 R 21,} CN, halogen, C ₃ -C ₇ cycloalkyl or optionally substituted by one or more of halogen atoms, C ₁ -C ₄ alkyl; R ⁴ Department of H, C ₁ - C ₄ alkoxy, OH, -NR ¹⁹ R ²¹ , CN, halogen, C ₃ -C ₇ cycloalkyl or C ₁ -C ₄ alkyl optionally substituted with one or more halogen atoms; m is 1, 2, 3, 4, 5, 6, 7 or 8; n is 0, 1, 2 or 3; p is 0, 1 or 2; R "is H or C ₁ optionally substituted with one or more halogen atoms -C ₄ alkyl; and R ⁷ is a divalent moiety represented by -phenyl-D-; or -pyridyl-D-, where D is O.

Embodiment 26. The compound of Embodiments 21 to 25, wherein R ¹ is-(CH ₂ ) _m -C (O) OR "; R ² is H, and C ₁ -optionally substituted with one or more halogen atoms C ₄ alkyl; R ³ is H, C ₁ -C ₄ alkoxy, OH, -NR ¹⁹ R ²¹ , CN, halogen, C ₃ -C ₇ cycloalkyl or optionally substituted with one or more halogen atoms C ₁ -C ₄ alkyl; R ⁴ is H, C ₁ -C ₄ alkoxy, OH, -NR ¹⁹ R ²¹ , CN, halogen, C ₃ -C ₇ cycloalkyl or optionally one or more C ₁ -C ₄ alkyl substituted with a halogen atom; m is 1, 2, 3, 4, 5, 6, 7, or 8; p is 0, 1 or 2; and R "is H or optionally by one or C ₁ -C ₄ alkyl substituted with multiple halogen atoms.

Embodiment 27. The compound of Embodiments 21 to 26, wherein R ¹ is-(CH ₂ ) _m -C (O) OR "; R ² is H; R ³ is H, C ₁ -C ₄ alkoxy, OH, -NR ¹⁹ R ²¹ , CN, halogen, C ₃ -C ₇ cycloalkyl or C ₁ -C ₄ alkyl optionally substituted with one or more halogen atoms; R ⁴ is H, C ₁ -C ₄ Alkoxy, OH, -NR ¹⁹ R ²¹ , CN, halogen, C ₃ -C ₇ cycloalkyl or C ₁ -C ₄ alkyl optionally substituted with one or more halogen atoms; R "is H; m Is 4, 5, or 6; and p is 0 or 1.

Embodiment 28. The compound of Embodiments 21 to 27, wherein R ¹ is

R ² series H, -CH ₃ or R "is H; m is 4, 5, or 6; and p is 0 or 1.

Embodiment 29. The compounds of Embodiments 21 to 27, wherein R ¹ is H, -CH ₃ , and R ¹ is

R ² series R "is H; m is 4, 5, or 6; and p is 0 or 1.

Embodiment 29.1. The compound of Embodiment 21, wherein R ² and R ^2a are pendant oxygen together; R ¹ is XY; R ³ is H, C ₁ -C ₄ alkoxy, OH, -NR ¹⁹ R ²¹ , CN, halogen, C ₃ -C ₇ cycloalkyl or C ₁ -C ₄ alkyl optionally substituted with one or more halogen atoms; R ⁴ is H, C ₁ -C ₄ alkoxy, OH, -NR ¹⁹ R ²¹ , CN, halogen, C ₃ -C ₇ cycloalkyl or C ₁ -C ₄ alkyl optionally substituted with one or more halogen atoms; X is optionally hydroxyl, halogen or C ₁ -C ₄ Alkyl substituted C ₁ -C ₆ alkylene; Y is -C (O) OH or -CONH-S (O) _q -R ^x , where R ^x is -C ₁ -C ₄ alkyl; and q is 2.

Embodiment 29. The compound of any of the preceding embodiments, wherein R ³ and R ^{4 are} independently H, OH, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₃ -C ₆ cycloalkane Group, cyano or halogen.

Embodiment 30. The compound of any of the preceding embodiments, wherein R ³ and R ^{4 are} independently H, OH, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₃ -C ₅ cycloalkane Radical or halogen.

Embodiment 31. The compound of any of the preceding embodiments, wherein R ³ and R ^{4 are} independently H, OH, methyl, ethyl, isopropyl, third butyl, methoxy, ethoxy, propane Oxy, butoxy, cyclopropyl, fluorine, bromine or chlorine.

Embodiment 32. A compound according to any one of the preceding embodiments, wherein Z is independently OH, C ₆ -aryl, OC ₆ -aryl, benzyl, O-benzyl, optionally via one or more OH groups or the group NH ₂ substituted C ₁ -C ₄ alkyl, optionally substituted with one or more of halogen atoms, C ₁ -C ₄ alkyl, optionally substituted with one or more OH groups or C ₁ -C ₄ Alkoxy-substituted C ₁ -C ₄ alkoxy, NR ¹⁸ (SO ₂ ) R ²¹ , (SO ₂ ) NR ¹⁹ R ²¹ , (SO ₂ ) R ²¹ , NR ¹⁸ C (O) R ²¹ , C ( O) NR ¹⁹ R ²¹ , NR ¹⁸ C (O) NR ¹⁹ R ²¹ , NR ¹⁸ C (O) OR ¹⁹ , NR ¹⁹ R ²¹ , C (O) OR ¹⁹ , C (O) R ¹⁹ , SR ¹⁹ , OR ¹⁹ , pendant oxygen, CN, NO ₂ , halogen or 4- to 6-membered heterocyclic group, wherein the heterocyclic group contains at least one heteroatom selected from N, O and S; R ¹⁸ is H or C ₁ -C ₄ Alkyl; R ¹⁹ and R ^{21 are} each independently H; C ₁ -C ₄ alkyl; C ₃ -C ₆ cycloalkyl; C ₁ -C ₄ alkoxy-C ₁ -C ₄ alkyl; (C _0- C ₄ alkyl) -aryl, optionally substituted with one or more groups selected from C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, and halogen; (C ₀ -C ₄ Alkyl) -4- to 6-membered heterocyclyl, the heterocyclyl includes one or more heteroatoms selected from N, O and S, It is optionally substituted with one or more groups selected from halogen, pendant oxy, C ₁ -C ₄ alkyl and C (O) C ₁ -C ₄ alkyl; (C ₀ -C ₄ alkyl)- O-aryl, optionally substituted with one or more groups selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, and halogen; and (C ₀ -C ₄ alkyl) -O 3 to 14-membered heterocyclyl group, the heterocyclyl group comprises one or more selected from N, O, and S heteroatoms of which is optionally substituted with one or more substituents selected from halo, C ₁ -C ₆ alkyl or C (O) C ₁ -C ₆ alkyl group substitution; wherein the alkyl groups are optionally substituted by one or more halogen atoms, C ₁ -C ₄ alkoxy, C (O) NH ₂ , C (O) NHC ₁ -C ₆ alkyl or C (O) N (C ₁ -C ₆ alkyl) ₂ substitution; or R ¹⁹ and R ²¹ together with the nitrogen atom to which they are attached form a 5- to 6-membered heterocyclic group, the heterocyclic ring Group includes one or more other heteroatoms selected from N, O, and S, and the heterocyclic group is optionally substituted with one or more substituents selected from: OH; halogen; aryl; 5- to 6-membered hetero A cyclic group including one or more heteroatoms selected from N, O, and S; S (O) ₂ -aryl; S (O) ₂ -C ₁ -C ₆ alkyl; C ₁ -C ₆ alkyl , which is optionally substituted by one or more halogen atoms; C ₁ -C ₄ alkoxy, Optionally substituted with one or more OH groups or C ₁ -C ₄ alkoxy; and C (O) OC ₁ -C ₆ alkyl, wherein the aryl and heterocyclic group substituents may themselves optionally substituted with C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl or C ₁ -C ₆ alkoxy substituted.

Example 33. The compound according to any one of the preceding embodiments of the embodiment, wherein Z is independently OH, optionally substituted with one or more OH groups of NH ₂ groups or C ₁ -C ₄ alkyl, optionally substituted with one or the more halogen atoms substituted C ₁ -C ₄ alkyl, optionally substituted by one or more OH groups or C ₁ -C ₄ alkoxy groups C ₁ -C ₄ alkoxy, NR ¹⁹ R ^21, C (O) OR ¹⁹ , C (O) R ¹⁹ , SR ¹⁹ , OR ¹⁹ , CN, NO ₂ or halogen; R ¹⁹ and R ^{21 are} each independently H; C ₁ -C ₄ alkyl; C ₃ -C ₆ Cycloalkyl; or C ₁ -C ₄ alkoxy-C ₁ -C ₄ alkyl, where all alkyl groups are optionally substituted with halogen.

Example 34. The compound according to any one of the preceding embodiments of the embodiment, wherein Z is independently OH, optionally substituted with one or more OH groups of NH ₂ groups or C ₁ -C ₄ alkyl, optionally substituted with one or the more halogen atoms substituted C ₁ -C ₄ alkyl, optionally substituted with one or more of OH groups or C ₁ -C ₄ alkoxy C ₁ -C ₄ alkoxy, C (O) oR ¹⁹ , C (O) R ¹⁹ , OR ¹⁹ , CN or halogen; R ¹⁹ is H; C ₁ -C ₄ alkyl; C ₃ -C ₆ cycloalkyl; or C ₁ -C ₄ alkoxy-C _1- C ₄ alkyl, where all alkyl groups are optionally substituted with halogen.

Example 35. The compound according to any one of the preceding embodiments of the embodiment, wherein Z is independently optionally substituted with one or more of halogen atoms, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy or halogen;

Embodiment 36. A compound according to any one of the preceding embodiments, wherein A is N.

Example 37. The compound of Examples 1 to 35, wherein A is CR '.

Embodiment 38. The compound of Embodiment 37, wherein R 'is H.

Embodiment 39. The compound of Embodiments 2 to 38, wherein Formula Ia has the following stereochemical structure:

Example 40. The compound of Example 2 which is 7- (6,7-diphenyl-3,4-dihydro-1,8-naphthyridin-1 (2H) -yl) heptanoic acid; 7 -(6,7-diphenyl-3,4-dihydro-1,8-naphthyridin-1 (2H) -yl) heptanoic acid ethyl ester; 2- (3-((6,7-diphenyl -3,4-dihydro-1,8-naphthyridin-1 (2H) -yl) methyl) phenoxy) acetic acid; 2- (3-((6,7-diphenyl-3,4- Dihydro-1,8-naphthyridin-1 (2H) -yl) methyl) phenoxy) ethyl acetate; 6- (6,7-diphenyl-3,4-dihydro-1,8- Naphthyridin-1 (2H) -yl) hexanoic acid; 6- (1-methyl-6,7-diphenyl-1,2,3,4-tetrahydro-1,8-naphthyridin-2-yl ) Enantiomer 1 of hexanoic acid; 6- (1-methyl-6,7-diphenyl-1,2,3,4-tetrahydro-1,8-naphthyridin-2-yl) hexyl Enantiomer 2 of acid; 7- (1-methyl-6,7-diphenyl-1,2,3,4-tetrahydro- [1,8] naphthyridin-2-yl) -heptane Enantiomer 1 of acid; 7- (1-methyl-6,7-diphenyl-1,2,3,4-tetrahydro- [1,8] naphthyridin-2-yl) -heptane Enantiomer 2 of acid; racemic -6- (1-methyl-6,7-diphenyl-1,2,3,4-tetrahydro- [1,8] naphthyridin-2- Enyl) -hexanoic acid; enantiomers of 7- (2-methyl-6,7-diphenyl-3,4-dihydro-1,8-naphthyridin-1 (2H) -yl) heptanoic acid Enantiomer 1; Enantiomer 2 of 7- (2-methyl-6,7-diphenyl-3,4-dihydro-1,8-naphthyridin-1 (2H) -yl) heptanoic acid; 7 -(2,3-diphenyl-7,8-dihydropyrido [3,2-b] pyrazine-5 (6H) -yl) heptanoic acid; 7- (2,3-bis (4-fluoro Phenyl) -7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -yl) heptanoic acid; 7- (2,3-di-p-tolyl-7,8-dihydro Pyrido [2,3-b] pyrazine-5 (6H) -yl) heptanoic acid; 7- (2,3-bis (4-methoxyphenyl) -7,8-dihydropyrido [2 , 3-b] pyrazine-5 (6H) -yl) heptanoic acid; racemic -7- (7-methyl-2,3-diphenyl-7,8-dihydropyrido [2,3 -b] pyrazine-5 (6H) -yl) heptanoic acid; 7- (7-methyl-2,3-diphenyl-7,8-dihydropyrido [2,3-b] pyrazine- Enantiomer 1 of 5 (6H) -yl) heptanoic acid; 7- (7-methyl-2,3-diphenyl-7,8-dihydropyrido [2,3-b] pyrazine -5 (6H) -yl) heptanoic acid enantiomer 2; racemic -7- (6-methyl-2,3-diphenyl-7,8-dihydropyrido [2,3 -b] pyrazine-5 (6H) -yl) heptanoic acid; racemic -7- (2,3-bis (4-fluorophenyl) -7-methyl-7,8-dihydropyrido [ 2,3-b] pyrazine-5 (6H) -yl) heptanoic acid; racemic -7- (2,3-bis (4-fluorophenyl) -6-methyl-7,8-dihydro Pyrido [2,3-b] pyrazine-5 (6H) -yl) heptanoic acid; 7- (2,3-bis (4- (trifluoromethyl) phenyl) -7,8-dihydropyridine Benzo [2,3-b] pyrazine-5 (6H) -yl) heptanoic acid; 7- (6-methyl-2,3-di-p-tolyl-7,8-dihydropyrido [ Enantiomer 1 of 2,3-b] pyrazine-5 (6H) -yl) heptanoic acid; 7- (6-methyl-2,3-di-p-tolyl-7,8-dihydropyridine Enantiomer 2 of benzo [2,3-b] pyrazine-5 (6H) -yl) heptanoic acid; 6- (2,3-diphenyl-7,8-dihydropyrido [3, 2-b] pyrazine-5 (6H) -yl) hexanoic acid; 5- (2,3-diphenyl-7,8-dihydropyrido [3,2-b] pyrazine-5 (6H) -Yl) pentanoic acid; 7- (3-phenyl-2-p-tolyl-7,8-dihydropyrido [2,3-b] pyrazin-5 (6H) -yl) heptanoic acid; 7- (2-phenyl-3-p-tolyl-7,8-dihydropyrido [2,3-b] pyrazin-5 (6H) -yl) heptanoic acid; 7- (2-m-tolyl-3 -P-tolyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -yl) heptanoic acid; 7- (2-phenyl-3-o-tolyl-7,8 -Dihydropyrido [2,3-b] pyrazine-5 (6H) -yl) heptanoic acid; 7- (2- (2,3-dihydrobenzofuran-7-yl) -3-p-toluene -7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -yl) heptanoic acid; 7- (3- (4-ethylphenyl) -2-phenyl-7 , 8-dihydropyrido [2,3-b] pyrazine-5 (6H) -yl) heptanoic acid; 7- (3-m-tolyl-2-p-tolyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -yl) heptanoic acid ethyl ester; 7- (3-m-tolyl-2-p-tolyl-7,8-dihydropyrido [2,3- b] pyrazine-5 (6H) -yl) heptanoic acid; 7- (2- (4-ethylphenyl) -3- Phenyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -yl) heptanoic acid; 7- (2,3-bis (3-fluoro-4-methylphenyl) ) -7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -yl) heptanoic acid; 7- (2,3-di-m-tolyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -yl) heptanoic acid; 7- (2,3-bis (4-ethylphenyl) -7,8-dihydropyrido [2,3- b] pyrazine-5 (6H) -yl) heptanoic acid; 7- (2,3-bis (3,4-dimethylphenyl) -7,8-dihydropyrido [2,3-b] Pyrazine-5 (6H) -yl) heptanoic acid; 7- (2,3-bis (3,4-difluorophenyl) -7,8-dihydropyrido [2,3-b] pyrazine- 5 (6H) -yl) heptanoic acid ethyl ester; 7- (2,3-bis (3,4-difluorophenyl) -7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -yl) heptanoic acid; 7- (2,3-bis (4-fluoro-3-methylphenyl) -7,8-dihydropyrido [2,3-b] pyrazine-5 ( 6H) -yl) heptanoic acid; racemic -7- (8-ethyl-2,3-diphenyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -Yl) heptanoic acid; racemic -7- (8-methyl-2,3-diphenyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -yl ) Heptanoic acid; racemic -7- (8-isopropyl-2,3-diphenyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -yl) Heptanoic acid; racemic -7- (8-cyclopropyl-2,3-diphenyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -yl) heptane Acid; 7- (8- Enantiomer 1 of propyl-2,3-diphenyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -yl) heptanoic acid 1; 7- (8 - cyclopropyl-2,3-diphenyl-7,8-dihydro-pyrido [2,3-b] pyrazin -5 (6H) - yl) heptanoic acid the enantiomer 2; racemic spin-7- (8- (dimethylamino) -2,3-diphenyl-7,8-dihydro-pyrido [2,3-b] pyrazin -5 (6H) - yl) heptanoic acid ; 7- (7,8-dihydroxy-2,3-diphenyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -yl) heptanoic acid Structure 1; 7- (7,8-dihydroxy-2,3-diphenyl-7,8-dihydropyrido [2,3-b] pyrazin-5 (6H) -yl) heptanoic acid Isomer 2; 7- (7,8-dihydroxy-2,3-di-p-tolyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -yl ) Isomer of heptanoic acid 1; 7- (7,8-dihydroxy-2,3-di-p-tolyl-7,8-dihydropyrido [2,3-b] pyrazine-5 ( 6H) -yl) Heptanoic acid isomer 2; (R) -7- (8-hydroxy-2,3-diphenyl-7,8-dihydropyrido [2,3-b] pyridine Pyrazin-5 (6H) -yl) heptanoic acid; (S) -7- (8-hydroxy-2,3-diphenyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -yl) heptanoic acid; racemic -7- (8-hydroxy-2,3-di-p-tolyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H ) -Yl) heptanoic acid; racemic-7- (8-methoxy-2,3- Phenyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -yl) heptanoic acid; 7- (8-methoxy-2,3-diphenyl-7, Enantiomer 1 of 8-dihydropyrido [2,3-b] pyrazine-5 (6H) -yl) heptanoic acid; 7- (8-methoxy-2,3-diphenyl- Enantiomer 2 of 7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -yl) heptanoic acid; racemic -7- (8-hydroxy-2,3- Diphenyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -yl) heptanoic acid; racemic -7- (8-hydroxy-2,3-bis (4 -(Trifluoromethyl) phenyl) -7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -yl) heptanoic acid; (E) -7- (2,3- Diphenyl-7,8-dihydropyrido [3,2-b] pyrazine-5 (6H) -yl) hept-3-enoic acid; 8- (2,3-di-p-tolyl-7, 8-dihydropyrido [2,3-b] pyrazine-5 (6H) -yl) octanoic acid; 2- (4- (2,3-diphenyl-7,8-dihydropyrido [2, 3-b] pyrazine-5 (6H) -yl) butoxy) acetic acid; 2- (3-((2,3-diphenyl-7,8-dihydropyrido [3,2-b] Pyrazine-5 (6H) -yl) methyl) phenoxy) acetic acid; 4- (2- (2,3-di-p-tolyl-7,8-dihydropyrido [2,3-b] pyridine Azine-5 (6H) -yl) ethylamino) -4-oxobutanoic acid; 7- (6-oxo-2,3-di-p-tolyl-7,8-dihydropyrido [ 2,3-b] pyrazine-5 (6H) -yl) heptanoic acid; 7- (2- (pyridin-4-yl) -3-p-methyl -7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -yl) heptanoic acid; 7- (3- (pyridin-4-yl) -2-p-tolyl-7 , 8-dihydropyrido [2,3-b] pyrazine-5 (6H) -yl) heptanoic acid; 7- (7-hydroxy-2,3-di-p-tolyl-7,8-dihydropyridine Enantiomer 1 of benzo [2,3-b] pyrazine-5 (6H) -yl) heptanoic acid; 7- (7-hydroxy-2,3-di-p-tolyl-7,8-dihydro Enantiomer 2 of pyrido [2,3-b] pyrazine-5 (6H) -yl) heptanoic acid; racemic -7- (2,3-di-p-tolyl-7,8-di Hydropyrido [2,3-b] pyrazine-5 (6H) -yl) -3,4-dihydroxyheptanoic acid; 7- (7-hydroxy-6- pendant oxygen-2,3-di-p-toluene -7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -yl) heptanoic acid; 7- (8-hydroxy-2,3-di-p-tolyl-7,8- Enantiomer 1 of dihydropyrido [2,3-b] pyrazine-5 (6H) -yl) heptanoic acid; 7- (8-hydroxy-2,3-di-p-tolyl-7,8 -Enantiomer 2 of dihydropyrido [2,3-b] pyrazine-5 (6H) -yl) heptanoic acid; 7- (7-methoxy-2,3-di-p-tolyl- Enantiomer 1 of 7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -yl) heptanoic acid; and 7- (7-methoxy-2,3-di Enantiomer 2 of p-tolyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -yl) heptanoic acid.

Example 41. The compound of Examples 1 to 38, which is represented by the following name: 7- (2,3-diphenyl-7,8-dihydropyrido [3,2-b] pyrazine-5 ( 6H) -yl) heptanoic acid; 7- (2,3-bis (4-fluorophenyl) -7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -yl) heptane Acid; 7- (2,3-di-p-tolyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -yl) heptanoic acid; 7- (2,3- Bis (4-methoxyphenyl) -7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -yl) heptanoic acid; 6- (2,3-diphenyl- 7,8-dihydropyrido [3,2-b] pyrazine-5 (6H) -yl) hexanoic acid; 5- (2,3-diphenyl-7,8-dihydropyrido [3, 2-b] pyrazine-5 (6H) -yl) pentanoic acid; 7- (6,7-diphenyl-3,4-dihydro-1,8-naphthyridin-1 (2H) -yl) heptane Acid; ethyl 7- (6,7-diphenyl-3,4-dihydro-1,8-naphthyridin-1 (2H) -yl) heptanoate; racemic -6- (1-methyl -6,7-diphenyl-1,2,3,4-tetrahydro-1,8-naphthyridin-2-yl) hexanoic acid; 7- (2-methyl-6,7-diphenyl- Enantiomer 1 of 3,4-dihydro-1,8-naphthyridin-1 (2H) -yl) heptanoic acid; 7- (1-methyl-6,7-diphenyl-1,2 Enantiomer 2 of 3,4-tetrahydro-1,8-naphthyridin-2-yl) heptanoic acid; 2- (3-((6,7-diphenyl-3,4-dihydro -1,8-naphthyridine-1 (2H) -yl) methyl) phenoxy) acetic acid; 2- (3-((6,7-diphenyl-3,4-dihydro-1,8- Naphthyridine-1 (2H) -yl) methyl) phenoxy) ethyl acetate; 7- (2-methyl-6,7-diphenyl-3,4-dihydro-1,8-naphthyridine Enantiomer 2 of -1 (2H) -yl) heptanoic acid; 6- (1-methyl-6,7-diphenyl-1,2,3,4-tetrahydro-1,8-naphthalene Enantiomer 1 of pyridin-2-yl) hexanoic acid; 6- (1-methyl-6,7-diphenyl-1,2,3,4-tetrahydro-1,8-naphthyridine- Enantiomer 2 of 2-yl) hexanoic acid; 6- (6,7-diphenyl-3,4-dihydro-1,8-naphthyridin-1 (2H) -yl) hexanoic acid; and Enantiomer 1 of 7- (1-methyl-6,7-diphenyl-1,2,3,4-tetrahydro-1,8-naphthyridin-2-yl) heptanoic acid.

Example 42. The compound of any one of Examples 1 to 41 or a pharmaceutically acceptable salt thereof, which is an agent for treating an individual's condition or disease by activating an IP receptor.

Embodiment 43. The use of a compound according to any one of Embodiments 1 to 41 or a pharmaceutically acceptable salt thereof for treating an individual's condition or disease by activating an IP receptor.

Embodiment 44. The use according to Embodiment 43, wherein the disease or condition is PAH, a condition requiring antiplatelet therapy, atherosclerosis, asthma, COPD, hyperglycemia, inflammatory disease, or fibrotic disease.

Embodiment 45. The use according to Embodiment 43, wherein the disease or disorder is PAH, atherosclerosis, asthma, COPD, hyperglycemia or fibrotic disease.

Embodiment 46. The use according to embodiment 43, wherein the disease or condition is PAH, asthma, COPD or cystic fibrosis.

Embodiment 47. The use according to embodiment 43, wherein the disease or disorder is PAH or COPD.

Embodiment 48. The use according to embodiment 43, wherein the disease or disorder is PAH or COPD.

Embodiment 49. The use according to Embodiment 43, wherein the disease or disorder is PAH.

Claims (7)

A compound represented by the following formula Ia Or a pharmaceutically acceptable salt thereof, wherein A is N; R ¹ is -XY, wherein -XY is-(CH ₂ ) _m -C (O) OR "; R ² is H; R ^2a is H; or R ² and R ^2a together are a side oxygen (oxo); R "is H; R ³ is H or OH; R ⁴ is H or OH; and m is 4, 5 or 6; R ⁵ is phenyl, as appropriate by the following groups: C ₁ -C ₄ alkoxy, halogen or optionally substituted by one or more of halogen atoms, C ₁ -C ₄ alkyl; and R ⁶ based phenyl which is optionally substituted with the following groups Substitution: C ₁ -C ₄ alkoxy, halogen or optionally C ₁ -C ₄ alkyl substituted with one or more halogen atoms. A compound as claimed in claim 1, which is selected from the group consisting of 7- (2-phenyl-3-p-tolyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H)- ) Heptanoic acid; 7- (8-hydroxy-2,3-di-p-tolyl-7,8-dihydropyrido [2,3-b] pyrazin-5 (6H) -yl) heptanoic acid; 7- (7-hydroxy-6- pendantoxy-2,3-di-p-tolyl-7,8-dihydropyrido [2,3-b] pyrazin-5 (6H) -yl) heptanoic acid; 7- (2,3-di-p-tolyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -yl) heptanoic acid; and 7- (3-phenyl-2 -A group consisting of p-tolyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -yl) heptanoic acid; or a pharmaceutically acceptable salt thereof. A pharmaceutical composition comprising: a therapeutically effective amount of a compound as claimed in claim 2 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers. A pharmaceutical combination comprising a therapeutically effective amount of a compound as claimed in claim 2 or a pharmaceutically acceptable salt thereof, and a second active agent. A compound as claimed in claim 2 or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for treating a condition or disease selected from the group consisting of pulmonary hypertension in an individual in need thereof. A compound as claimed in claim 2 or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament, wherein the medicament is used to treat a condition or disease affected by the activation of a prostacyclin receptor in an individual in need thereof. The use as claimed in claim 5 or 6, wherein the compound is of the formula 7- (2,3-di-p-tolyl-7,8-dihydropyrido [2,3-b] pyrazine-5 (6H) -yl) heptanoic acid, or a pharmaceutically acceptable one thereof salt.