Chromane and chromene derivatives and their use as CRAC modulators

The invention relates to compounds of Formula (I) and their pharmaceutically acceptable salts, wherein the substituents are as described herein, and their use in medicine for the treatment of diseases, disorders associated with the modulation of calcium release-activated calcium (CRAC) channel. The invention also relates to pharmaceutical compositions containing such compounds in treating diseases disorders associated with calcium release-activated calcium (CRAC) channel modulators.

RELATED APPLICATIONS

The present application is a National Stage Application of International Patent Application No. PCT/IB2014/062538, filed Jun. 23, 2014, which claims benefit of Indian Provisional Patent Application No. 2135/MUM/2013 filed on Jun. 24, 2013 and 3946/MUM/2013 filed on Dec. 17, 2013 and which applications are incorporated herein by reference. To the extent appropriate, a claim of priority is made to each of the above disclosed applications.

TECHNICAL FIELD OF THE INVENTION

The invention relates to substituted heterocyclic compounds, pharmaceutically acceptable salts thereof and pharmaceutical compositions for the treatment, management, and/or lessening of severity of diseases, disorders, syndromes or conditions associated with the modulation of calcium release-activated calcium (CRAC) channel. The invention also relates to methods of treating, managing and/or lessening the severity of the diseases disorders, syndromes or conditions associated with the modulation of CRAC. The invention also relates to processes for the preparation of the compounds of the invention.

BACKGROUND OF THE INVENTION

Inflammation is the response by the body to infection, irritation or injury; wherein the immune cells of the body are activated in response to any of these stimuli. Inflammation plays a key role in many diseases not only of the immune cells such as allergy, asthma, arthritis, dermatitis, multiple sclerosis, systemic lupus but also organ transplant, diabetes, cardiovascular disease, Alzheimer's disease, Parkinson's disease, inflammatory and/or irritable bowel syndrome (Di Sabatino et. al., J. Immunol., 183, 3454-3462, 2009), psoriasis, and cancer. An initial inflammatory response to pathogens or injury is necessary and required to fight infection or heal the wound, but sustained or persistent inflammation can lead to any of the chronic disorders; characterized by the production of inflammatory cytokines as, specified above.

Inflammation is characterized by the production of different cytokines such as IL-2, IL-4, IL-10, IL-13, IL-17, IL-21, IL-23, IL-28, IFN-γ, TNF-α, etc., that have been implicated in playing a role in different diseases. Any drug which can modulate the production of these cytokines would help to alleviate the disease symptoms and may also cure it.

Ca+2signals have been shown to be essential for diverse cellular functions in different cell types including differentiation, effector functions, and gene transcription in cells of the immune system as well as regulating the cytokine signaling pathway through calcineurin and nuclear factor of activated T cells (NFAT).

In immune cells, sustained Ca+2influx has been shown to be necessary for complete and long-lasting activation of calcineurin-NFAT pathways, essential for cytokine production. Engagement of receptors such as T-cell antigen receptor (TCR), the B-cell antigen receptor (BCR), and the Fc receptors (FcR) on mast cells, macrophages, and NK cells, leads to the tyrosine phosphorylation and activation of phospholipase C-γ (PLC-γ). PLC-γ hydrolyzes phosphatidylinositol-3,4-biphosphate (PIP2) to the second messengers, inositol-1,4,5-triphosphate (IP3) and diacylglycerol (DAG). IP3binds to IP3receptors (IP3R) in the membrane of the endoplasmic reticulum (ER) and induces the release of ER Ca+2stores into the cytoplasma. The decrease in the Ca+2concentration in the ER induces store-operated Ca+2entry (SOCE) through plasma membrane Ca+2channels. SOCE through highly Ca+2-selective Ca+2release-activated Ca+2(hereinafter, CRAC) channels constitutes the major pathway of intracellular Ca+2entry in T cells, B cells, macrophages, mast cells, and other cell types (Parekh and Putney, Physiol. Rev., 85, 757-810, 2005).

The CRAC channel is comprised of two family proteins, one which functions in sensing Ca+2levels in the ER—the stromal interacting molecules (STIM)-1 and -2 and the other which is a pore-forming protein—Orai1, 2 and 3. The STIM proteins are single transmembrane proteins localized on the ER membrane with their N-termini oriented toward the lumen and containing an EF-hand Ca+2binding motif. Depletion of Ca+2from the ER causes Ca+2to dissociate from STIM, which causes a conformational change that promotes oligomerization and migration of STIM molecules to closely apposed ER-plasma membrane junctions. At the junctions, the STIM oligomers interact with the Orai proteins. In resting cells, Orai channels are dispersed across the plasma membrane and on depletion of Ca+2from the stores, they aggregate in the vicinity of the STIM punctae. The eventual increase in intracellular Ca+2concentration activates the calcineurin-NFAT pathway. NFAT activates transcription of several genes including cytokine genes such as IL-2, etc along with other transcription factors such as AP-1, NFκB and Foxp3 (Fahmer et. al., Immuno. Rev., 231, 99-112, 2009).

The role of CRAC channel in different diseases such as allergy, inflammatory bowel disease, thrombosis and breast cancer has been reported in literature (Parekh, Nat. Rev., 9, 399-410, 2010). It has been reported in the art that STIM1 and Orai1 are essential in in vitro tumor cell migration and in vivo tumor metastasis. Thus the involvement of store operated Ca2+entry in tumor metastasis renders STIM1 and Orai1 proteins potential targets for cancer therapy (Yang et. al., Cancer Cell, 15, 124-134, 2009). Additional literature available on the involvement of CRAC channel in cancer are Abeele et. al., Cancer Cell, 1, 169-179, 2002, Motiani et al., J. Biol. Chem., 285; 25, 19173-19183, 2010.

Recent literature reports the role of STIM1 and Orai1 in collagen dependent arterial thrombosis in mice in vivo and that deficiency in either protects against collagen dependent arterial thrombus formation as well as brain infarction (Varga-Szabo et. al., J. Exp. Med., 205, 1583-1591, 2008; Braun et. al., Blood, 113, 2056-2063, 2009). The role of STIM1-Orai1 mediated SOCE in thrombus formation makes Orai1 a potential target for treatment of thrombosis and related conditions (Gillo et. al., JBC, 285; 31, 23629-23638, 2010).

As the Orai pore channel proteins have been shown to be essential for transmitting the signal induced by the binding of antigens to the cellular receptors on the immune cells, a potential Orai channel interacting drug would be able to modulate the signaling thereby impacting the secretion of the cytokines involved in, as mentioned herein before, inflammatory conditions, cancer, allergic disorders, immune disorders, rheumatoid arthritis, cardiovascular diseases, thrombocytopathies, arterial and/or venous thrombosis and associated or related conditions which can be benefitted by the CRAC channel modulatory properties of the compounds described herein.

SUMMARY OF THE INVENTION

In accordance with one aspect, the invention provides the compounds having the structure of Formula (I):

A and B are independently CR3or N;

ring R is selected from Formula (i) to (iii):

L is selected from —NR8C(O)—, —C(O)NR8— and —NR8CH2—;

X is CR or N where R is selected from hydrogen, halogen or substituted or unsubstituted alkyl;

R1, which may be same or different at each occurrence, is independently selected from halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkoxy and substituted or unsubstituted haloalkoxy;

R2, which may be same or different at each occurrence, is independently selected from halogen, cyano, nitro, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, —NR9R10and substituted or unsubstituted cycloalkyl, —COOR8and CONR9R10;

each of R3is independently selected from hydrogen, halogen and substituted or unsubstituted alkyl;

R4and R5, which may be same or different and are independently selected from hydrogen, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl and —NR9R10; or

R4and R5together with the carbon atom to which they are attached form oxo (C═O);

one of R6and R7is substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkoxyalkyland the other is selected from hydrogen, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkoxyalkyl, —NR9R10, substituted or unsubstituted cycloalkyl, —COOR8and —COR9R10; or R6and R7together with the carbon atom to which they are attached may form substituted or unsubstituted 3 to 7 membered carbocyclic ring or 4 to 7 membered heterocyclic ring;

R8is hydrogen or substituted or unsubstituted alkyl;

R9and R10, which may be same or different, are independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, and substituted or unsubstituted cycloalkyl; or R9and R10, together with the nitrogen atom to which they are attached, may form a substituted or unsubstituted, saturated or unsaturated 5 to 7 membered cyclic ring, wherein the unsaturated cyclic ring may have one or two double bonds;

Raand Rb, which may be same or different and are independently selected from hydrogen, cyano, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, substituted or unsubstituted cycloalkyl, —NR9R10, —COOR8and —CONH2;

‘n’ is an integer ranging from 1 to 3, both inclusive; and

‘p’ is an integer ranging from 0 to 2, both inclusive;

or a pharmaceutically acceptable salt thereof.

According to one embodiment, there are provided compounds having the structure of Formula (II):

A and B are independently CR3or N;

L is selected from —NHC(O)—, —C(O)NH— and —NHCH2—;

X is CH or N;

R1, which may be same or different at each occurrence, is independently selected from halogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkoxy and substituted or unsubstituted haloalkoxy;

R2is selected from halogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted haloalkyl and substituted or unsubstituted alkoxy;

R3is selected from hydrogen, halogen and substituted or unsubstituted alkyl;

R4and R5, which may be same or different and are independently selected from hydrogen, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy and —NR9R10; or R4and R5together with the carbon atom to which they are attached form oxo (C═O);

one of R6and R7is substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted hydroxyalkyl and the other is selected from hydrogen, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkoxyalkyl, —NR9R10, substituted or unsubstituted cycloalkyl, —COOR8, and CONH2; or R6and R7together with the carbon atom to which they are attached may form substituted or unsubstituted 3 to 6 membered carbocyclic ring or 4 to 7 membered heterocyclic ring;

R8is hydrogen or substituted or unsubstituted alkyl;

R9and R10are independently hydrogen or substituted or unsubstituted alkyl;

Raand Rbare independently hydrogen or substituted or unsubstituted alkyl;

‘n’ is an integer ranging from 1 to 2, both inclusive; and

‘p’ is an integer ranging from 0 to 1, both inclusive;

or a pharmaceutically acceptable salt thereof.

According to another embodiment, there are provided compounds having the structure of Formula (III):

A and B are independently CR3or N;

L is —NHC(O)— or —C(O)NH—;

X is CH or N;

R1, which may be same or different at each occurrence, is independently selected from halogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkoxy and substituted or unsubstituted haloalkoxy;

R2is selected from halogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted haloalkyl and substituted or unsubstituted alkoxy;

R3is selected from hydrogen, halogen and substituted or unsubstituted alkyl;

one of R6and R7is substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted hydroxyalkyl and the other is selected from hydrogen, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkoxyalkyl, —NR9R10, substituted or unsubstituted cycloalkyl, —COOR8, and —CONH2; or R6and R7together with the carbon atom to which they are attached may form substituted or unsubstituted 3 to 6 membered carbocyclic ring;

R8is hydrogen or substituted or unsubstituted alkyl;

R9and R10are independently hydrogen or substituted or unsubstituted alkyl;

Rais hydrogen or substituted or unsubstituted alkyl;

‘n’ is an integer ranging from 1 to 2, both inclusive; and

‘p’ is an integer ranging from 0 to 1, both inclusive;

or a pharmaceutically acceptable salt thereof.

According to another embodiment, there are provided compounds having the structure of Formula (IV):

A and B are independently CR3or N;

L is —NHC(O)— or —C(O)NH—;

X is CH or N;

R1, which may be same or different at each occurrence, is independently selected from halogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkoxy and substituted or unsubstituted haloalkoxy;

R2is selected from halogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted haloalkyl and substituted or unsubstituted alkoxy;

R3is selected from hydrogen, halogen and substituted or unsubstituted alkyl;

one of R6and R7is substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted hydroxyalkyl and the other is selected from hydrogen, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkoxyalkyl, —NR9R10, substituted or unsubstituted cycloalkyl, —COOR8, and —CONH2; or R6and R7together with the carbon atom to which they are attached may form substituted or unsubstituted 3 to 6 membered carbocyclic ring;

R8is hydrogen or substituted or unsubstituted alkyl;

R9and R10are independently hydrogen or substituted or unsubstituted alkyl;

Raand Rbare independently hydrogen or substituted or unsubstituted alkyl;

‘n’ is an integer ranging from 1 to 2, both inclusive; and

‘p’ is an integer ranging from 0 to 1, both inclusive;

or a pharmaceutically acceptable salt thereof.

It should be understood that the Formula (I), Formula (II), Formula (III) and/or Formula (IV), structurally encompasses all tautomers, stereoisomers, enantiomers and diastereomers, including isotopes wherever applicable and pharmaceutically acceptable salts that may be contemplated from the chemical structure of the genera described herein.
The details of one or more embodiments of the invention set forth in the below are illustrative in nature only and not intended to limit to the scope of the invention. Other features, objects and advantages of the inventions will be apparent from the description and claims.

According to another embodiment there are provided compounds of Formula (I) wherein

L is selected from —NHC(O)—, —C(O)NH— and —NHCH2—.

According to another embodiment there are provided compounds of Formula (I) wherein

X is N or CH.

According to another embodiment there are provided compounds of Formula (I) wherein A and B may be same or different and are independently CR3or N wherein R3is hydrogen, halogen or substituted or unsubstituted alkyl.

According to another embodiment there are provided compounds of Formula (I) wherein each of R1may be same or different and are independently selected from hydrogen, halogen, and substituted or unsubstituted alkyl; and ‘n’ is 1 or 2.

According to another embodiment there are provided compounds of Formula (I) wherein ring R is Formula (i)

wherein R2is halogen or substituted or unsubstituted alkyl; ‘p’ is 0 to 1; R4and R5may be same or different and are independently selected from hydrogen, hydroxyl, substituted or unsubstituted alkyl and —NR9R10or R4and R5together with the carbon atom to which they are attached form oxo (C═O); one of R6and R7is substituted or unsubstituted alkyl, substituted or unsubstituted hydroxyalkyl and the other is selected from hydrogen, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted alkoxyalkyl, substituted or unsubstituted cycloalkyl, —NR9R10, —COOH, —COO— alkyl, and CONH2; or R6and R7together form substituted or unsubstituted 3 to 6 membered carbocyclic ring or 4 to 7 membered heterocyclic ring; R9and R10are selected from hydrogen or substituted or unsubstituted alkyl; and Raand Rbare hydrogen.

According to another embodiment there are provided compounds of Formula (I) wherein ring R is Formula (ii) or Formula (iii)

wherein R2is halogen or substituted or unsubstituted alkyl; ‘p’ is 0 to 1; one of R6and R7is substituted or unsubstituted alkyl, substituted or unsubstituted hydroxyalkyl and the other is selected from hydrogen, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted alkoxyalkyl, substituted or unsubstituted cycloalkyl, —NR9R10, —COOH, —COO-alkyl, and CONH2; or R6and R7together form substituted or unsubstituted 3 to 6 membered carbocyclic ring; R9and R10are hydrogen or substituted or unsubstituted alkyl; and Raand Rbare hydrogen.

According to another embodiment there are provided compounds of Formula (I) wherein R6and R7together with carbon atom to which they are attached to form a ring is selected from

According to another embodiment there are provided compounds of Formula (I)

wherein L is selected from —NHC(O)—, —C(O)NH— and —NHCH2—; X is CH or N; A and B are independently CR3or N; R1is halogen, substituted or unsubstituted alkyl or substituted or unsubstituted haloalkyl; ‘n’ is 1 or 2; R3is hydrogen or substituted or unsubstituted alkyl; and ring R is Formula (i)

wherein R2is halogen or substituted or unsubstituted alkyl; ‘p’ is 0 or 1; R4and R5, which may be same or different and are independently selected from hydrogen, hydroxyl, —NR9R10where R9and R10are hydrogen or substituted or unsubstituted alkyl, or R4and R5together form oxo (C═O); one of R6and R7is substituted or unsubstituted alkyl or substituted or unsubstituted hydroxyalkyl and the other is selected from hydrogen, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted alkoxyalkyl, —C(O)OH, —C(O)Oalkyl, and —CONH2, or R6and R7together with the carbon atom to which they are attached may form substituted or unsubstituted 3 to 4 membered carbocyclic ring or 4 to 7 membered heterocyclic ring; and Raand Rbare hydrogen.

According to another embodiment there are provided compounds of Formula (I)

wherein L is —NHC(O)—, —C(O)NH—; X is CH or N; A and B are independently CR3or N; R1is halogen, substituted or unsubstituted alkyl or substituted or unsubstituted haloalkyl; ‘n’ is 1 or 2; R3is hydrogen or substituted or unsubstituted alkyl; and ring R is Formula (ii) or Formula (iii)

R2is halogen or substituted or unsubstituted alkyl; ‘p’ is 0 or 1; one of R6and R7is substituted or unsubstituted alkyl or substituted or unsubstituted hydroxyalkyl and the other is selected from hydrogen, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted alkoxyalkyl, —C(O)OH, —C(O)Oalkyl, —CONH2, or R6and R7together with the carbon atom to which they are attached may form substituted or unsubstituted 3 to 4 membered carbocyclic ring; and Raand Rb, are hydrogen.

In another aspect, the invention provides a pharmaceutical composition comprising at least one compound of Formula (I) and at least one pharmaceutically acceptable excipient.

In another aspect of the invention, there is provided a compound of Formula (I) useful in treating, managing and/or lessening the severity of the diseases, disorders, syndromes or conditions associated with the modulation of CRAC channel.

In another aspect, the invention provides a pharmaceutical composition of a compound of Formula (I) useful in treating, managing and/or lessening the severity of the diseases disorders, syndromes or conditions associated with the modulation of CRAC channel in a subject in need thereof by administering to the subject, one or more compounds described herein in therapeutic effective amount.

In another aspect, the invention provides a method of modulating ion channel activity, for Example, CRAC channel, by administering effective amount of a compound of Formula (I) and/or pharmaceutically acceptable salts.

In another aspect, the invention provides a method of modulating the secretion of cytokines, for Example IL-2, IL-4, IL-10, IL-13, IL-17, IL-21, IL-23, IL-28, IFN-γ and TNF-α and the like, by regulating the cytokine signaling pathway through calcineurin and NFAT cells.

In another aspect, there are provided processes for the preparation of compounds of Formula (II):

where A, B, L, X, R1, R2, R3, R4, R5, R6, R7, Ra, Rb‘n’ and ‘p’ are as described herein above; the process comprising any of the process (A) to (C):process (A):reacting compound of Formula (1) where X′ is halogen, with compound of Formula (2) where P is pinacolatoboronate to give compound of Formula (II) by using suitable reagents Pd(PPh3)2O2, Pd2dba3, Pd(PPh3)4, or Pd(OAc)2and a suitable ligand 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP), xanthophos, or triphenylphosphine

process(B)reacting a compound of Formula (3) where P is pinacolatoboronate, with compound of Formula (4) where X′ is halogen, to give compound of Formula (II) by using suitable reagents Pd(PPh3)2Cl2, Pd2dba3, Pd(PPh3)4, or Pd(OAc)2and a suitable ligand 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP), xanthophos, or triphenylphosphine,

process (C), which comprising the step-a and step-b:a) reacting halo compound of the Formula (1) where X′ is halogen with borate compound of the Formula (5) where L′ is NHR8; or COOH, COO-alkyl or COCl to give compound of Formula (6)

b) coupling of compound of Formula (6) with Formula (7) where L″ is COOH, COOalkyl, COCl; or NHR8to give compound of Formula (II) using suitable coupling agent.

In another aspect, there are provided processes for the preparation compounds of Formula (III) and (IV);

A, B, L, X, R1, R2, R3, R4, R5, R6, R7, Ra, Rb‘n’ and ‘p’ are as described herein above; the process comprising the steps:a) reacting of compound of Formula (8) with compound of Formula (2) where P is pinacolatoboronate to give compound of Formula (III) by using suitable reagents

orreacting compound of Formula (9) where P is pinacolatoboronate with compound of Formula (4) where X′ is halogen to give compound of Formula (III) by using suitable reagents

b) reducing a compound of Formula (III) to compound of Formula (IV) using catalyst such as Pd—C, Ra—Ni, Pt—C.

DETAILED DESCRIPTION OF THE INVENTION

Definitions and Abbreviations:

For purposes of interpreting the specification, the following definitions will apply and whenever appropriate, terms used in the singular will also include the plural and vice versa.

Unless otherwise stated, in the present application “oxo” means C(═O) group. Such an oxo group may be a part of either a cycle or a chain in the compounds of the invention.

The term “alkyl” refers to an alkane derived hydrocarbon radical that includes solely carbon and hydrogen atoms in the backbone, contains no unsaturation, has from one to six carbon atoms, and is attached to the remainder of the molecule by a single bond, e.g., methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl) and the like. Unless set forth or recited to the contrary, all alkyl groups described or claimed herein may be straight chain or branched, substituted or unsubstituted.

The term “alkenyl” refers to a hydrocarbon radical containing from 2 to 10 carbon atoms and including at least one carbon-carbon double bond. Non-limiting Examples of alkenyl groups include ethenyl, 1-propenyl, 2-propenyl (allyl), iso-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl and the like. Unless set forth or recited to the contrary, all alkenyl groups described or claimed herein may be straight chain or branched, substituted or unsubstituted.

The term “alkynyl” refers to a hydrocarbon radical containing 2 to 10 carbon atoms and including at least one carbon-carbon triple bond. Non-limiting Examples of alkynyl groups include ethynyl, propynyl, butynyl and the like. Unless set forth or recited to the contrary, all alkynyl groups described or claimed herein may be straight chain or branched, substituted or unsubstituted.

The term “alkoxy” refers to an alkyl group attached via an oxygen linkage. Non-limiting Examples of such groups are methoxy, ethoxy and propoxy and the like. Unless set forth or recited to the contrary, all alkoxy groups described or claimed herein may be straight chain or branched, substituted or unsubstituted.

The term “alkoxyalkyl” refers to an alkoxy group as defined above directly bonded to an alkyl group as defined above, e.g., —CH2—O—CH3, —CH2—O—CH2CH3, —CH2CH2—O—CH3and the like. Unless set forth or recited to the contrary, all alkoxyalkyl groups described or claimed herein may be substituted or unsubstituted.

The term “cycloalkyl” refers to a non-aromatic mono or multicyclic ring system having 3 to 12 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. Examples of multicyclic cycloalkyl groups include, but are not limited to, perhydronapththyl, adamantyl and norbornyl groups, bridged cyclic groups or spirobicyclic groups, e.g., spiro(4,4)non-2-yl and the like. Unless set forth or recited to the contrary, all cycloalkyl groups described or claimed herein may be substituted or unsubstituted.

The term “cycloalkenyl” refers to a non-aromatic mono or multicyclic ring system having 3 to 12 carbon atoms and including at least one carbon-carbon double bond, such as cyclopentenyl, cyclohexenyl, cycloheptenyl and the like. Unless set forth or recited to the contrary, all cycloalkenyl groups described or claimed herein may be substituted or unsubstituted.

The term “cycloalkylalkyl” refers to a cycloalkyl group as defined above, directly bonded to an alkyl group as defined above, e.g., cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclohexylethyl, etc. Unless set forth or recited to the contrary, all cycloalkylalkyl groups described or claimed herein may be substituted or unsubstituted.

The term “haloalkyl” refers to an alkyl group as defined above that is substituted by one or more halogen atoms as defined above. Preferably, the haloalkyl may be monohaloalkyl, dihaloalkyl or polyhaloalkyl including perhaloalkyl. A monohaloalkyl can have one iodine, bromine, chlorine or fluorine atom. Dihaloalkyl and polyhaloalkyl groups can be substituted with two or more of the same halogen atoms or a combination of different halogen atoms. Preferably, a polyhaloalkyl is substituted with up to 12 halogen atoms. Non-limiting Examples of a haloalkyl include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl and the like. A perhaloalkyl refers to an alkyl having all hydrogen atoms replaced with halogen atoms.

The term “haloalkoxy” refers to an haloalkyl, defined herein, group attached via an oxygen linkage. Non-limiting Examples of such groups are monohaloalkoxy, dihaloalkoxy or polyhaloalkoxy including perhaloalkoxy. Unless set forth or recited to the contrary, all haloalkoxy groups described or claimed herein may be straight chain or branched, substituted or unsubstituted.

The term “hydroxyalkyl” refers to an alkyl group, as defined above that is substituted by one or more hydroxy groups. Preferably, the hydroxyalkyl is monohydroxyalkyl or dihydroxyalkyl. Non-limiting Examples of a hydroxyalkyl include 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, and the like.

The term “aryl” refers to an aromatic radical having 6- to 14-carbon atoms, including monocyclic, bicyclic and tricyclic aromatic systems, such as phenyl, naphthyl, tetrahydronaphthyl, indanyl, and biphenyl and the like. Unless set forth or recited to the contrary, all aryl groups described or claimed herein may be substituted or unsubstituted.

The term “arylalkyl” refers to an aryl group as defined above directly bonded to an alkyl group as defined above, e.g., —CH2C6H5and —C2H4C6H5. Unless set forth or recited to the contrary, all arylalkyl groups described or claimed herein may be substituted or unsubstituted.

A “5-7 membered cyclic ring” as used herein refers to a monocyclic, bicyclic heterocyclic ring system. This heterocyclic ring is as described herein.

A “carbocyclic ring” or “carbocycle” as used herein refers to a 3- to 7 membered saturated or partially unsaturated, monocyclic fused bicyclic, spirocyclic ring containing carbon atoms, which may optionally be substituted, for Example, carbocyclic rings include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylene, cyclohexanone, etc.

The term “heterocyclic ring” or “heterocyclyl ring” or “heterocyclyl”, unless otherwise specified, refers to substituted or unsubstituted non-aromatic 3- to 15-membered ring which consists of carbon atoms and with one or more heteroatom(s) independently selected from N, O or S. The heterocyclic ring may be a mono-, bi- or tricyclic ring system, which may include fused, bridged or spiro ring systems and the nitrogen, carbon, oxygen or sulfur atoms in the heterocyclic ring may be optionally oxidized to various oxidation states. In addition, the nitrogen atom may be optionally quaternized, the heterocyclic ring or heterocyclyl may optionally contain one or more olefinic bond(s), and one or two carbon atoms(s) in the heterocyclic ring or heterocyclyl may be interrupted with —CF2—, —C(O)—, —S(O)—, S(O)2, —C(═N-alkyl)-, or —C(═N-cycloalkyl), etc. In addition heterocyclic ring may also be fused with aromatic ring. Non-limiting Examples of heterocyclic rings include azetidinyl, benzopyranyl, chromanyl, decahydroisoquinolyl, indanyl, indolinyl, isoindolinyl, isochromanyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, oxazolinyl, oxazolidinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, octahydroindolyl, octahydroisoindolyl, perhydroazepinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, piperidinyl, phenothiazinyl, phenoxazinyl, quinuclidinyl, tetrahydroisquinolyl, tetrahydrofuryl, tetrahydropyranyl, thiazolinyl, thiazolidinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone indoline, benzodioxole, tetrahydroquinoline, tetrahydrobenzopyran and the like. The heterocyclic ring may be attached by any atom of the heterocyclic ring that results in the creation of a stable structure. Unless set forth or recited to the contrary, all heterocyclyl groups described or claimed herein may be substituted or unsubstituted; substituents may be on same or different ring atom.

The term “heteroaryl” unless otherwise specified, refers to a substituted or unsubstituted 5- to 14-membered aromatic heterocyclic ring with one or more heteroatom(s) independently selected from N, O or S. The heteroaryl may be a mono-, bi- or tricyclic ring system. The heteroaryl ring may be attached by any atom of the heteroaryl ring that results in the creation of a stable structure. Non-limiting Examples of a heteroaryl ring include oxazolyl, isoxazolyl, imidazolyl, furyl, indolyl, isoindolyl, pyrrolyl, triazolyl, triazinyl, tetrazolyl, thienyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzofuranyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzothienyl, carbazolyl, quinolinyl, isoquinolinyl, quinazolinyl, cinnolinyl, naphthyridinyl, pteridinyl, purinyl, quinoxalinyl, quinolyl, isoquinolyl, thiadiazolyl, indolizinyl, acridinyl, phenazinyl, phthalazinyl and the like. Unless set forth or recited to the contrary, all heteroaryl groups described or claimed herein may be substituted or unsubstituted.

The term “heterocyclylalkyl” refers to a heterocyclic ring radical directly bonded to an alkyl group. The heterocyclylalkyl radical may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure. Unless set forth or recited to the contrary, all heterocyclylalkyl groups described or claimed herein may be substituted or unsubstituted.

The term “heteroarylalkyl” refers to a heteroaryl ring radical directly bonded to an alkyl group. The heteroarylalkyl radical may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure. Unless set forth or recited to the contrary, all heteroarylalkyl groups described or claimed herein may be substituted or unsubstituted.

The term “stereoisomer” refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures which are not interchangeable. The three-dimensional structures are called configurations. As used herein, the term “enantiomer” refers to two stereoisomers whose molecules are nonsuperimposable mirror images of one another. The term “chiral center” refers to a carbon atom to which four different groups are attached. As used herein, the term “diastereomers” refers to stereoisomers which are not enantiomers. The terms “racemate” or “racemic mixture” refer to a mixture of equal parts of enantiomers.

A “tautomer” refers to a compound that undergoes rapid proton shifts from one atom of the compound to another atom of the compound. Some of the compounds described herein may exist as tautomers with different points of attachment of hydrogen. The individual tautomers as well as mixture thereof are encompassed with compounds of Formula (I).

The term “treating” or “treatment” of a state, disease, disorder, condition or syndrome includes: (a) delaying the appearance of clinical symptoms of the state, disease, disorder, condition or syndrome developing in a subject that may be afflicted with or predisposed to the state, disease, disorder, condition or syndrome but does not yet experience or display clinical or subclinical symptoms of the state, disease, disorder, condition or syndrome; (b) inhibiting the state, disease, disorder, condition or syndrome, i.e., arresting or reducing the development of the disease or at least one clinical or subclinical symptom thereof; c) lessening the severity of a disease disorder or condition or at least one of its clinical or subclinical symptoms thereof; and/or (d) relieving the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms.

The term “modulate” or “modulating” or “modulation” refers to a decrease or inhibition in the amount, quality, or effect of a particular activity, function or molecule; by way of illustration that block or inhibit calcium release-activated calcium (CRAC) channel. Any such modulation, whether it be partial or complete inhibition is sometimes referred to herein as “blocking” and corresponding compounds as “blockers”. For Example, the compounds of the invention are useful as modulators of the CRAC channel.

The term “subject” includes mammals, preferably humans and other animals, such as domestic animals; e.g., household pets including cats and dogs.

A “therapeutically effective amount” means the amount of a compound that, when administered to a subject for treating a disease, disorder, syndrome or condition, is sufficient to cause the effect in the subject which is the purpose of the administration. The “therapeutically effective amount” will vary depending on the compound, the disease and its severity and the age, weight, physical condition and responsiveness of the subject to be treated.

Unless otherwise stated, in the present application “protecting group” refers to the groups intended to protect an otherwise labile group, e.g., an amino group, a carboxy group and the like, under specific reaction conditions. Various protecting groups along with the methods of protection and deprotection are generally known to a person of ordinary skilled in the art. Incorporated herein in this regard as reference isGreene's Protective Groups in Organic Synthesis,4th Edition, John Wiley & Sons, New York. In the invention, preferred amino protecting groups are t-butoxycarbonyl, benzyloxycarbonyl, acetyl and the like; while preferred carboxy protecting groups are esters, amides and the like.

The compounds of the invention may form salts with acid or base. The compounds of invention may be sufficiently basic or acidic to form stable nontoxic acid or base salts, administration of the compound as a pharmaceutically acceptable salt may be appropriate. Non-limiting Examples of pharmaceutically acceptable salts are inorganic, organic acid addition salts formed by addition of acids including hydrochloride salts. Non-limiting Examples of pharmaceutically acceptable salts are inorganic, organic base addition salts formed by addition of bases. The compounds of the invention may also form salts with amino acids. Pharmaceutically acceptable salts may be obtained using standard procedures well known in the art, for Example by reacting a sufficiently basic compound such as an amine with a suitable acid affording a physiologically acceptable anion.

With respect to the overall compounds described by the Formula (I), the invention extends to these stereoisomeric forms and to mixtures thereof. To the extent prior art teaches synthesis or separation of particular stereoisomers, the different stereoisomeric forms of the invention may be separated from one another by a method known in the art, or a given isomer may be obtained by stereospecific or asymmetric synthesis or chiral HPLC (high performance liquid chromatography). Tautomeric forms and mixtures of compounds described herein are also contemplated.

Pharmaceutical Compositions

The invention relates to pharmaceutical compositions containing the compound of Formula (I). In particular, the pharmaceutical compositions contain a therapeutically effective amount of at least one compound of Formula (I) and at least one pharmaceutically acceptable excipient (such as a carrier or diluent). Preferably, the pharmaceutical compositions include the compound(s) described herein in an amount sufficient to modulate the calcium release-activated calcium (CRAC) channel to treat CRAC channel mediated diseases such as inflammatory diseases, autoimmune diseases, allergic disorders, organ transplant, cancer and cardiovascular disorders when administered to a subject.

The compound of the invention may be incorporated with a pharmaceutically acceptable excipient (such as a carrier or a diluent) or be diluted by a carrier, or enclosed within a carrier which can be in the form of a capsule, sachet, paper or other container. The pharmaceutically acceptable excipient includes a pharmaceutical agent that does not itself induce the production of antibodies harmful to the individual receiving the composition, and which may be administered without undue toxicity.

The pharmaceutical composition may also include one or more pharmaceutically acceptable auxiliary agents, wetting agents, emulsifying agents, suspending agents, preserving agents, salts for influencing osmotic pressure, buffers, sweetening agents, flavoring agents, colorants, or any combination of the foregoing. The pharmaceutical composition of the invention may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the subject by employing procedures known in the art.

The pharmaceutical compositions described herein may be prepared by conventional techniques known in the art. For Example, the active compound can be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier, which may be in the form of an ampoule, capsule, sachet, paper, or other container. When the carrier serves as a diluent, it may be a solid, semi-solid, or liquid material that acts as a vehicle, excipient, or medium for the active compound. The active compound can be adsorbed on a granular solid container, for Example, in a sachet.

The pharmaceutical compositions may be administered in conventional forms, for Example, capsules, tablets, aerosols, solutions, suspensions or products for topical application.

The route of administration may be any route which effectively transports the active compound of the invention to the appropriate or desired site of action. Suitable routes of administration include, but are not limited to, oral, nasal, pulmonary, buccal, subdermal, intradermal, transdermal, parenteral, rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic (such as with an ophthalmic solution) or topical (such as with a topical ointment).

Solid oral Formulations include, but are not limited to, tablets, caplets, capsules (soft or hard gelatin), orally disintegrating tablets, dragees (containing the active ingredient in powder or pellet form), troches and lozenges. Tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like are particularly suitable for oral application. Liquid Formulations include, but are not limited to, syrups, emulsions, suspensions, solutions, soft gelatin and sterile injectable liquids, such as aqueous or non-aqueous liquid suspensions or solutions. For parenteral application, particularly suitable are injectable solutions or suspensions, preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil.

For administration to human patients, the total daily dose of the compounds of the invention depends, of course, on the mode of administration. For Example, oral administration may require a higher total daily dose, than an intravenous (direct into blood). The quantity of active component in a unit dose preparation may be varied or adjusted from 0.1 mg to 10000 mg, more typically 1.0 mg to 1000 mg, and most typically 10 mg to 500 mg, according to the potency of the active component or mode of administration.

Suitable doses of the compounds for use in treating the diseases disorders, syndromes and conditions described herein can be determined by those skilled in the relevant art. Therapeutic doses are generally identified through a dose ranging study in humans based on preliminary evidence derived from the animal studies. Doses must be sufficient to result in a desired therapeutic benefit without causing unwanted side effects for the patient. For Example, the daily dosage of the CRAC channel modulator can range from about 0.1 to about 30.0 mg/kg. Mode of administration, dosage forms, suitable pharmaceutical excipients, diluents or carriers can also be well used and adjusted by those skilled in the art. All changes and modifications are envisioned within the scope of the invention.

Method of Treatment

In a further embodiment, the invention is directed to the treatment or prophylaxis of inflammatory conditions by administering an effective amount of a compound of the invention.

Inflammation is part of the normal host response to infection and injury or exposure to certain substances prone to cause it. Inflammation begins with the immunologic process of elimination of invading pathogens and toxins to repair damaged tissue. Hence, these responses are extremely ordered and controlled. However, excessive or inappropriate inflammation contributes to a range of acute and chronic human diseases and is characterized by the production of inflammatory cytokines, arachidonic acid-derived eicosanoids (prostaglandins, thromboxanes, leukotrienes, and other oxidized derivatives), other inflammatory agents (e.g., reactive oxygen species), and adhesion molecules. As used herein, the term “inflammatory conditions” is defined as a disease or disorder or abnormality characterized by involvement of inflammatory pathways leading to inflammation, and which may result from, or be triggered by, a dysregulation of the normal immune response.

The inflammatory bowel diseases also include Crohn's disease, ulcerative colitis, indeterminate colitis, necrotizing enterocolitis, and infectious colitis.

“Allergic disorders” are defined as disorders/diseases that are caused by a combination of genetic and environmental factors resulting in a hypersensitivity disorder of the immune system. Allergic diseases are characterized by excessive immunoglobulin E (IgE) production, mast cell degranulation, tissue eosinophilia and mucus hypersecretion, resulting in an extreme inflammatory response. These responses also take place during infection with multicellular parasites, and are linked to the production of a characteristic set of cytokines by T helper (Th) 2 cells. For Example asthma is a chronic inflammatory condition of the lungs, characterized by excessive responsiveness of the lungs to stimuli, in the form of infections, allergens, and environmental irritants. Allergic reactions can also result from food, insect stings, and reactions to medications like aspirin and antibiotics such as penicillin. Symptoms of food allergy include abdominal pain, bloating, vomiting, diarrhea, itchy skin, and swelling of the skin during hives. Food allergies rarely cause respiratory (asthmatic) reactions, or rhinitis. Insect stings, antibiotics, and certain medicines produce a systemic allergic response that is also called anaphylaxis. The main therapeutic interest around CRAC in allergic disorders, originates from its role in lymphocytes and mast cells, CRAC activation being a requirement for lymphocyte activation.

The compound(s) of the invention are useful in treatment of allergic disorders including, but not limited to, atopic dermatitis, atopic eczema, Hay fever, asthma, urticaria (including chronic idiopathic urticaria), vernal conjunctivitis, allergic rhinoconjunctivitis, allergic rhinitis (seasonal and perennial), sinusitis, otitis media, allergic bronchitis, allergic cough, allergic bronchopulmonary aspergillosis, anaphylaxis, drug reaction, food allergies and reactions to the venom of stinging insects.

In yet another embodiment, the invention is directed to the treatment of “immune disorders” by administering an effective amount of a compound of the invention.

The compounds of this invention can be used to treat subjects with immune disorders. As used herein, the term “immune disorder” and like terms mean a disease, disorder or condition caused by dysfunction or malfunction of the immune system as a whole or any of its components including autoimmune disorders. Such disorders can be congenital or acquired and may be characterized by the component(s) of the immune system getting affected or by the immune system or its components getting overactive Immune disorders include those diseases, disorders or conditions seen in animals (including humans) that have an immune component and those that arise substantially or entirely due to immune system-mediated mechanisms. In addition, other immune system mediated diseases, such as graft-versus-host disease and allergic disorders, will be included in the definition of immune disorders herein. Because a number of immune disorders are caused by inflammation or lead to inflammation, there is some overlap between disorders that are considered immune disorders and inflammatory disorders. For the purpose of this invention, in the case of such an overlapping disorder, it may be considered either an immune disorder or an inflammatory disorder. An autoimmune disorder is a condition that occurs when the immune system mistakenly attacks and destroys its own body cells, tissues and/or organs. This may result in temporary or permanent destruction of one or more types of body tissue, abnormal growth of an organ, changes in organ function, etc. For Example, there is destruction of insulin producing cells of the pancreas in Type 1 diabetes mellitus. Different autoimmune disorders can target different tissues, organs or systems in an animal while some autoimmune disorders target different tissues, organs or systems in different animals. For Example, the autoimmune reaction is directed against the gastrointestinal tract in Ulcerative colitis and the nervous system in multiple sclerosis whereas in systemic lupus erythematosus (lupus), affected tissues and organs may vary among individuals with the same disease. For Example, one person with lupus may have affected skin and joints whereas another may have affected kidney, skin and lungs.

Specific autoimmune disorders that may be ameliorated using the compounds and methods of this invention include without limitation, autoimmune disorders of the skin (e.g., psoriasis, dermatitis herpetiformis, pemphigus vulgaris, and vitiligo), autoimmune disorders of the gastrointestinal system (e.g., Crohn's disease, ulcerative colitis, primary biliary cirrhosis, and autoimmune hepatitis), autoimmune disorders of the endocrine glands (e.g., Type 1 or immune-mediated diabetes mellitus, Grave's disease. Hashimoto's thyroiditis, autoimmune oophoritis and orchitis, and autoimmune disorder of the adrenal gland), autoimmune disorders of multiple organs (including connective tissue and musculoskeletal system diseases) (e.g., rheumatoid arthritis, systemic lupus erythematosus, scleroderma, polymyositis, dermatomyositis, spondyloarthropathies such as ankylosing spondylitis, and Sjogren's syndrome), autoimmune disorders of the nervous system (e.g., multiple sclerosis, myasthenia gravis, autoimmune neuropathies such as Guillain-Barre, and autoimmune uveitis), autoimmune disorders of the blood (e.g., autoimmune hemolytic anemia, pernicious anemia, and autoimmune thrombocytopenia) and autoimmune disorders of the blood vessels (e.g., temporal arteritis, anti-phospholipid syndrome, vasculitides such as Wegener's granulomatosis, and Behcet's disease).

“Treatment of an immune disorder” herein refers to administering a compound or a composition of the invention alone or in combination with other agents to a subject, who has an immune disorder, a sign or symptom of such a disease or a risk factor towards such a disease, with a purpose to cure, relieve, alter, affect, or prevent such disorder or sign or symptom of such a disease, or the predisposition towards it.

In another embodiment, the invention is directed to the treatment of cancer by administering an effective amount of a compound of the invention.

It has been reported in the art that STIM1 and Orai1 are essential in in vitro tumor cell migration and in vivo tumor metastasis. Thus the involvement of store operated Ca2+entry in tumor metastasis renders STIM1 and Orai1 proteins potential targets for cancer therapy (Yang et. al., Cancer Cell, 15, 124-134, 2009). Additional literature available on the involvement of CRAC channel in cancer are Abeele et. al., Cancer Cell, 1, 169-179, 2002, Motiani et al., J. Biol. Chem., 285; 25, 19173-19183, 2010.

The compound(s) of the invention may be useful in treatment of cancers and/or its metastasis including, but not limited to, breast cancer, lung cancer, pancreatic cancer, ovarian cancer, colon cancer, neck cancer, kidney cancer, bladder cancer, thyroid, blood cancer, skin cancer and the like.

In yet another embodiment, the invention is directed to the treatment or prophylaxis of allergic disorders by administering an effective amount of a compound of the invention.

In yet another embodiment, the invention is directed to the treatment or prophylaxis of cardiovascular diseases or disorders by administering an effective amount of a compound of the invention.

The compounds of this invention can be used to treat subjects with cardiovascular disorders. “Cardiovascular disorder” refers to a structural and functional abnormality of the heart and blood vessels, comprised of diseases including but not limited to, atherosclerosis, coronary artery disease, arrhythmia, heart failure, hypertension, diseases of the aorta and its branches, disorders of the peripheral vascular system, aneurysm, endocarditis, pericarditis, heart valve disease. It may be congenital or acquired. One of the main pathological feature of all these diseases is clogged and hardened arteries, obstructing the blood flow to the heart. The effects differ depending upon which vessels are clogged with plaque. The arteries carrying oxygen rich blood, if clogged, result in coronary artery disease, chest pain or heart attack. If the arteries reaching the brain are affected, it leads to transient ischemic attack or stroke. If the vessels in arms or legs are affected, leads to peripheral vascular disease. Because a number of cardiovascular diseases may also be related to or arise as a consequence of thrombocytopathies, there is some overlap between disorders that are considered under heading cardiovascular disorders and thrmobocytopathies. For the purpose of this invention, in the case of such an overlapping disorder, it may be considered either a cardiovascular disorder or a thrombocytopathy.

STIM1 is located on the endoplasmic reticulum (ER) and functions as a calcium sensor. Orai1 is a pore forming subunit of calcium channel located on the plasma membrane, the depletion of calcium in the endoplasmic reticulum is sensed by STIM1, and calcium enters via Orai1 to refill the endoplasmic reticulum. This pathway of filling the calcium is called store operated calcium entry (SOCE), which plays an important role in calcium homeostasis, cellular dysfunction and has a significant importance in cardiovascular diseases. In cardiomyocytes, calcium is not only involved in excitation-contraction coupling but also acts as a signalling molecule promoting cardiac hypertrophy. Hypertrophic hearts are susceptible to abnormalities of cardiac rhythm and have impaired relaxation. Vascular smooth muscle cells (VSMCs) are responsible for the maintenance of vascular tone. VSMCs disorders, usually manifested as a phenotype change, are involved in the pathogenesis of major vascular diseases such as atherosclerosis, hypertension and restenosis. SOCE was also found increased in metabolic syndrome (MetS) swine coronary smooth muscle cells. The compound of this invention can be used to treat neointimal hyperplasia, occlusive vascular diseases, MetS—which is a combination of medical disorders including coronary artery disease, stroke and type 2 diabetes, abdominal aortic aneurysm, angina, transient ischemic attack, stroke, peripheral artery occlusive disease which includes inflammation, complement activation, fibrinolysis, angiogenesis and/or diseases related to FXII-induced kinin formation such as hereditary angioedema, bacterial infection of the lung, trypanosome infection, hypotensive shock, pancreatitis, chagas disease, thrombocytopenia or articular gout, myocardial infarction, portal vein thrombosis which leads to hypertension, pulmonary hypertension, deep vein thrombosis, jugular vein thrombosis, systemic sepsis, pulmonary embolism, and papilledema, Budd-Chiari syndrome, Paget-Schroetter disease, cerebral venous sinus thrombosis ischemic cardiomyopathy, hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, Prinzmetal angina, angina pectoris, chronic venous insufficiency, acute coronary syndrome, endocarditis, conceptual apraxia, pulmonary valve stenosis, thrombophlebitis, ventricular tachycardia, temporal arteritis, tachycardia, paroxysmal atrial fibrillation, persistent atrial fibrillation, permanent atrial fibrillation, respiratory sinus arrhythmia, carotid artery dissection, cerebrovascular diseases include, hemorrhagic stroke and ischemic stroke (where the thrombo-inflammatory cascade results in infarct growth), cardiomegaly, endocarditis, pericarditis, pericardial effusion. Valvular heart disease, vascular diseases or vascular inflammation is the result of ruptured atherosclerotic plaque which initiates thrombus formation. Platelet activation play an important role in vascular inflammation leading to myocardial infarction and ischaemic stroke, the compound of this invention will prevent platelet activation and plaque formation and would also be useful to treat all peripheral vascular diseases (PVD), pulmonary thromboembolism, and venous thrombosis.

“Treatment of cardiovascular disorders” herein refers to administering a compound or a composition of the invention alone or in combination with other agents to a subject, who has a cardiovascular disease, a sign or symptom of such a disease or a risk factor towards such a disease, with a purpose to cure, relieve, alter, affect, or prevent such disorder or sign or symptom of such a disease, or the predisposition towards it.

In yet another embodiment, the invention is directed to the treatment of “thrombocytopathies” by administering an effective amount of a compound of the invention.

Thrombocytopathies: The compounds of this invention can be used to treat subjects with thrombocytopathies. Thrombocytopathy is an abnormality of platelets or its functions. It may be congenital or acquired. It may cause a thrombotic or a bleeding tendency or may be part of a wider disorder such as myelodysplasia. Thrombocytopathies include such vascular disorders that arise due to dysfunction of platelets or coagulation system or diseases or complications that arise as a result of partial or complete restriction of blood flow to different organs or systems due to such thrombocytopathies. Thrombocytopathies will thus include without limitation diseases due to superficial vein thrombosis, diseases due to deep vein thrombosis, diseases due to arterial thrombosis, peripheral vascular diseases, thrombophilia, thrombophlebitis, embolisms, thromboembolism, ischemic cardiovascular diseases including but not limited to myocardial ischemia, angina, ischemic cerebrovascular diseases including but not limited to stroke, transient ischemia attack, cerebral venous sinus thrombosis (CYST) and complications arising due to thrmobocytopathies. Besides this, the disorder related to venous or arterial thrombus formation can be inflammation, complement activation, fibrinolysis, angiogenesis and/or diseases related to FXII-induced kinin formation such as hereditary angioedema, bacterial infection of the lung, trypanosome infection, hypotensitive shock, pancreatitis, chagas disease, thrombocytopenia or articular gout.

Under normal circumstances, when the endothelial cells lining blood vessels are breached, platelets interact with von Willebrand factor (vWF) via the membrane glycoprotein 1b complex to help seal the breach. Glycoprotein IIb/Ia complex attracts other platelets, which combine to form aggregates. The platelets contain granules which break down to release fibrinogen, vWF, platelet-derived growth factor adenosine 5′-diphosphate (ADP), calcium and 5-hydroxytryptamine (5-HT)-serotonin. All this helps to promote the formation of a haemostatic plug (primary haemostasis). Activated platelets also synthesise thromboxane A2 from arachidonic acid as well as presenting negatively charged phospholipids on the outer leaflet of the platelet membrane bilayer. This negative surface provides binding sites for enzymes and cofactors of the coagulation system. The total effect is therefore to stimulate the coagulation system to form a clot (secondary haemostasis).

Thus physiological platelet activation and thrombus formation are essential to stop bleeding in case of vascular injury, whereas under pathological conditions this may lead to vessel occlusion due to inadequate triggering of the same process in diseased vessels leading to thrombosis, thromboembolism or tissue ischemia of vital organs. A central step in platelet activation is agonist-induced elevation of the intracellular Ca(2+) concentration. This happens on the one hand through the release of Ca(2+) from intracellular stores and on the other hand through Ca(2+) influx from the extracellular space. In platelets, the major Ca(2+) influx pathway is through store operated Ca(2+) entry (SOCE), induced by store depletion. STIM1 is the Ca(2+) sensor in the endoplasmic reticulum (ER) membrane, whereas Orai1 is the major store operated Ca(2+) (SOC) channel in the plasma membrane, which play a key role in platelet SOCE.

“Treatment of thrombocytopathy” herein refers to administering a compound or a composition of the invention alone or in combination with other agents to a subject, who has a thrombocytopathy, a sign or symptom or complication of such a disease or a risk factor towards such a disease, with the purpose to cure, relieve, alter, affect, or prevent such a disorder or sign or symptom, or the predisposition towards it.

General Methods of Preparation

The compounds of the invention, including compounds of general Formula (I) and specific Examples are prepared through the reaction sequences illustrated in synthetic Scheme-1, Scheme-2 and Scheme-3 where A, B, L, R1, R2, R3, R4, R5, R6, R7, Ra, Rb‘n’ and ‘p’ are as defined herein above. Starting materials are commercially available or may be prepared by the procedures described herein or by the procedures known in the art. Furthermore, in the following synthetic schemes, where specific acids, bases, reagents, coupling agents, solvents, etc., are mentioned, it is understood that other bases, acids, reagents, coupling agents, solvents etc., known in the art may also be used and are therefore included within the scope of the invention. Variations in reaction conditions and parameterslike temperature, pressure, duration of reaction, etc., which may be used as known in the art are also within the scope of the invention. All the isomers of the compounds described in these schemes, unless otherwise specified, are also encompassed within the scope of this invention.

The compounds obtained by using the general reaction sequences may be of insufficient purity. These compounds can be purified by using any of the methods for purification of organic compounds known in the art, for Example, crystallization or silica gel or alumina column chromatography using different solvents in suitable ratios. Unless mentioned otherwise, room temperature (RT) refers to a temperature in the range of 22° C. to 27° C.

1H-NMR spectra of the compounds of the invention were recorded using a Bruker instrument (model: Avance-III), 400 MHz. Liquid chromatography-mass spectra (LCMS) of the compounds of the invention were recorded using Agilent ion trap model 6320 and Thermo Scientific Single Quad model MSQ plus instruments. IUPAC nomenclature for the compounds of the invention was used according to ChemBioDraw Ultra 12.0 software.

The compounds of Formula (II) wherein A, B, X, L, R1, R2, R3, R4, R5, R6, R7, Ra, Rb, ‘n’ and ‘p’ are as defined herein above, is prepared by the reaction of various haloderivatives of Formula (1) with pinacolatoboronate derivative of Formula (2) as depicted in Scheme-1.

Alternatively, the compounds of the Formula (II) can also be prepared by the reaction of the pinacolatoboronate derivatives of the Formula (3) with halo derivatives of the Formula (4) as shown in Scheme 1. The same transformation may also be carried out by other suitable coupling methods known in the art. The compound of Formula (1), (2), (3) and Formula (4) can be prepared by following the methods known in the art.

The said reaction can be mediated by a suitable catalyst known in the art such as Pd(PPh3)2Cl2, Pd(dppf)Cl2, Pd2dba3, Pd(PPh3)4, Pd(OAc)2or mixture(s) thereof; a suitable ligand known in the art such as 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP), xanthophos, triphenylphosphine or mixture(s) thereof; in the presence of a suitable base, preferably inorganic bases such as alkali-metal carbonates like sodium carbonate, cesium carbonate and phosphates like potassium phosphate or mixture(s) thereof.

Alternatively, compound of Formula (II) can be prepared by reacting a halo compound of the Formula (1) with borate compound of the Formula (5) followed by amide coupling reaction using general amide coupling reagents known in the art. The coupling of halo derivatives of the Formula (1) with borate derivatives of the Formula (5) are carried out as per methods known in the art or as described in the Scheme 1.

The compound of the Formula (6) is transformed to compound of Formula (II) using the suitable techniques known in the art. Such reactions are carried out in one or more suitable solvents using suitable base for Examplesodium hydride, triethylamine, N-ethyldiisopropylamine; 4-dialkylaminopyridines like 4-dimethylaminopyridine, pyridine or mixture(s) thereof.

The compounds of Formula (III) and (IV) wherein A, B, L, X, R1, R2, R3, R6, R7, Ra, ‘n’ and ‘p’ are as defined herein above, are prepared by the reaction of various triflatederivatives of Formula (8) with borate derivative of Formula (2) as depicted in Scheme-3. Alternatively, compounds of the Formula (III) can also be prepared by the reaction of borate derivatives of the Formula (9) with halo derivatives of the Formula (4). The compound of Formula (2), (4), (8) and (9) are prepared as per the procedure known in the art.

Further, the compounds of the Formula (III) are converted to the compounds of the Formula (IV) under metal catalyzed hydrogenation conditions. The catalyst used for such transformation as known in the art such as Pd—C, Ra—Ni, Pt—C thereof; in presence of suitable solvent such as esters like ethyl acetate, ethers like THF, dioxane or mixture(s) thereof.

EXPERIMENTAL

Intermediates

7-Bromo-2,2,6-trimethylchroman-4-one and

Step-1: 7-bromo-2,2,6-trimethylchroman-4-one: A mixture of 1-(4-bromo-2-hydroxy-5-methylphenyl)ethanone (prepared by following the similar procedure as described in WO2012028629; 2.0 g, 8.73 mmol), propan-2-one (830 μL, 11.35 mmol) and pyrrolidine (505 μL, 6.11 mmol) in methanol (25 mL) was refluxed for 16 h. The reaction was cooled to room temperature and the solvent was evaporated under vacuum. Ethyl acetate (100 mL) was added to the above obtained residue followed by 10% HCl (50 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with water (50 mL), saturated aqueous NaHCO3(50 mL) and brine (50 mL) The organic layer was dried (Na2SO4) and filtered. The filtrate was rotary evaporated and the crude product was purified by flash column chromatography to afford 1.50 g (63%) of the title compound as colorless liquid.1HNMR (400 MHz, CDCl3) δ 7.70 (s, 1H), 7.20 (s, 1H), 2.70 (s, 2H), 2.35 (s, 3H), 1.45 (s, 6H); GC-MS (m/z) 268, 270 [M+, Br79,81].

Step-2: 2,2,6-Trimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)chroman-4-one: To a nitrogen purged suspension of potassium acetate (228 mg, 2.32 mmol) in toluene (10 mL) in a microwave vial was added step-1 Intermediate (250 mg, 0.929 mmol) followed by bis(pinacolato)diboron (259 mg, 1.02 mmol). The resulting mixture was thoroughly deoxygenated by purging nitrogen gas for another 10 minutes, and PdCl2(dppf)-CH2Cl2adduct (38 mg, 0.046 mmol) was added to the above mixture. The microwave vial was capped and heated at 150° C. for 13 min in a microwave reactor (Biotage). The reaction mixture was cooled to room temperature and filtered through celite. The filtrate was rotary evaporated and the crude product was purified by flash column chromatography (silica gel, ethyl acetate-hexanes system as eluent) to afford 100 mg (34%) of the title compound as white solid.1HNMR (400 MHz, CDCl3) δ 7.62 (s, 1H), 7.35 (s, 1H), 2.71 (s, 2H), 2.46 (s, 3H), 1.44 (s, 6H), 1.35 (s, 12H); ESI-MS (m/z) 317 (MH)+.

7-Bromo-6-ethyl-2,2-dimethylchroman-4-one and

The title compounds were prepared by following the similar procedure as described in Intermediate-1a and Intermediate-1b

7-Bromo-2,2,8-trimethylchroman-4-one and

Step-1: 3-Bromo-2-methylphenyl acetate: To the (0° C.) cooled and stirred solution of 3-bromo-2-methylphenol (10.0 g, 53.5 mmol) in DCM (100 mL) was added pyridine (10.8 mL, 134 mmol) followed by drop-wise addition of a solution of acetyl chloride (5.70 mL, 80 mmol) in DCM (30 mL). The resulting mixture was then stirred at room temperature for 18 h. The reaction was then cooled to 0° C. and water (100 mL) was added to the above mixture followed by DCM (50 mL) The layers were separated and the aqueous layer was extracted with DCM (2×100 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4and filtered. The filtrate was evaporated and the crude product was purified by flash column chromatography (silica gel, 4% ethyl acetate in hexanes system as eluent) to afford 6.50 g (53%) of the title compound as brown oil.1H NMR (400 MHz, CDCl3) δ 7.46 (d, J=8.0, Hz, 1H), 7.11-7.09 (m, 1H), 7.00 (d, J=8.0 Hz, 1H), 2.35 (s, 3H), 2.26 (s, 3H); GC-MS (m/z) 228, 230 [M+, Br79,81].

Step-2: 1-(4-Bromo-2-hydroxy-3-methylphenyl)ethanone: A mixture of 3-bromo-2-methylphenyl acetate (6.50 g, 28.4 mmol) and aluminium chloride (4.54 g, 34.1 mmol) was heated at 100° C. for 2 h. The reaction mixture was cooled to 0° C. and aqueous HCl (10%, 50 mL) was added to the above mixture and then continued heating at 120° C. for 2 h. The reaction was then cooled to room temperature and diluted with DCM (200 mL) The layers were separated and the organic layer was washed with water (50 mL), dried (Na2SO4) and filtered. The filtrate was rotary evaporated and the crude product was purified by flash column chromatography (silica gel, 4% ethyl acetate in hexane system as eluent) to afford 4.0 g (61%) of the title compound as white solid.1HNMR (400 MHz, CDCl3) δ 12.87 (s, 1H), 7.45 (d, J=8.5 Hz, 1H), 7.12 (d, J=8.5 Hz, 1H), 2.63 (s, 3H), 2.36 (s, 3H); GC-MS (m/z) 228, 230 [M+, Br79,81].

Step-3: 7-Bromo-2,2,8-trimethylchroman-4-one: To a 0° C. cooled and stirred solution of step 2 Intermediate (2.0 g, 8.73 mmol) in methanol (15 mL) was added acetone (0.96 mL, 13.1 mmol) and pyrrolidine (1.50 mL, 17.4 mmol) sequentially. The resulting mixture was stirred at room temperature for 15 min and then at 75° C. for 18 h. The reaction was cooled to room temperature and the solvent was evaporated under vacuum. Aqueous HCl (10%, 50 mL) was added to the above residue followed by the addition of ethyl acetate (200 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with water (50 mL), brine (50 mL), dried (Na2SO4) and filtered. The filtrate was rotary evaporated and the crude product was purified by flash column chromatography (silica gel, 5% ethyl acetate in hexanes system as eluent) to afford 1.50 g (64%) of the title compound as colorless oil.1HNMR (400 MHz, CDCl3) δ 7.58 (d, J=8.0, 1H), 7.19 (d, J=8.0 Hz, 1H), 2.72 (s, 2H), 2.33 (s, 3H), 1.48 (s, 6H); ESI-MS (m/z) 269, 271 [(MH)+, Br79,81].

7-Bromo-2,2,8-trimethylchroman-4-ol and

7-Bromo-2,2,8-trimethylchroman and

7-Bromo-2-(((tert-butyldimethylsilyl)oxy)methyl)-2,6-dimethylchroman-4-one and

Step-2: Methyl-7-bromo-2,6-dimethyl-4-oxochroman-2-carboxylate: To the (0° C.) cooled and stirred solution of step-1 Intermediate (2.0 g, 6.69 mmol) in DMF (20 mL) was added K2CO3(1.38 g, 10.03 mmol). The reaction mixture was warmed to room temperature and stirred for 1 h. Iodomethane (544 μL, 8.69 mmol) was added and maintained for another 5 h. The reaction mixture was cooled to 0° C., water (50 mL) was added to the reaction followed by ethyl acetate (100 mL). The layers were separated and aqueous layer was extracted with ethyl acetate (2×50 mL) The combined organic layers were washed with water (2×50 mL), brine (50 mL), dried (Na2SO4) and filtered. The filtrate was rotary evaporated and the crude product was purified by flash column chromatography (silica gel, 20% ethyl acetate in hexane system as eluent) to afford 1.6 g (76%) of the title compound as white semisolid.1HNMR (400 MHz, CDCl3) δ 7.69 (s, 1H), 7.35 (s, 1H), 3.71 (s, 3H), 3.19 (d, J=16.5 Hz, 1H), 2.86 (d, J=16.5 Hz, 1H), 2.36 (s, 3H), 1.73 (s, 3H); ESI-MS (m/z) 313, 315 [(MH)+, Br79,81].

Step-1: 7-Bromo-2,2,6-trimethylchroman-4-one oxime: A mixture of Intermediate-1a (2.10 g, 7.80 mmol) and hydroxylamine hydrochloride (1.62 g, 23.41 mmol) in methanol (5 mL) was heated at 125° C. for 30 min in a microwave reactor (Biotage). The reaction mixture was cooled to room temperature and the solvent was evaporated under vacuum. Water (20 mL) was added to the residue followed by ethyl acetate (50 mL) The layers were separated and aqueous layer was extracted with ethyl acetate (2×30 mL) The combined organic layers were washed with brine (20 mL), dried (Na2SO4) and filtered. The filtrate was rotary evaporated to afford 2.10 g (95%) of the title compound as white solid.1HNMR (400 MHz, CDCl3) δ 7.70 (s, 1H), 7.11 (s, 1H), 2.87 (s, 2H), 2.34 (s, 3H), 1.39 (s, 6H); LC-MS (m/z), 284, 286 [(MH)+, Br79,81]

Step-2: 7-Bromo-2,2,6-trimethylchroman-4-amine: To a stirred solution of step-1 Intermediate (300 mg, 1.05 mmol) in acetic acid (10 mL) was added zinc (690 mg, 10.56 mmol) and the resulting mixture was stirred at room temperature for 10 min and then at 110° C. for 6 h. The reaction was cooled to room temperature and filtered through celite bed. The celite cake was washed with acetic acid (20 mL) and the combined filtrates were evaporated under vacuum. The residue was diluted with ethyl acetate (50 mL) and sat. aq. Na2CO3solution (10 mL) was added. The layers were separated and aqueous layer was extracted with ethyl acetate (2×20 mL). The combined organic layers were washed with brine (20 mL), dried (Na2SO4) and filtered. The filtrate was rotary evaporated and the crude product was purified by flash column chromatography (silica gel, 5% methanol in dichloromethane system as eluent) to afford 115 mg (40%) of the title compound as white solid.1HNMR (400 MHz, CDCl3) δ 7.33 (s, 1H), 7.00 (s, 1H), 3.95 (dd, J=11.0 & 6.0 Hz, 1H), 2.34 (s, 3H), 2.13-2.05 (m, 1H), 1.71-1.63 (m, 1H), 1.42 (s, 3H), 1.27 (s, 3H); GC-MS (m/z) 269, 271 [M+, Br79,81]

7-Bromo-2,2-bis(((tert-butyldimethylsilyl)oxy)methyl)-6-methylchroman-4-one and

The title compounds were prepared by following the similar procedure as described in Intermediate-5.

Step-1: 1-(3-Bromo-6-hydroxy-2-methylphenyl)ethanone: To a stirred solution of 1-(2-hydroxy-6-methylphenyl)ethanone (prepared by following the similar procedure as reported inEur. J. Med. Chem.,2010, 45(11), 4788; (200 mg, 1.33 mmol) in acetonitrile (5 mL) was added p-toluenesulfonic acid monohydrate (127 mg, 0.66 mmol) at RT. The resulting mixture was stirred for 5 min then added NBS (237 mg, 1.33 mmol) and further maintained for 2 h at the same temperature. The reaction was then quenched by the addition of Na2S2O3(10%, 2 mL) followed by the addition of water (5 mL) and diethyl ether (5 mL) The layers were separated and the aqueous layer was extracted with diethyl ether (2×10 mL). The combined organic layers were washed with brine (10 mL), dried (Na2SO4) and filtered. The filtrate was evaporated and the crude product was purified by flash column chromatography (silica gel, 5% ethyl acetate-hexanes system as eluent) to afford 200 mg (65%) of the title compound as white solid.1HNMR (400 MHz, CDCl3) δ 10.76 (s, 1H), 7.55 (d, J=8.0 Hz, 1H), 6.75 (d, J=8.0 Hz, 1H), 2.64 (s, 3H), 2.59 (s, 3H); ESI-MS (m/z) 227, 229 [(M-H), Br79,81].

7-Bromo-6-methylspiro[chroman-2,1′-cyclobutan]-4-one and

Intermediate-12b and

6-Bromo-7-methylspiro[chroman-2,1′-cyclobutan]-4-one and

Step-1: 3-Bromo-2-methylphenyl acetate: To an ice cooled solution of 3-bromo-2-methylphenol (prepared by following the similar procedure as reported in US20110082165; 4.0 g, 21.39 mmol) and pyridine (1.73 mL, 21.39 mmol) in DCM (20 mL) was added acetyl chloride (1.52 mL, 21.39 mmol) drop-wise and the mixture was then stirred for 16 h at RT. Water (50 mL) was then added to the reaction followed by DCM (50 mL). The layers were separated and the aqueous layer was extracted with DCM (2×50 mL) and the combined organic layers were washed with brine, dried (Na2SO4) and filtered. The filtrate was evaporated and the crude product was purified by flash column chromatography to afford 3.80 g (78%) of the title product as oil.1H NMR (400 MHz, CDCl3) δ 7.46 (d, J=8.0, Hz, 1H), 7.09 (t, J=8.0 Hz, 1H), 7.00 (d, J=8.0, Hz, 1H), 2.35 (s, 3H), 2.27 (s, 3H).

Step-2: 1-(4-Bromo-2-hydroxy-3-methylphenyl)ethanone: A mixture of step-1 Intermediate (3.0 g, 13.10 mmol) and aluminum chloride (2.62 g, 19.64 mmol) in a sealed tube was heated at 110° C. for 3 h. The reaction was then cooled to RT, 10% aqueous hydrochloric acid (5 mL) was added to the reaction and then heated to reflux for another 10 min. The reaction was cooled to RT, DCM (100 mL) was then added followed by water (50 mL) and the layers were separated. The aqueous layer was extracted with DCM (2×50 mL) and the combined organic layers were washed with brine (50 mL), dried (Na2SO4) and filtered. The filtrate was rotary evaporated and the crude product was purified by flash column chromatography (silica gel, 5% ethyl acetate in hexanes system as eluent) to afford 2.20 g (73%) of the title compound as oil.1H NMR (400 MHz, CDCl3) δ 12.87 (s, 1H), 7.45 (d, J=8.5 Hz, 1H), 7.12 (d, J=8.5 Hz, 1H), 2.63 (s, 3H), 2.36 (s, 3H).

7-Bromo-6-ethylspiro[chroman-2,1′-cyclobutan]-4-one and

Step-1: Spiro[chromene-2,1′-cyclobutan]-4-yl trifluoromethanesulfonate: To a (−78° C.). cooled and stirred solution of spiro[chroman-2,1′-cyclobutan]-4-one (1.50 g, 7.97 mmol; prepared by following the similar procedure as described in WO2007042906) in THF (30 mL) was added sodium bis(trimethylsilyl)amide (15.9 mL, 15.9 mmol, 1M in THF) followed by 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonimide (5.98 g, 16.74 mmol) in THF (20 mL). The resulting mixture was allowed to warm to room temperature over a period of 3 h. Ice cooled water (20 mL) was added to the reaction followed by ethyl acetate (50 mL) The layers were separated and the aqueous layer was extracted with ethyl acetate (2×50 mL) The combined organic layers were washed with brine (20 mL), dried (Na2SO4) and filtered. The filtrate was rotary evaporated and the crude product was purified by flash column chromatography (silica gel, ethyl acetate-hexanes system as eluent) to afford 1.0 g (39%) of the title compound as colorless oil.1HNMR (400 MHz, CDCl3) δ 7.28-7.23 (m, 2H), 6.96 (t, J=8.0 Hz, 1H), 6.88 (d, J=8.0 Hz, 1H), 5.98 (s, 1H), 2.61-2.53 (m, 2H), 2.39-2.29 (m, 2H), 1.98-1.88 (m, 1H), 1.79-1.69 (m, 1H); ESI-MS (m/z) 321 (MH)+

The following Intermediates (17a-30a) given in Table-1 were prepared from the corresponding starting materials by following the similar procedure as described in Intermediate-16a.

The following Intermediates (19b-24b, 26b-30b) given in Table-2 were prepared from the corresponding starting materials by following the similar procedure as described in Intermediate-18b.

The title compound was prepared by following the similar procedure as reported in WO2013164769.

The below Intermediates (32-37) given in Table-3 were prepared from the corresponding starting materials by following the similar procedure as described in WO2012056478.

Step-2: N-(2,6-Difluorophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide: To a stirred and nitrogen purged solution of step-1 Intermediate (5.40 g, 17.3 mmol) in dioxane (50 mL), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (5.27 g, 20.7 mmol), potassium acetate (5.43 g, 55.4 mmol) and [1,1′-bis(diphenyl phosphino)-ferrocene)dichloro palladium(II) dichloro methane complex (0.706 g, 0.86 mmol) were sequentially added. The resulting mixture was then thoroughly deoxygenated again by subjecting to a vacuum/nitrogen cycle three times and then heated at 100° C. for 6 h under nitrogen atmosphere. The reaction mixture was cooled to room temperature and filtered through celite. The filtrate was concentrated under vacuum and the crude product was purified by flash column chromatography (silica gel, ethyl acetate-hexane system as eluent) to afford 4.80 g (77%) of the Intermediate 6 as a white solid.1HNMR (400 MHz, CDCl3) δ 7.95-7.90 (m, 4H), 7.47 (s, 1H), 7.27-7.23 (m, 1H), 7.01 (t, J=8.0 Hz, 2H); ESI-MS (m/z) 360 (MH)+.

The title compound was prepared by following the similar procedure as reported in US20120088764.

Step-1: 4-Bromo-N-(2,6-difluorobenzyl)aniline: To a (0° C.) cooled and stirred solution of 4-bromoaniline (2.0 g, 11.63 mmol) in Methanol (20 mL) was added 2,6-difluorobenzaldehyde (1.27 mL, 11.63 mmol) and acetic acid (600 μL, 11.63 mmol). The resulting mixture was stirred at RT for 30 min. Sodium cyanoborohydride (1.16 g, 18.60 mmol) was added to the above mixture and further stirred for 15 h at the same temperature. The solvent was then evaporated under vacuum and the residue was diluted with water (15 mL) followed by ethyl acetate (20 mL) The layers were separated and the aqueous layer was extracted with ethyl acetate (2×20 mL). The combined organic layers was washed with saturated brine (20 mL) and dried (Na2SO4) and filtered. The filtrate was concentrated under vacuum. The crude product was purified by flash chromatography (silica gel, ethyl acetate-hexanes system as eluent) to give 2.60 g (75%) of the title product as white solid.1HNMR (400 MHz, CDCl3) δ 7.33-7.18 (m, 3H), 6.90 (t, J=8.0 Hz, 2H), 6.61 (d, J=8.5 Hz, 2H), 4.41 (s, 2H); ESI-MS (m/z) 298, 300 [(MH)+, Br79,81].

The title compound was prepared by reacting 2-bromo-5-aminopyridine with 2,6-difluorobenzaldehyde by following the similar procedure as described in Intermediate-40. ESI-MS (m/z) 299, 301 [(MH)+, Br79,81].

EXAMPLES

The below Examples (2 to 21) given in Table-4 were prepared by following the similar procedure as described in Example-1 by using the appropriate Intermediates.

The below Examples (31-45) given in Table-5 were prepared by following the similar procedure as described in Example-30 by using the appropriate Intermediates.

N-(4-(6-Ethyl-4-hydroxy-2,2-dimethylchroman-7-yl)phenyl)-2,6-difluorobenzamide and

The below Examples (52-58) given in Table-6 were prepared by following the similar procedure as described in Example-51 by using the appropriate Intermediates.

Step-3: N-(3,5-Difluoropyridin-4-yl)-4-(6-methyl-4-oxospiro[chroman-2,1′-cyclobutan]-7-yl)benzamide: To a stirred solution of step-2 Intermediate (0.30 g, 0.93 mmol) in a CH2Cl2(5 mL) was added dropwise thionyl chloride (3 mL) and the resulting mixture was refluxed for 2 h. The excess thionyl chloride was removed under vacuum to afford the crude acid chloride. To a pre-washed suspension of NaH (67 mg, 2.79 mmol) in DMF (5 mL) was added drop wise a solution of 3,5-difluoropyridin-4-amine (0.121 g, 0.931 mmol) in DMF (3 mL) at 0° C. After stirring for 15 min, an ice-cooled solution of the above prepared acid chloride in CH2Cl2(5 mL) was added dropwise to the mixture. The resulting mixture was stirred at rt for 16 h. The reaction mixture was quenched with ice-cold water and extracted with CH2Cl2(2×20 mL) The combined organic layers were washed with 10% aq HCl (10 mL), water (10 mL), dried (Na2SO4) and filtered. The filtrate was rotary evaporated and the crude product was purified by flash column chromatography (silica gel, ethyl acetate-hexane system as eluent) to afford 10 mg (3%) of the desired product as a white solid.1HNMR (400 MHz, DMSO-d6) δ 10.77 (s, 1H), 8.65 (s, 2H), 8.09 (d, J=8.0 Hz, 2H), 7.67 (s, 1H), 7.59 (d, J=8.0 Hz, 2H), 6.95 (s, 1H), 3.00 (s, 2H), 2.29-2.21 (m, 2H), 2.20 (s, 3H), 2.18-2.10 (m, 2H), 1.84-1.74 (m, 2H); ESI-MS (m/z) 467 (MH)+.

The following Examples (65-67) given in Table-7 were prepared by following the similar procedure as described in Example-64 from the appropriate Intermediates.

The following Examples (70-92) given in Table-8 were prepared from the corresponding Intermediates by following the similar procedure as described in Example-68 and Example-69.

The following Examples (94-97) given in Table-9 were prepared from the corresponding Intermediates by following the similar procedure as described in Example-93.

The following Examples (98-111) given in Table-10 were prepared from the corresponding Intermediates by following the similar procedure as described in Example-68.

Biological Assays and Utility:

The CRAC channel modulatory activity of the compounds were thus evaluated by measuring the secretion of IL-2 by antigen stimulated T-cells in vitro. Alternatively, such activity can also be evaluated by assay methods known to one skilled in the art.

In Vitro Assay

Inhibition of IL-2 secretion: Jurkat T cells were seeded at a density of 0.5 to 1 million cells per well in RPMI medium. Test compounds from this invention were added to the cells at different concentrations. This was followed by the addition of PHA, a T cell mitogen after 10 minutes. The cells were then incubated for 20 to 24 hours in a CO2incubator at 37° C. After incubation with the compounds, cells were centrifuged; the supernatant was collected and processed for ELISA to quantitate the amount of IL-2 secreted. A commercial ELISA kit (R&D Systems, Inc. Minneapolis, Minn., USA) was used to estimate the IL-2 concentrations. Amount of IL-2 secreted by cells stimulated with PHA was considered as a 100% maximal signal and the decrease in amount of IL-2 secreted by cells treated with the test compounds was expressed as percent inhibition of the maximal signal. The dose response data was analyzed using 4-parametric sigmoidal dose response (variable slope) curve-fit.

In the above IL-2 assay, compounds of the invention were found to have IC50(nM) values as shown below:

Thus, compounds of the invention are shown to inhibit IL-2 secretion.

SOCE inhibition: Jurkat E6.1 cells were seeded at a density of 1-2×105cells per well in calcium-4 dye prepared in calcium free HBSS (Sigma, USA). Test compounds from this invention were added to the cells at different concentrations. This was followed by the addition of Thapsigargin (TG), a SERCA inhibitor, to empty the stores of calcium. Calcium chloride was added to the cells after 10-30 min to induce calcium influx and the fluorescence was measured for 10 min using the FLIPR-Tetra detection system. Fluorescence was also measured using a plate reader at 485 nm excitation and 520 nm emission (Synergy2, Biotek, USA) after 30-90 minutes of calcium addition. Fluorescence observed in cells treated with Thapsigargin and calcium chloride solution was considered 100% maximal signal and the reduced fluorescent signal observed in the presence of test compounds was expressed as percent inhibition of the maximal signal. The dose response data was analyzed using 4-parametric sigmoidal dose response (variable slope) curve-fit.

In the above SOCE inhibition assay, compounds of the invention showed activity less than <1000 nM against SOCE. Thus, compounds of the invention are shown to have CRAC channel modulation activity by inhibition of SOCE.

NFAT Transcriptional Activity: HEK 293 cells were stably co-transfected with a NFAT-FireflyLuciferase and Tk-Renilla Luciferase reporter genes 30,000-80,000 cells were seeded per well. Test compounds from this invention were added to the cells at different concentrations. Thapsigargin (TG) was added after 10 mins and the cells were incubated for 4-8 h. The NFAT-Firefly luciferase and Tk-Renilla luciferase activity was measured using Dual-Glo reagent (Promega USA). The Renilla luciferase activity was used for protein normalization. Luminescence observed in cells treated with thapsigargin was considered 100% maximal signal and the reduced fluorescent signal observed in the presence of test compounds was expressed as percent inhibition of the maximal signal. The data was analyzed using 4-parametric sigmoidal dose response (variable slope) curve-fit.

In the above NFAT transcriptional activity assay, compounds of the invention showed activity less than <1000 nM. Thus, compounds of the invention are shown to inhibit NFAT transcription activity.

Thus, the in vitro screening assays showed that the compounds of invention inhibit CRAC channel activity.

As mentioned hereinbefore, the CRAC channel is involved with numerous biological responses through various Ca2+signaling pathways. The compounds of the invention are therefore useful for the treatment and/or prophylaxis of, although not limited to, inflammatory conditions, cancer, rheumatoid arthritis, allergic disorders, immune disorders, cardiovascular diseases, thrombocytopathies and all related conditions which can be benefitted by the CRAC channel modulatory properties of the compounds described herein.

The compounds of the invention can be administered to a warm-blooded animal, including human being, for the treatment and/or prophylaxis of one or many diseases or disorders mentioned hereinabove which can be benefitted by the CRAC channel modulatory properties of the compounds described herein. The compounds may be Formulated according to the methods known in the art as well as by new methods and may be administered to the body system via gastro-intestinal tract as well as via other routes known to a person skilled in the art. Thus, administration of the compounds of the invention via oral route, parenteral route, inhalation and/or topical applications are within the scope of this application. Any combination of a compound of the invention with excipients and/or other therapeutic agents known in the art for the said conditions, diseases and/or disorders are also encompassed by the invention.

Although certain embodiments and Examples have been described in detail above, those having ordinary skill in the art will clearly understand that many modifications are possible in the embodiments and Examples without departing from the teachings thereof. All such modifications are intended to be encompassed within the below claims of the invention.