CN1913898A - Substituted piperazines - Google Patents

Abstract

Compounds are provided which are potent antagonists of the CCR1 receptor and which have anti-inflammatory activity in vivo. The compounds are generally aryl piperazine derivatives and are useful in pharmaceutical compositions, methods for treating CCR 1-mediated diseases, and as controls in assays for identifying competitive CCR1 antagonists.

Description

Substituted piperazines

Cross References to Related Applications

This application is a continuation-in-part of U.S. Patent Application No. 10/979,882, filed November 1, 2004, which is a continuation in part of U.S. Patent Application No. 10/979,882, filed December 9, 2003 A continuation-in-part, U.S. Patent Application No. 10/732,897 is a continuation-in-part of U.S. Patent Application No. 10/460,752, filed June 11, 2003, which claims the benefit of June 12, 2002 The content of each patent application is incorporated herein by reference for the benefit of filed US Patent Provisional Application No. 60/453,711 (USSN 10/171,398 originally filed June 12, 2002).

Claims Regarding Inventions Made Under Federally Sponsored Research or Development

Not applied

"Sequence Listings", tables or computer programs submitted as attachments on high-density diskettes

none.

Background of the invention

The present invention provides compounds and pharmaceutical compositions, which contain one or more compounds or pharmaceutically acceptable salts thereof, which can effectively inhibit various chemokines, such as MIP-1α, leukotactin, MPIF -1 and RANTES bind to the CCR1 receptor. As antagonists or modulators of the CCR1 receptor, the compounds and compositions are useful in the treatment of inflammatory or immune disorder conditions and diseases.

Human health depends on the body's ability to detect and destroy foreign pathogens that may ingest valuable resources from an individual and/or cause disease. The immune system is the body's defense system that includes white blood cells (white blood cells (WBC): T and B lymphocytes, monocytes, macrophages, granulocytes, NK cells, mast cells, dendritic cells, and immune-derived cells (such as bone cells), lymphoid tissue, and lymphatic vessels. To defend against infection, white blood cells circulate throughout the body to detect pathogens. Once a pathogen is detected, innate immune cells, especially cytotoxic T cells, gather at the site of infection to destroy the pathogen. Trend Chemokines serve as molecular markers of accumulation and activation of immune cells such as lymphocytes, monocytes, and granulocytes, which identify sites where pathogens are present.

In addition to immune system regulation of pathogens, certain inappropriate chemokines can also signal and trigger or perpetuate inflammatory diseases such as rheumatoid arthritis and multiple sclerosis. For example, in rheumatoid arthritis, accumulation of unregulated chemokines in bone joints attracts and activates infiltrating macrophages and T cells. Activation of these cells induces synovial cell proliferation, which leads, at least in part, to inflammation and ultimately bone and cartilage loss (see DeVries, M.E. et al., Semin Immunol 11(2):95-104 (1999)). A hallmark of some demyelinating diseases such as multiple sclerosis is the chemokine-mediated recruitment of monocytes/macrophages and T cells to the central nervous system (see Kennedy et al., J. Clin. Immunol. 19(5): 273-279 (1999)). Chemokine-mediated accumulation of destructive WBCs to grafts is associated with subsequent rejection. See DeVries, M.E. et al., ibid. Since chemokines play key roles in inflammation and lymphocyte development, the ability to specifically manipulate their activity is important for alleviating and curing diseases for which there is currently no satisfactory treatment. In addition, graft rejection is minimized without the systemic effects and complications of costly immunosuppressive drugs.

Chemokines are a collection of more than 40 small peptides (7-10kD) that bind to receptors expressed primarily on WBC or immune-derived cells and signal through a G-protein-coupled signaling cascade to mediate their chemical Attractive and chemical stimulation functions. Receptors can bind more than one ligand; for example, the receptor CCR1 binds RANTES (Regulatory Factor Expressed by Normal T Cells Upon Activation), MIP-1α (Macrophage Inflammatory Protein), MPIF-L/CKβ8, and Leukotactin Chemokines (the less affinity chemokines of these). Twenty-four chemokine receptors are known to date. Chemokines, the precise number of multiligand-binding receptors, and the distinct receptor profiles on immune cells can tightly control specific immune responses. See Rossi et al., Ann. Rev. Immunol. 18(1):217-242 (2000). The activity of chemokines can be controlled by modulating their corresponding receptors, and enables the treatment of related inflammatory and immune diseases as well as organ and tissue transplantation.

The receptor CCR1 and its chemokine ligands, including for example MIP-1α, MPIF-1/CKβ8, Leukotactin and RANTES, are obvious therapeutic targets (see Saeki et al., Current Pharmaceutical Design 9:1201-1208 (2003)), This is due to their association with rheumatoid arthritis, graft rejection (see DeVries, M.E. et al., ibid.) and multiple sclerosis (see Fischer et al., J. Neuroimmunol. 110(1-2): 195-208 (2000) ; Izikson et al., J.Exp.Med.192 (7): 1075-1080 (2000); Rottman et al., Eur.J.Immunol.30 (8): 2372-2377 (2000). In fact, blocking function Antibodies, modified chemokine receptor ligands, and small organic compounds have been discovered, some of which have been successfully demonstrated to prevent or treat some chemokine-mediated diseases (see Rossi et al., ibid.) It should be noted that in experimental models of rheumatoid arthritis, disease progression was slowed when the signal-blocking, modified RANTES ligand was administered (see Plater-Zyberk et al., Immunol Lett.57( 1-3): 117-120 (1997)). Although functionally blocking antibodies and small peptide therapeutics are promising, once administered, they risk degradation, have an extremely short half-life, and develop and manufacture them intolerable. cost, which is characteristic of most protein drugs. Small organic compounds are better because they usually have a longer half-life in vivo, are effective in smaller doses, are usually administered orally, and are less expensive. CCR1 Some organic antagonists have been described (see Hesselgesser et al., J.Biol.Chem.273 (25): 15687-15692 (1998); Ng et al., J.Med.Chem.42 (22): 4680-4694 (1999 ); Liang et al., J.Biol.Chem.275(25):19000-19008(2000) and Liang et al., Eur.J.Pharmacol.389(1):41-49(2000)). Considering that in animal models Therapeutic effect of the disease that has been confirmed in (see Liang et al., J.Biol.Chem.275 (25): 19000-19008 (2000)), is continuing to seek, identify other can be used for the treatment of the disease mediated by CCR1 signaling generation compound of.

Summary of the invention

The present invention provides a compound having the following formula, or a pharmaceutically acceptable salt or N-oxide thereof.

In the above formula, the subscript n represents an integer of 1-2, preferably 1. The subscript m represents an integer of 0-10, limited by the number of available substituent positions on the piperazine or homopiperazine ring to which it is connected. For example, piperazine derivatives (n is 1) may have 0-8 R ¹ groups, preferably 0-4, more preferably 0, 1 or 2 R ¹ groups. Each ^R is a substituent independently selected from the group consisting of C _1-8 alkyl, C _1-8 haloalkyl, C _3-6 cycloalkyl, C _2-8 alkenyl and C _2-8 alkynyl, -COR ^a , -CO ₂ R ^a , -CONR ^a R ^b , -NR ^a COR ^b , -SO ₂ R ^a , -X ¹ COR ^a , -X ¹ CO ₂ R ^a , -X ¹ CONR ^a R ^b , -X ¹ NR ^a COR ^b , -X ¹ SO ₂ R ^a , -X ¹ SO ₂ NR ^a R ^b , -X ¹ NR ^a R ^b and -X ¹ OR ^a , wherein, X ¹ is selected from C _1-4 alkylene C _2-4 alkenylene and C _2-4 alkynylene, R ^a and R ^b are each independently selected from: hydrogen, C _1-8 alkyl, C _1-8 haloalkyl, C _3-6 ring Alkyl and aryl-C _1-4 alkyl, or optionally when R ^a and R ^b are attached to the same nitrogen atom, they combine with this nitrogen atom to form a five or six-membered ring, wherein the aliphatic portion of each R ¹ is optionally substituted by 1-3 of the following groups: -OH, -OR ^m , -OC(O)NHR ^m , -OC(O)N( R ^m ) ₂ , -SH, -SR ^m , -S(O)R ^m , -S(O) ₂ R ^m , -SO ₂ NH ₂ , -S(O) ₂ NHR ^m , -S(O) ₂ N(R ^m ) ₂ , -NHS(O) ₂ R ^m , -NR ^m S(O) ₂ R ^m , -C(O)NH ₂ , -C(O)NHR ^m , -C(O)N( R ^m ) ₂ , -C(O)R ^m , -NHC(O)R ^m , -NR ^m C(O)R ^m , -NHC(O)NH ₂ , -NR ^m C(O)NH ₂ , - NR ^m C(O)NHR ^m , -NHC(O)NHR ^m , -NR ^m C(O)N(R ^m ) ₂ , -NHC(O)N(R ^m ) ₂ , -CO ₂ H, -CO ₂ R ^m , -NHCO ₂ R ^m , -NR ^m CO ₂ R ^m , -CN, -NO ₂ , -NH ₂ , -NHR ^m , -N(R ^m ) ₂ , -NR ^m S(O)NH ₂ and -NR ^m S(O) ₂ NHR ^m , wherein each R ^m is independently an unsubstituted C _1-6 alkyl group.

The symbol ^Ar represents optionally substituted aryl or heteroaryl. Preferred aryl groups are phenyl and naphthyl. Preferred heteroaryl groups are those having 5-10 ring atoms, at least one of which is a nitrogen atom (e.g., pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, quinolinyl, quinolyl oxalinyl, purinyl, etc.). Each Ar ^ring is optionally substituted with 1-5 ^{R substituents} independently selected from: halogen, ^-ORc , -OC(O) ^Rc , ^{-NRcRd ,} -SR ^c , -R ^e , -CN, -NO ₂ , -CO ₂ R ^c , -CONR ^c R ^d , -C(O)R ^c , -OC(O)NR ^c R ^d , -NR ^d C(O) R ^c , -NR ^d C(O) ₂ R ^e , -NR ^c -C(O)NR ^c R ^d , -NH-C(NH ₂ )=NH, -NR ^e C(NH ₂ )=NH, - NH-C(NH ₂ )=NR ^e , -NH-C(NHR ^e )=NH, -NR ^e C(NHR ^e )=NH, -NR ^e C(NH ₂ )=NR ^e , -NH-C( NHR ^e )=NR ^e , -NH-C(NR ^e R ^e )=NH, -S(O)R ^e , -S(O) ₂ R ^e , -NR ^c S(O) ₂ R ^e , -S (O) ₂ NR ^c R ^d , -N ₃ , -C(NOR ^c )R ^d , -C(NR ^c W)=NW, -N(W)C(R ^c )=NW, -NR ^c C( S) NR ^c R ^d , -X ² C(NOR ^c )R ^d , -X ² C(NR ^c W )=NW, -X ² N(W)C(R ^c )=NW, -X ² NR ^c C(S)NR ^c R ^d , -X ² OR ^c , -OX ² OR ^c , -X ² OC(O)R ^c , -X ² NR ^c R ^d , -OX ² NR ^c R ^d , -X ² SR ^c , -X ² CN , -X ² NO ₂ , -X ² CO ₂ R ^c , -OX ² CO ₂ R ^c , -X ² CONR ^c R ^d , -OX ² CONR ^c R ^d , -X ² C (O)R ^c , -X ² OC(O)NR ^c R ^d , -X ² NR ^d C(O)R ^c , -X ² NR ^d C(O) ₂ R ^e , -X ² NR ^c C( O) NR ^c R ^d , -X ² NH-C(NH ₂ )=NH, -X ² NR ^e C(NH ₂ )=NH, -X ² NH-C(NH ₂ )=NR ^e , -X ² NH-C(NHR ^e )=NH, -X ² S(O) ^Re , -X ² S(O) ₂ R ^e , -X ² NR ^c S(O) ₂ R ^e , -X ² S(O ) ₂ NR ^c R ^d , -X ² N ₃ , -NR ^d -X ² OR ^c , -NR ^d -X ² NR ^c R ^d , -NR ^d -X ² CO ₂ R ^c and -NR ^d -X ² CONR ^c R ^d , wherein, W is selected from R ^c , -CN, -CO ₂ R ^c and -NO ₂ , X ² is selected from C _1-4 alkylene, C _2-4 alkenylene and C _2-4 Alkynylene, R ^c and R ^d are each independently selected from: hydrogen, C _1-8 alkyl, C _1-8 haloalkyl, C _3-6 cycloalkyl, C _2-8 alkenyl, C _2-8 Alkynyl, aryl, heteroaryl, aryl-C _1-4 alkyl and aryloxy-C _1-4 alkyl, or when R ^c and R ^d are connected to the same nitrogen atom, they and the nitrogen atom Combined to form a five- or six-membered ring having 0-2 additional heteroatoms as ring atoms; each R ^is independently selected from: C _1-8 alkyl, C _1-8 haloalkyl, C _3-6 cycloalkane Base, C _2-8 alkenyl, C _2-8 alkynyl, aryl, heteroaryl, aryl-C _1-4 alkyl and aryloxy-C _1-4 alkyl, R ^c , R ^d and R ^e are each further optionally substituted with 1-3 groups selected from -OH, -OR ⁿ , -OC(O)NHR ⁿ , -OC(O)N(R ⁿ ) ₂ , -SH, - SR ⁿ , -S(O)R ⁿ , -S(O) ₂ R ⁿ , -SO ₂ NH ₂ , -S(O) ₂ NHR ⁿ , -S(O) ₂ N(R ⁿ ) ₂ , -NHS (O) ₂ R ⁿ , -NR ⁿ S(O) ₂ R ⁿ , -C(O)NH ₂ , -C(O)NHR ⁿ , -C(O)N(R ⁿ ) ₂ , -C(O )R ⁿ , -NHC(O)R ⁿ , -NR ⁿ C(O)R ⁿ , -NHC(O)NH ₂ , -NR ⁿ C(O)NH ₂ , -NR ⁿ C(O)NHR ⁿ , -NHC(O)NHR ⁿ , -NR ⁿ C(O)N(R ⁿ ) ₂ , -NHC(O)N(R ⁿ ) ₂ , -CO ₂ H, -CO ₂ R ⁿ , -NHCO ₂ R ⁿ , -NR ⁿ CO ₂ R ⁿ , -CN, -NO ₂ , -NH ₂ , -NHR ⁿ , -N(R ⁿ ) ₂ , -NR ⁿ S(O)NH ₂ and -NR ⁿ S(O) ₂ NHR ⁿ , wherein each R ⁿ is independently an unsubstituted C _1-6 alkyl group. Optionally, two ^R substituents on adjacent carbon atoms combine to form a five- or six-membered ring with 0-3 heteroatoms as ring atoms.

The symbol HAr stands for optionally substituted heteroaryl. The heteroaryl group of HAr may be the same as or different from the heteroaryl group of ^Ar1 . Typically, the HAr group is monocyclic, but can also be a fused bicyclic ring system having 5-10 ring atoms, at least one of which is a nitrogen atom. Certain preferred heteroaryl groups are 5- or 6-membered rings having at least one nitrogen atom as a ring atom, and fused ring systems having a 5-membered ring fused to a benzene ring, e.g., pyrazolyl, imidazolyl , triazolyl, tetrazolyl, _azolyl, iso_azolyl, _diazolyl, _thiadiazolyl (oxathiadiazolyl), pyrrolyl, thiazolyl, isothiazolyl, benzimidazolyl, benzopyryl Azolyl and benzotriazolyl, each of which may be substituted by 1-5 ^R3 substituents independently selected from: ^halogen , ^-ORf , -OC(O) ^Rf , ^{-NRfR g} , -SR ^f , -R ^h , -CN, -NO ₂ , -CO ₂ R ^f , -CONR ^f R ^g , -C(O)R ^f , -OC(O)NR ^f R ^g , -NR ^g C(O)R ^f , -NR ^g C(O) ₂ R ^h , -NR ^f -C(O)NR ^f R ^g , -NH-C(NH ₂ )=NH, -NR ^h C(NH ₂ ) =NH, -NH-C(NH ₂ )=NR ^h , -NH-C(NHR ^h )=NH, -NR ^h C(NHR ^h )=NH, -NR ^h C(NH ₂ )=NR ^h , - NH-C(NHR ^h )=NR ^h , -NH-C(NR ^h R ^h )=NH, -S(O)R ^h , -S(O) ₂ R ^h , -NR ^f S(O) ₂ R ^h , -S(O) ₂ NR ^f R ^g , -NR ^f S(O) ₂ NR ^f R ^g , -N ₃ , -C(NOR ^f )R ^g , -C(NR ^f W ^a )=NW ^a , -N(W ^a )C(R ^f )=NW ^a , -X ³ C(NOR ^f )R ^g , -X ³ C(NR ^f W ^a )=NW ^a , -X ³ N(W ^a )C (R ^f )=NW ^a , -NR ^f C(S)NR ^f R ^g , -X ³ NR ^f C(S)NR ^f R ^g , -X ³ OR ^f , -X ³ OC(O)R ^f , X ³ NR ^f R ^g , -X ³ SR ^f , -X ³ CN, -X ³ NO ₂ , -X ³ CO ₂ R ^f , -X ³ CONR ^f R ^g , -X ³ C(O)R ^f , -X ³ OC(O)NR ^f R ^g , -X ³ NR ^g C(O)R ^f , -X ³ NR ^g C(O) ₂ R ^h , -X ³ NR ^f -C(O)NR ^f R ^g , -X ³ NH-C(NH ₂ )=NH, -X ³ NR ^h C(NH ₂ )=NH, -X ³ NH-C(NH ₂ )=NR ^h , -X ³ NH-C(NHR ^h )=NH, -X ³ S(O)R ^h , -X ³ S(O) ₂ R ^h , -X ³ NR ^f S(O) ₂ R ^h , -X ³ S(O) ₂ NR ^f R ^g , -Y, -SO ₂ Y , -C(O)Y, -X ³ Y , -X ³ N ₃ , -OX ³ OR ^f , -OX ³ NR ^f R ^g , -OX ³ CO ₂ R ^f , -OX ³ CONR ^f R ^g , -NR ^g -X ³ OR ^f , -NR ^g -X ³ NR ^f R ^g , -NR ^g -X ³ CO ₂ R ^g , and -NR ^g -X ³ CONR ^f R ^g , Wherein, Y is a 5-10 membered aryl, heteroaryl or heterocyclic ring, optionally substituted by 1-3 substituents selected from the group consisting of: halogen, -OR ^f , -NR ^f R ^g , -R ^h , - SR ^f , -CN, -NO ₂ , -CO ₂ R ^f , -CONR ^f R ^g , -C(O)R ^f , -NR ^g C(O)R ^f , -S(O)R ^h , -S (O) ₂ R ^h , -NR ^f S(O) ₂ R ^h , -S(O) ₂ NR ^f R ^g , -C(NOR ^f )R ^g , -C(NR ^f W ^a )=NW ^a , -N(W ^a )C(R ^f )=NW ^a , -X ³ C(NOR ^f )R ^g , -X ³ C(NR ^f W ^a )=NW ^a , -X ³ N(W ^a )C( R ^f )=NW ^a , -X ³ OR ^f , -X ³ NR ^f R ^g , -X ³ NR ^f S(O) ₂ R ^h and -X ³ S(O) ₂ NR ^f R ^g , where W ^a is selected from R ^f , -CN, -CO ₂ R ^h and -NO ₂ , each X ³ is independently selected from C _1-4 alkylene, C _2-4 alkenylene and C _2-4 alkynylene, R ^f and R ^g are each independently selected from: hydrogen, C _1-8 alkyl, C _1-8 haloalkyl, C _3-6 cycloalkyl, C _2-8 alkenyl, C _2-8 alkynyl, aryl group, heteroaryl, aryl-C _1-4 alkyl and alkoxy-C _1-4 alkyl, or when R ^f and R ^g are connected to the same nitrogen atom, they can be combined with the nitrogen atom to form O- A five-membered or six-membered ring with 2 additional heteroatoms as ring atoms, each ^Rh independently selected from: C _1-8 alkyl, C _1-8 haloalkyl, C _3-6 cycloalkyl, C _{2- 8} alkenyl, C _2-8 alkynyl, aryl, heteroaryl, aryl-C _1-4 alkyl and alkoxy-C _1-4 -alkyl, wherein, R ^f , R ^g and ^Rh The aliphatic portion of is also optionally substituted with 1-3 substituents selected from -OH, -OR ^o , -OC(O)NHR ^o , -OC(O)N(R ^o ) ₂ , -SH, -SR ^o , -S(O)R ^o , -S(O) ₂ R ^o , -SO ₂ NH ₂ , -S(O) ₂ NHR ^o , -S(O) ₂ N(R ^o ) ₂ , - NHS(O) ₂ R ^o , -NR ^o S(O) ₂ R ^o , -C(O)NH ₂ , -C(O)NHR ^o , -C(O)N(R ^o ) ₂ , -C( O)R ^o , -NHC(O)R ^o , -NR ^o C(O)R ^o , -NHC(O)NH ₂ , -NR ^o C(O)NH ₂ , -NR ^o C(O)NHR ^o , -NHC(O)NHR ^o , -NR ^o C(O)N(R ^o ) ₂ , -NHC(O)N(R ^o ) ₂ , -CO ₂ H, -CO ₂ R ^o , -NHCO ₂ R ^o , -NR ^o CO ₂ R ^o , -CN, -NO ₂ , -NH ₂ , -NHR ^o , -N(R ^o ) ₂ , -NR ^o S(O)NH _{2 ,} and -NR ^o S(O) ₂ NHR ^o , wherein each R ⁰ is independently unsubstituted C _1-6 alkyl. Among the most preferred HAr groups are substituted or unsubstituted pyrazole and benzopyrazole, and substituted or unsubstituted triazole and benzotriazole. Preferably, substituted or unsubstituted pyrazoles and benzopyrazoles are attached to the remainder of the molecule through the nitrogen atom of the pyrazole ring. Alternatively, two ^R3 substituents on adjacent carbon atoms combine to form a five- or six-membered ring with 0-3 heteroatoms as ring atoms. In other embodiments, HAr can be a furan ring or a thiophene ring (eg, without ring nitrogen atoms), and can be optionally substituted as described above.

Symbol L ¹ represents a linking group containing 1-3 main chain atoms selected from C, N, O and S, and may be substituted by 1-3 substituents selected from: halogen, phenyl, -OR ⁱ , -OC(O)R ⁱ , -NR ⁱ R ^j , -SR ⁱ , -R ^k , -CN, -NO ₂ , -CO ₂ R ⁱ , -CONR ⁱ R ^j , -C(O)R ⁱ , - OC(O)NR ⁱ R ^j , -NR ^j C(O)R ⁱ , -NR ^j C(O) ₂ R ^k , -X ⁴ OR ⁱ , -X ⁴ OC(O)R ⁱ , -X ⁴ NR ⁱ R ^j , -X ⁴ SRi, -X ⁴ CN, -X ⁴ NO ₂ , -X ⁴ CO ₂ R ⁱ , -X ⁴ CONR ⁱ R ^j , -X ⁴ C(O)R ⁱ , -X ⁴ OC (O)NR ⁱ R ^j , -X ⁴ NR ^j C(O)R ⁱ and -X ⁴ NR ^j C(O) ₂ R ^k , wherein X ⁴ is selected from C _1-4 alkylene, C _{2- 4} alkenylene and C _2-4 alkynylene, R ⁱ and R ^j are each independently selected from: hydrogen, C _1-8 alkyl, C _1-8 haloalkyl, C _3-6 cycloalkyl, C _{2 -8} alkenyl, C _2-8 alkynyl, aryl, heteroaryl, aryl-C _1-4 alkyl and aryloxy-C _1-4 -alkyl, each R ^k is independently selected from: C _1-8 alkyl, C _1-8 haloalkyl, C _3-6 cycloalkyl, C _2-8 alkenyl, C _2-8 alkynyl, aryl, heteroaryl, aryl-C _1-4 alkane and aryloxy-C _1-4 alkyl. In certain preferred embodiments, the linker is unsubstituted, while in other preferred embodiments, substituents are present which increase the amount partitioned into the chosen solvent or into the chosen tissue. For example, the addition of a hydroxyl group to the propylene chain generally provides a compound with better solubility in water. Preferably, L ¹ is selected from -CH ₂ -, -CH ₂ CH ₂ -, -CH ₂ CH ₂ CH ₂ -, -CH ₂ O-, -CH ₂ NH-, -CH ₂ OCH ₂ - and -CH ₂ NHCH ₂ -. More preferably, L ¹ is -CH ₂ -.

In addition to the compounds provided herein, the present invention also provides pharmaceutical compositions containing one or more of these compounds, as well as methods of using these compounds in methods of treatment, primarily for the treatment of diseases associated with CCR1 signaling activity.

Brief description of the drawings

Figures 1A to 1G provide selected and preferred ^Ar1 groups for compounds of formulas I, II and III.

Figures 2A to 2Z, 2AA to 2HH and 3 provide selected and preferred HAr groups for compounds of formulas I, II, III and IV.

Figures 4A to 4C provide structures of selected commercially available starting materials.

Figures 5A to 5L provide a general formula for a preferred embodiment of the invention.

Detailed description of the invention

I. Abbreviations and Definitions

Unless otherwise indicated, the term "alkyl", by itself or as part of another substituent, refers to a straight or branched chain hydrocarbon group containing the indicated number of carbon atoms (ie, _C1-8 means 1-8 carbon atoms). Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, etc. . The term "alkenyl" refers to an unsaturated alkyl group containing one or more double bonds. Similarly, the term "alkynyl" refers to an unsaturated alkyl group containing one or more triple bonds. Examples of such unsaturated alkyl groups include vinyl, 2-propenyl, 2-butenyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3- (1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, higher homologues and isomers. The term "cycloalkyl" refers to a hydrocarbon ring containing the specified number of ring atoms (e.g., _C3-6 cycloalkyl), which may be fully saturated or have not more than one double bond between ring atoms, e.g., "cycloalkane The "group" also refers to bicyclic or polycyclic hydrocarbon rings, such as bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, etc.

_{The term} "alkylene" by itself or as part of another substituent refers to a divalent radical _derived from an alkane, eg _{-CH2CH2CH2CH2-} . Typically, the alkyl (or alkylene) group contains 1 to 24 carbon atoms, with 10 or fewer carbon atoms being preferred in the present invention. "Lower alkyl" or "lower alkylene" are shorter chain alkyl or alkylene groups, usually containing four or fewer carbon atoms. Similarly, "alkenylene" and "alkynylene" refer to unsaturated forms of "alkylene" having double or triple bonds, respectively.

The terms "alkoxy", "alkylamino" and "alkylthio" (thioalkoxy) are used in their conventional sense to refer to those alkyl groups attached to the rest of the molecule through an oxygen, amino or sulfur atom, respectively. base. In addition, for dialkylamino groups, the alkyl moieties may be the same or different, and may combine with the N atom to which they are attached to form a 3-7 membered ring. Thus, the group -NR ^a R ^b may include piperidinyl, pyrrolidinyl, morpholinyl, azetidinyl, and the like.

Unless otherwise stated, the term "halo" or "halogen", by itself or as part of another substituent, refers to a fluorine, chlorine, bromine, iodine atom. In addition, the term "haloalkyl" is intended to include monohaloalkyl, polyhaloalkyl. For example, the term "C _1-4 haloalkyl" is meant to include trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl and the like.

Unless otherwise indicated, the term "aryl" refers to a polyunsaturated, usually aromatic, hydrocarbon group which may be monocyclic or polycyclic (up to three rings), the rings being fused to each other or covalently linked. The term "heteroaryl" refers to an aryl group (or ring) containing 1-5 heteroatoms selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized change. A heteroaryl can be attached to the rest of the molecule through a heteroatom. Non-limiting examples of aryl include: phenyl, naphthyl and biphenyl, non-limiting examples of heteroaryl include: 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-pyrazole Base, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-iso _Azolyl, 5-iso_azolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl , 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, benzopyrazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolinyl and 6-quinolinyl. Substituents for the above aryl, heteroaromatic ring systems are selected from the acceptable substituents described below.

Briefly, the term "aryl" when used in conjunction with other terms (eg, aryloxy, arylthiooxy, arylalkyl) is meant to include aryl and heteroaryl rings as defined above. Thus, the term "arylalkyl" is intended to include those groups in which the aryl is attached to an alkyl group (eg, benzyl, phenethyl, pyridylmethyl, etc.).

In some embodiments, the above terms (eg, "alkyl," "aryl," and "heteroaryl") are intended to encompass both substituted and unsubstituted forms of such groups. Preferred substituents for various types of radicals are provided below. Briefly, the terms aryl and heteroaryl refer to the substituted or unsubstituted forms provided below, while the term "alkyl" and related aliphatic groups mean the unsubstituted forms (unless substituted is specified).

Substituents for alkyl groups (including those commonly referred to as alkylene, alkenyl, alkynyl, cycloalkyl) may be various groups selected from: -halogen, -OR', -NR'R ", -SR', -SiR'R"R_, -OC(O)R', -C(O)R', -CO ₂ R', -CONR'R", -OC(O)NR'R" , -NR"C(O)R', -NR'-C(O)NR"R_, -NR"C(O) ₂ R', -NH-C(NH ₂ )=NH, -NR'C( NH ₂ )=NH, -NH-C(NH ₂ )=NR', -S(O)R', -S(O) ₂ R', -S(O) ₂ NR'R", -NR'S(O ) ₂ R", -CN and -NO ₂ , the number of substituents is 0 to (2m'+1), wherein m' is the total number of carbon atoms in the group. R', R" and R_respectively Independently refers to hydrogen, unsubstituted C _1-8 alkyl, unsubstituted heteroalkyl, unsubstituted aryl, 1-3 halogen, unsubstituted C _1-8 alkyl, C _1-8 alkane Oxygen or C _1-8 thioalkoxy substituted aryl, or unsubstituted aryl-C _1-4 alkyl. When R' and R" are bound to the same nitrogen atom, they may combine with the nitrogen atom to form a 3-, 4-, 5-, 6- or 7-membered ring. For example, -NR'R" means including 1- Pyrrolidinyl and 4-morpholinyl.

Similarly, aryl and heteroaryl groups can have a variety of substituents, usually selected from: -halogen, -OR', -OC(O)R', -NR'R", -SR', -R', -CN, -NO ₂ , -CO ₂ R', -CONR'R", -C(O)R', -OC(O)NR'R", -NR"C(O)R', -NR" C(O) ₂ R',, -NR'-C(O)NR"R_, -NH-C(NH ₂ )=NH, -NR'C(NH ₂ )=NH, -NH-C(NH ₂ )=NR', -S(O)R', -S(O) ₂ R', -S(O) ₂ NR'R", -NR'S(O) ₂ R", -N ₃ , perfluoro(C ₁ -C ₄ )alkoxy and perfluoro(C ₁ -C ₄ )alkyl, the number of substituents is from 0 to the total number of chemical valences opened by the aromatic ring system; and R', R" and R_ Each independently selected from: hydrogen, C _1-8 alkyl, C _3-6 cycloalkyl, C _2-8 alkenyl, C _2-8 alkynyl, unsubstituted aryl and heteroaryl, (unsubstituted Aryl)-C _1-4 alkyl and unsubstituted aryloxy-C _1-4 alkyl. Other suitable substituents include the above-mentioned aryl groups bonded to ring atoms through an alkylene chain of 1-4 carbon atoms. Each substituent of the group.

Two substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced by substituents of the formula -TC(O)-(CH ₂ ) _q -U-, wherein T and U are independently -NH -, -O-, -CH ₂ - or a single bond, and q is an integer of 0-2. Alternatively, two substituents on adjacent atoms of an aromatic or heteroaryl ring may optionally be replaced by substituents of the formula -A-(CH ₂ ) _r -B-, wherein A and B are independently -CH ₂ -, -O-, -NH-, -S-, -S(O)-, -S(O) ₂ -, -S(O) ₂ NR'- or a single bond, r is an integer of 1-3. One single bond of the new ring thus formed may optionally be replaced by a double bond. Alternatively, two substituents on adjacent atoms of the aromatic or heteroaryl ring may optionally be replaced by substituents of the formula -(CH ₂ ) _s -X-(CH ₂ ) _t -, wherein s and t are independently is an integer of 0-3, and X is -O-, -NR', -S-, -S(O)-, -S(O) ₂ - or -S(O) ₂ NR'-. The R' substituent in -NR'- and -S(O) ₂ NR'- is selected from hydrogen or unsubstituted C _1-6 alkyl.

As used herein, the term "heteroatom" is meant to include oxygen (O), nitrogen (N), sulfur (S) and silicon (Si).

The term "pharmaceutically acceptable salt" is meant to include salts of the active compounds which may be prepared with relatively nontoxic acids or bases, depending on the particular substituents found in the compounds described herein. When compounds of the present invention contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of the compound with a sufficient amount of the desired base, either directly or in a suitable inert solvent. Salts derived from pharmaceutically acceptable inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganese, manganous, potassium, sodium , zinc salt, etc. Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary and tertiary amines, including substituted amines, cyclic amines, naturally occurring amines and the like, such as arginine, betaine, caffeine, choline, N , N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine , glucosamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucosamine, morpholine, piperazine, piperadine, polyamine resin, procaine, purine, Theobromine, triethylamine, trimethylammonium, tripropylamine, tromethamine, etc.

When compounds of the present invention contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either directly or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids, such as hydrochloric, hydrobromic, nitric, carbonic, monohydrocarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydrogen Salts of iodic acid or phosphorous acid, etc., and derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, mandelic acid, phthalic acid, Salts of benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, etc. Also included are salts of amino acids, such as arginine salts, etc., and salts of organic acids, such as glucuronic acid or galacturonic acid, etc. (see, e.g., Berge, S.M. et al., "Pharmaceutical Salts (Pharmaceutical Salts)", Journal of Pharmaceutical Science, 1977, 66, 1-19). Some particular compounds of the invention contain both base and acid functionalities, which allow conversion of the compounds into base or acid addition salts.

The neutral forms of the compounds can be prepared by contacting the salt with a base or acid and isolating the parent compound in the usual manner. The parent form of the compound differs from many of the salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for purposes of the present invention.

In addition to salt forms, the present invention provides compounds in prodrug form. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present invention. In addition, prodrugs can be converted to compounds of the invention by chemical or biochemical methods in an in vitro setting. For example, a prodrug can be slowly converted to a compound of the invention when it is placed in a transdermal patch reservoir containing a suitable enzyme or chemical reagent.

Some of the compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are also within the scope of the present invention. Some of the compounds of the present invention may exist in polymorphic or amorphous forms. In general, all physical forms are equivalent for the uses of the present invention and are intended to be within the scope of the present invention.

Some of the compounds of the present invention contain asymmetric carbon atoms (optical centers) or double bonds; racemates, diastereomers, geometric isomers, regioisomers and individual isomers (e.g., separated enantiomers) are included within the scope of the present invention. The compounds of the present invention may contain non-naturally occurring atomic isotopes at one or more of the atoms that constitute the compounds. For example, the compound may be labeled with a radioactive isotope, such as tritium ( ^3H ), iodine-125 ( ^125I ), or carbon-14 ( ^14C ). All isotopic variations of the compounds of the invention, whether radioisotopic or not, are included within the scope of the invention.

II. Overview

The present invention arose from the discovery that compounds of formula I (and sub-formulas II, III and IV) are potent antagonists of the CCR1 receptor. The compounds have anti-inflammatory activity in vivo. Accordingly, the compounds provided herein are useful in pharmaceutical compositions, methods of treating CCR1-mediated diseases, and as controls in assays to identify competitive CCR1 antagonists.

III. Compounds

In one aspect, the invention provides a compound having the formula, or a pharmaceutically acceptable salt or N-oxide thereof:

In the above formula, subscript n is an integer of 1-2, preferably 1. The subscript m is an integer of 0-10, limited by the number of available substituent positions on the piperazine or homopiperazine ring to which it is connected. For example, piperazine derivatives (n is 1) may have 0-8 R ¹ groups, preferably 0-4 R ¹ groups, more preferably 0, 1 or 2 R ¹ groups.

The symbol ^Ar represents optionally substituted aryl or heteroaryl. Preferred aryl groups are phenyl and naphthyl. Preferred heteroaryl groups are those having 5-10 ring atoms, at least one of which is a nitrogen atom (e.g., pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, quinolinyl, quinolyl oxalinyl, purinyl, etc.). Each Ar ^ring is optionally substituted with 1-5 ^{R substituents} independently selected from: halogen, ^-ORc , -OC(O) ^Rc , ^{-NRcRd ,} -SR ^c , -R ^e , -CN, -NO ₂ , -CO ₂ R ^c , -CONR ^c R ^d , -C(O)R ^c , -OC(O)NR ^c R ^d , -NR ^d C(O) R ^c , -NR ^d C(O) ₂ R ^e , -NR ^c -C(O)NR ^c R ^d , -NH-C(NH ₂ )=NH, -NR ^e C(NH ₂ )=NH, - NH-C(NH ₂ )=NR ^e , -NH-C(NHR ^e )=NH, -NR ^e C(NHR ^e )=NH, -NR ^e C(NH ₂ )=NR ^e , -NH-C( NHR ^e )=NR ^e , -NH-C(NR ^e R ^e )=NH, -S(O)R ^e , -S(O) ₂ R ^e , -NR ^c S(O) ₂ R ^e , -S (O) ₂ NR ^c R ^d , -N ₃ , -C(NOR ^c )R ^d , -C(NR ^c W)=NW, -N(W)C(R ^c )=NW, -NR ^c C( S) NR ^c R ^d , -X ² C(NOR ^c )R ^d , -X ² C(NR ^c W )=NW, -X ² N(W)C(R ^c )=NW, -X ² NR ^c C(S)NR ^c R ^d , -X ² OR ^c , -OX ² OR ^c , -X ² OC(O)R ^c , -X ² NR ^c R ^d , -OX ² NR ^c R ^d , -X ² SR ^c , -X ² CN , -X ² NO ₂ , -X ² CO ₂ R ^c , -OX ² CO ₂ R ^c , -X ² CONR ^c R ^d , -OX ² CONR ^c R ^d , -X ² C (O)R ^c , -X ² OC(O)NR ^c R ^d , -X ² NR ^d C(O)R ^c , -X ² NR ^d C(O) ₂ R ^e , -X ² NR ^c C( O) NR ^c R ^d , -X ² NH-C(NH ₂ )=NH, -X ² NR ^e C(NH ₂ )=NH, -X ² NH-C(NH ₂ )=NR ^e , -X ² NH-C(NHR ^e )=NH, -X ² S(O) ^Re , -X ² S(O) ₂ R ^e , -X ² NR ^c S(O) ₂ R ^e , -X ² S(O ) ₂ NR ^c R ^d , -X ² N ₃ , -NR ^d -X ² OR ^c , -NR ^d -X ² NR ^c R ^d , -NR ^d -X ² CO ₂ R ^c and -NR ^d -X ² CONR ^c R ^d , wherein, W is selected from R ^c , -CN, -CO ₂ R ^c and -NO ₂ , X ² is selected from C _1-4 alkylene, C _2-4 alkenylene and C _2-4 Alkynylene, R ^c and R ^d are each independently selected from: hydrogen, C _1-8 alkyl, C _1-8 haloalkyl, C _3-6 cycloalkyl, C _2-8 alkenyl, C _2-8 Alkynyl, aryl, heteroaryl, aryl-C _1-4 alkyl and aryloxy-C _1-4 alkyl, or when R ^c and R ^d are connected to the same nitrogen atom, they and the nitrogen atom Combined to form a five- or six-membered ring having 0-2 additional heteroatoms as ring atoms; each R ^is independently selected from: C _1-8 alkyl, C _1-8 haloalkyl, C _3-6 cycloalkane Base, C _2-8 alkenyl, C _2-8 alkynyl, aryl, heteroaryl, aryl-C _1-4 alkyl and aryloxy-C _1-4 alkyl, R ^c , R ^d and R ^e are each further optionally substituted with 1-3 groups selected from -OH, -OR ⁿ , -OC(O)NHR ⁿ , -OC(O)N(R ⁿ ) ₂ , -SH, - SR ⁿ , -S(O)R ⁿ , -S(O) ₂ R ⁿ , -SO ₂ NH ₂ , -S(O) ₂ NHR ⁿ , -S(O) ₂ N(R ⁿ ) ₂ , -NHS (O) ₂ R ⁿ , -NR ⁿ S(O) ₂ R ⁿ , -C(O)NH ₂ , -C(O)NHR ⁿ , -C(O)N(R ⁿ ) ₂ , -C(O )R ⁿ , -NHC(O)R ⁿ , -NR ⁿ C(O)R ⁿ , -NHC(O)NH ₂ , -NR ⁿ C(O)NH ₂ , -NR ⁿ C(O)NHR ⁿ , -NHC(O)NHR ⁿ , -NR ⁿ C(O)N(R ⁿ ) ₂ , -NHC(O)N(R ⁿ ) ₂ , -CO ₂ H, -CO ₂ R ⁿ , -NHCO ₂ R ⁿ , -NR ⁿ CO ₂ R ⁿ , -CN, -NO ₂ , -NH ₂ , -NHR ⁿ , -N(R ⁿ ) ₂ , -NR ⁿ S(O)NH ₂ and -NR ⁿ S(O) ₂ NHR ⁿ , wherein each R ⁿ is independently an unsubstituted C _1-6 alkyl group. Optionally, two ^R substituents on adjacent carbon atoms combine to form a five- or six-membered ring with 0-3 heteroatoms as ring atoms.

HAr is optionally substituted heteroaryl. The heteroaryl group of HAr may be the same as or different from the heteroaryl group of ^Ar1 . Typically, the HAr group is monocyclic, but can also be a fused bicyclic ring system having 5-10 ring atoms, at least one of which is a nitrogen atom. Certain preferred heteroaryl groups are 5- or 6-membered rings having at least one nitrogen atom as a ring atom, and fused ring systems having a 5-membered ring fused to a benzene ring, e.g., pyrazolyl, imidazolyl , triazolyl, tetrazolyl, oxazolyl, isoxazolyl, _diazolyl, _thiadiazolyl, pyrrolyl, thiazolyl, isothiazolyl, benzimidazolyl, benzopyrazolyl and Benzotriazolyl. Preferably, when present, the fused bicyclic HAr moiety is linked to the remainder of the molecule through the 5-membered ring. In addition, each HAr may be substituted with 1-5 ^R3 substituents independently selected from: halogen ^{, -ORf} , -OC(O) ^Rf , ^{-NRfRg , -SRf} , - R ^h , -CN, -NO ₂ , -CO ₂ R ^f , -CONR ^f R ^g , -C(O)R ^f , -OC(O)NR ^f R ^g , -NR ^g C(O)R ^f , -NR ^g C(O) ₂ R ^h , -NR ^f -C(O)NR ^f R ^g , -NH-C(NH ₂ )=NH, -NR ^h C(NH ₂ )=NH, -NH-C (NH ₂ )=NR ^h , -NH-C(NHR ^h )=NH, -NR ^h C(NHR ^h )=NH, -NR ^h C(NH ₂ )=NR ^h , -NH-C(NHR ^h ) =NR ^h , -NH-C(NR ^h R ^h )=NH, -S(O)R ^h , -S(O) ₂ R ^h , -NR ^f S(O) ₂ R ^h , -S(O) ₂ NR ^f R ^g , -NR ^f S(O) ₂ NR ^f R ^g , -C(NOR ^f )R ^g , -C(NR ^f W ^a )＝NW ^a , -N(W ^a )C(R ^f )=NW ^a , -N ₃ , -X ³ OR ^f , -X ³ OC(O)R ^f , -X ³ NR ^f R ^g , -X ³ SR ^f , -X ³ CN, -X ³ NO ₂ , -X ³ CO ₂ R ^f , -X ³ CONR ^f R ^g , -X ³ C(O)R ^f , -X ³ OC(O)NR ^f R ^g , -X ³ NR ^g C(O)R ^f , -X ³ NR ^g C(O) ₂ R ^h , -X ³ NR ^f -C(O)NR ^f R ^g , -X ³ NH-C(NH ₂ )=NH, -X ³ NR ^h C(NH ₂ )=NH, -X ³ NH-C(NH ₂ )=NR ^h , -X ³ NH-C(NHR ^h )=NH, -X ³ S(O)R ^h , -X ³ S(O) ₂ R ^h , -X ³ NR ^f S(O) ₂ R ^h , -X ³ S(O) ₂ NR ^f R ^g , -X ³ C(NOR ^f )R ^g , -X ³ C(NR ^f W ^a )= NW ^a , -X ³ N(W ^a )C(R ^f )=NW ^a , -Y, -SO ₂ Y, -C(O)Y, -X ³ Y, -X ³ N ₃ , -OX ³ OR ^f , -OX ³ NR ^f R ^g , -OX ³ CO ₂ R ^f , -OX ³ CONR ^f R ^g , -NR ^g -X ³ OR ^f , -NR ^g -X ³ NR ^f R ^g , -NR ^g - X ³ CO ₂ R ^f and -NR ^g -X ³ CONR ^f R ^g , wherein, Y is a 5-10 membered aryl, heteroaryl or heterocyclic ring, optionally substituted by 1-3 substituents selected from the following : Halogen, -OR ^f , -NR ^f R ^g , -R ^h , -SR ^f , -CN, -NO ₂ , -CO ₂ R ^f , -CONR ^f R ^g , -C(O)R ^f , -NR ^g C(O)R ^f , -S(O)R ^h , -S(O) ₂ R ^h , -NR ^f S(O) ₂ R ^h , -S(O) ₂ NR ^f R ^g , -C( NOR ^f )R ^g , -C(NR ^f W ^a )=NW ^a , -N(W ^a )C(R ^f )=NW ^a , -X ³ C(NOR ^f )R ^g , -X ³ C(NR ^f W ^a )=NW ^a , -X ³ N(W ^a )C(R ^f )=NW ^a , -X ³ OR ^f , -X ³ NR ^f R ^g , -X ³ NR ^f S(O) ₂ R ^h and -X ³ S(O) ₂ NR ^f R ^g , wherein W ^a is selected from R ^f , -CN, -CO ₂ R ^h and -NO ₂ , and each X ³ is independently selected from C _1-4 alkylene C _2-4 alkenylene and C _2-4 alkynylene, R ^f and R ^g are each independently selected from: hydrogen, C _1-8 alkyl, C _1-8 haloalkyl, C _3-6 ring Alkyl, C _2-8 alkenyl, C _2-8 alkynyl, aryl, heteroaryl, aryl-C _1-4 alkyl and alkoxy-C _1-4 -alkyl, or when R ^f When R ^g is attached to the same nitrogen atom, it can be combined with the nitrogen atom to form a five-membered or six-membered ring with 0-2 additional heteroatoms as ring atoms, and each R ^h is independently selected from: C _1-8 alkyl , C _1-8 haloalkyl, C _3-6 cycloalkyl, C _2-8 alkenyl, C _2-8 alkynyl, aryl, heteroaryl, aryl-C _1-4 alkyl and alkoxy -C _1-4 -Alkyl, wherein the aliphatic part of R ^f , R ^g and ^Rh is optionally substituted by 1-3 substituents selected from: -OH, -OR ^o , -OC(O )NHR ^o , -OC(O)N(R ^o ) ₂ , -SH, -SR ^o , -S(O)R ^o , -S(O) ₂ R ^o , -SO ₂ NH ₂ , -S(O ) ₂ NHR ^o , -S(O) ₂ N(R ^o ) ₂ , -NHS(O) ₂ R ^o , -NR ^o S(O) ₂ R ^o , -C(O)NH ₂ , -C(O )NHR ^o , -C(O)N(R ^o ) ₂ , -C(O)R ^o , -NHC(O)R ^o , -NR ^o C(O)R ^o , -NHC(O)NH ₂ , -NR ^o C(O)NH ₂ , -NR ^o C(O)NHR ^o , -NHC(O)NHR ^o , -NR ^o C(O)N(R ^o ) ₂ , -NHC(O)N(R o ) ^o ) ₂ , -CO ₂ H, -CO ₂ R ^o , -NHCO ₂ R ^o , -NR ^o CO ₂ R ^o , -CN, -NO ₂ , -NH ₂ , -NHR ^o , -N(R ^o ) _2. -NR ^o S(O)NH ₂ and -NR ^o S(O) ₂ NHR ^o , wherein each R ⁰ is independently an unsubstituted C _1-6 alkyl group. Optionally, 2 ^R3 groups on adjacent carbon atoms together form a five- or six-membered ring with 0-3 heteroatoms as ring atoms. Among the most preferred HAr groups are substituted or unsubstituted pyrazole and benzopyrazole, and substituted or unsubstituted triazole and benzotriazole. Preferably, the substituted or unsubstituted pyrazole is attached to the rest of the molecule through the nitrogen atom of the pyrazole ring.

Symbol L ¹ represents a linking group containing 1-3 main chain atoms selected from C, N, O and S, and may be substituted by 1-3 substituents selected from: halogen, phenyl, -OR ⁱ , -OC(O)R ⁱ , -NR ⁱ R ^j , -SR ⁱ , -R ^k , -CN, -NO ₂ , -CO ₂ R ⁱ , -CONR ⁱ R ^j , -C(O)R ⁱ , - OC(O)NR ⁱ R ^j , -NR ^j C(O)R ⁱ , -NR ^j C(O) ₂ R ^k , -X ⁴ OR ⁱ , -X ⁴ OC(O)R ⁱ , -X ⁴ NR ⁱ R ^j , -X ⁴ SR ⁱ , -X ⁴ CN, -X ⁴ NO ₂ , -X ⁴ CO ₂ R ⁱ , -X ⁴ CONR ⁱ R ^j , -X ⁴ C(O)R ⁱ , -X ⁴ OC(O)NR ⁱ R ^j , -X ⁴ NR ^j C(O)R ⁱ and -X ⁴ NR ^j C(O) ₂ R ^k , wherein X ⁴ is selected from C _1-4 alkylene, C _{2 -4} alkenylene and C _2-4 alkynylene, R ⁱ and R ^j are each independently selected from: hydrogen, C _1-8 alkyl, C _1-8 haloalkyl, C _3-6 cycloalkyl, C _2-8 alkenyl, C _2-8 alkynyl, aryl, heteroaryl, aryl-C _1-4 alkyl and aryloxy-C _1-4 -alkyl, each ^R independently selected from: C _1-8 alkyl, C _1-8 haloalkyl, C _3-6 cycloalkyl, C 2-8 alkenyl, C _2-8 alkynyl, aryl, heteroaryl, aryl- _{C 1-4} Alkyl and aryloxy-C _1-4 alkyl. In certain preferred embodiments, the linker is unsubstituted, while in other preferred embodiments, substituents are present which increase the amount partitioned into the chosen solvent or into the chosen tissue. For example, the addition of hydroxyl groups to the propylene chain generally provides compounds with better solubility in water. Preferably, L ¹ is selected from -CH ₂ -, -CH ₂ CH ₂ -, -CH ₂ CH ₂ CH ₂ -, -CH ₂ O-, -CH ₂ NH-, -CH ₂ OCH ₂ - and -CH ₂ NHCH ₂ -. More preferably L ¹ is -CH ₂ -.

Returning to the piperazine or homopiperazine moiety of the compound, each ^R is a substituent independently selected from C _1-8 alkyl, C _1-8 haloalkyl, C _3-6 cycloalkyl, C _2-8 Alkenyl and C _2-8 alkynyl, -COR ^a , -CO ₂ R ^a , -CONR ^a R ^b , -NR ^a COR ^b , -SO ₂ R ^a , -X ¹ COR ^a , -X ¹ CO ₂ R ^a , -X ¹ CONR ^a R ^b , -X ¹ NR ^a COR ^b , -X ¹ SO ₂ R ^a , -X ¹ SO ₂ NR ^a R ^b , -X ¹ NR ^a R ^b , -X ¹ OR ^a , Wherein, X ¹ is selected from C _1-4 alkylene, C _2-4 alkenylene, C _2-4 alkynylene, R ^a and R ^b are each independently selected from hydrogen, C _1-8 alkyl, C _{1 -8} haloalkyl, C _3-6 cycloalkyl and aryl-C _1-4 alkyl, or, when R ^a and R ^b are connected on the same nitrogen atom, another O- A 5- or 6-membered ring with 2 heteroatoms as ring atoms, wherein the aliphatic portion of each ^R substituent is optionally substituted with 1-3 groups selected from: -OH, ^-ORm , -OC (O)NHR ^m , -OC(O)N(R ^m ) ₂ , -SH, -SR ^m , -S(O)R ^m , -S(O) ₂ R ^m , -SO ₂ NH ₂ , -S (O) ₂ NHR ^m , -S(O) ₂ N(R ^m ) ₂ , -NHS(O) ₂ R ^m , -NR ^m S(O) ₂ R ^m , -C(O)NH ₂ , -C (O)NHR ^m , C(O)N(R ^m ) ₂ , -C(O)R ^m , -NHC(O)R ^m , -NR ^m C(O)R ^m , -NHC(O)NH ₂ , -NR ^m C(O)NH ₂ , -NR ^m C(O)NHR ^m , -NHC(O)NHR ^m , -NR ^m C(O)N(R ^m ) ₂ , -NHC(O)N( R ^m ) ₂ , -CO ₂ H, -CO ₂ R ^m , -NHCO ₂ R ^m , -NR ^m CO ₂ R ^m , -CN, -NO ₂ , -NH ₂ , -NHR ^m , -N(R ^m ) ₂ , -NR ^m S(O)NH ₂ and -NR ^m S(O) ₂ NHR ^m , wherein each R ^m is independently unsubstituted C ₁ - ₆ alkyl. In some preferred embodiments, when R ¹ exists, it is selected from: methyl, ethyl, isopropyl, -CH ₂ OH, -CH ₂ OCH ₃ , -CH ₂ OCH ₂ CH ₃ , -CH ₂ OCH (CH ₃ ) ₂ , -CH(CH ₃ )OH and -CH(CH ₃ )OCH ₃ , more preferably methyl, -CH ₂ OH and -CH ₂ OCH ₃ .

In addition to the above general formula, and each compound of the following formula, there are commercially available or known in the literature, including: CAS Reg.No.492422-98-7, 1-[[4-bromo-5- Methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-4-(5-chloro-2-methylphenyl)-piperazine; CAS Reg.No.351986- 92-0,1-[[4-chloro-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-4-(4-fluorophenyl)-piper Azine; CASReg.No.356039-23-1,1-[(3,5-Dimethyl-4-nitro-1H-pyrazol-1-yl)acetyl]-4-(4-fluorophenyl )-piperazine; 1-(2-{4-nitro-3,5-dimethyl-1H-pyrazol-1-yl}propionyl)-4-phenylpiperazine; 2-(2,4 -Dinitro-imidazol-1-yl)-1-[4-(4-fluorophenyl)-piperazin-1-yl]-ethanone; 2-(2,4-Dinitro-imidazole-1 -yl)-1-(4-phenyl-piperazin-1-yl)-ethanone; 2-(4-nitro-imidazol-1-yl)-1-(4-phenyl-piperazine-1 -yl)-ethanone; and CAS Reg.No.492992-15-1,3-[3-fluoro-4-[4-[(1-pyrazolyl)acetyl]piperazin-1-yl]benzene Base]-5-[[(isoxazol-3-yl)amino]methyl]isoxazole.

A number of embodiment groups can be listed below.

In a first group of preferred embodiments, the compound can be represented by formula I, wherein Ar ^is selected from:

(i) phenyl, substituted by 1-5 ^R groups;

(ii) pyridyl, substituted by 1-4 ^R groups; and

(iii) pyrimidinyl, substituted by 1-3 ^R groups;

(iv) pyrazinyl, substituted by ^1-3 R groups; and

(v) pyridazinyl, substituted by 1-3 ^R groups;

Wherein, each R ² is independently selected from halogen, -OR ^c , -OC(O)R ^c , -NR ^c R ^d , -SR ^c , -R ^e , -CN, -NO ₂ , -CO ₂ R ^c , -CONR ^c R ^d , -C(O)R ^c , -OC(O)NR ^c R ^d , -NR ^d C(O)R ^c , -NR ^d C(O) ₂ R ^e , -NR ^c -C (O)NR ^c R ^d , -C(NOR ^c )R ^d , -C(NR ^c W )=NW, -N(W)C(R ^c )=NW, -S(O)R ^e , -S (O) ₂ ^Re , -NR ^c S(O) ₂ ^Re , -S(O) ₂ NR ^c R ^d and -N ₃ , wherein R ^c and R ^d are each independently selected from: hydrogen, C _{1- 8} alkyl, C _1-8 haloalkyl, C _3-6 cycloalkyl, C _2-8 alkenyl and C _2-8 alkynyl, each R ^e is independently selected from C _1-8 alkyl, C _1-8 Haloalkyl, C _3-6 cycloalkyl, C _2-8 alkenyl and C _2-8 alkynyl, wherein, the aliphatic part of R ^c , R ^d and R ^e is optionally selected from 1-3 Group substitution: OH, O(C _1-8 alkyl), SH, S(C _1-8 alkyl), CN, NO ₂ , NH ₂ , NH(C _1-8 alkyl) and N(C _{1 -8} alkyl) ₂ . More preferably, Ar ¹ is phenyl substituted by 1-3 R ² groups. Preferred embodiments are those wherein the Ar ^group represents the following:

Wherein, Hal is F, Cl or Br, and each R is independently C _1-6 alkyl or cycloalkyl.

In other preferred embodiments, L ¹ is -CH ₂ -, optionally replaced by phenyl, -R ^k , -X ⁴ OR ⁱ , -X ⁴ OC(O)R ⁱ , -X ⁴ NR ⁱ R ^j , -X ⁴ SR ⁱ , -X ⁴ CN or -X ⁴ NO ₂ . In a further preferred embodiment, HAr is selected from pyrazolyl ^and triazolyl, each of which is optionally substituted by ^1-3 R groups independently selected from: halogen, phenyl, thienyl,

-OR ^f , -OC(O)R ^f , -NR ^f R ^g , -SR ^f , -R ^h , -CN, -NO ₂ , -CO ₂ R ^f , -CONR ^f R ^g , -C(O) R ^f , -OC(O)NR ^f R ^g , -NR ^g C(O)R ^f , -NR ^g C(O) ₂ R ^h , -NR ^f -C(O)NR ^f R ^g , -S( O)R ^h , -S(O) ₂ R ^h , -S(O) ₂ NR ^f R ^g , -NR ^f S(O) ₂ R ^h , -NR ^f S(O) ₂ NR ^f R ^g , - N ₃ , -X ³ OR ^f , -X ³ OC(O)R ^f , -X ³ NR ^f R ^g , -X ³ SR ^f , -X ³ CN, -X ³ NO ₂ , -X ³ CO ₂ R ^f , -X ³ CONR ^f R ^g , -X ³ C(O)R ^f , -X ³ OC(O)NR ^f R ^g , -X ³ NR ^g C(O)R ^f , -X ³ NR ^g C (O) ₂ R ^h , -X ³ NR ^f -C(O)NR ^f R ^g , -X ³ S(O)R ^h , -X ³ S(O) ₂ R ^h , -X ³ NR ^f S( O) ₂ R ^h , -X ³ S(O) ₂ NR ^f R ^g and -X ³ N ₃ , wherein R ^f and R ^g are each independently selected from H, C _1-8 alkyl and C _1-8 haloalkane Each R ^h is independently selected from C _1-8 alkyl and C _1-8 haloalkyl. In a further preferred embodiment, subscript n is 1, m is 0, 1 or 2, ^Ar is phenyl substituted by 1-3 ^R groups, HAr is pyrazole substituted by ³ R groups group, L ¹ is -CH ₂ -. In certain preferred embodiments of this group, ^Ar1 is selected from those substituted phenyl moieties provided in Figures 1A to 1G.

In a second group of embodiments, the compound can be represented by formula I, wherein Ar ^is selected from:

(i) phenyl, substituted by 1-5 ^R groups;

(ii) pyridyl, substituted by 1-4 ^R groups; and

(iii) pyrimidinyl, substituted by 1-3 ^R groups;

(iv) pyrazinyl, substituted by ^1-3 R groups; and

(v) pyridazinyl, substituted by 1-3 ^R groups;

Wherein, each R ² is independently selected from: halogen, -X ² OR ^c , -OX ² OR ^c , -X ² OC(O)R ^c , -X ^{2 NR c} R ^d , -OX ² NR ^c R ^d , -X ² SR ^c , -X ² CN, -X ² NO ₂ , -X ² CO ₂ R ^c , -OX ² CO ₂ R ^c , -X ² CONR ^c R ^d , -OX ² CONR ^c R ^d , - X ² C(O)R ^c , -X ² OC(O)NR ^c R ^d , -X ² NR ^d C(O)R ^c , -X ² NR ^d C(O) ₂ R ^e , -X ² NR ^c C(O)NR ^c R ^d , -X ² NH-C(NH ₂ )=NH, -X ² NR ^e C(NH ₂ )=NH, -X ² NH-C(NH ₂ )=NR ^e , -X ² NH-C(NHR ^e )=NH, -X ² C(NOR ^c )R ^d , -X ² C(NR ^c W )=NW, -X ² N(W)C(R ^c )=NW , -X ² S(O)R ^e , -X ² S(O) ₂ R ^e , -X ² NR ^c S(O) ₂ R ^e , -X ² S(O) ₂ NR ^c R ^d and -X ² N ₃ .

In a third group of embodiments, the compound can be represented by formula I, wherein HAr is selected from pyrazolyl and triazolyl, and can be optionally substituted by 1-3 R ³ groups, said R ³ groups are independently selected from From: Halogen, -OR ^f , -OC(O)R ^f , -NR ^f R ^g , -SR ^f , -R ^h , -CN, -NO ₂ , -CO ₂ R ^f , -CONR ^f R ^g , - C(O)R ^f , -OC(O)NR ^f R ^g , -NR ^g C(O)R ^f , -NR ^g C(O) ₂ R ^h , -NR ^f -C(O)NR ^f R ^g , -NH-C(NH ₂ )=NH, -NR ^h C(NH ₂ )=NH, -NH-C(NH ₂ )=NR ^h , -NH-C(NHR ^h )=NH, -S(O )R ^h , -S(O) ₂ R ^h , -NR ^f S(O) ₂ R ^h , -S(O) ₂ NR ^f R ^g , -NR ^f S(O) ₂ R ^h , -NR ^f S (O) ₂ NR ^f R ^g , -N ₃ , -X ³ OR ^f , -X ³ OC(O)R ^f , -X ³ NR ^f R ^g , -X ³ SR ^f , -X ³ CN, -X ³ NO ₂ , -X ³ CO ₂ R ^f , -X ³ CONR ^f R ^g , -X ³ C(O)R ^f , -X ³ OC(O)NR ^f R ^g , -X ³ NR ^g C(O )R ^f , -X ³ NR ^g C(O) ₂ R ^h , -X ³ NR ^f -C(O)NR ^f R ^g , -X ³ NH-C(NH ₂ )=NH, -X ³ NR ^h C(NH ₂ )=NH, -X ³ NH-C(NH ₂ )=NR ^h , -X ³ NH-C(NHR ^h )=NH, -X ³ S(O)R ^h , -X ³ S( O) ₂ R ^h , -X ³ NR ^f S(O) ₂ R ^h , -X ³ S(O) ₂ NR ^f R ^g , -Y, -X ³ Y and -X ³ N ₃ , wherein Y is 5-10 membered aryl, heteroaryl or heterocycle, optionally substituted by 1-3 substituents selected from the group consisting of halogen, -OR ^f , -NR ^f R ^g , -R ^h , -SR ^f , -CN, -NO ₂ , -CO ₂ R ^f , -CONR ^f R ^g , -C(O)R ^f , -NR ^g C(O)R ^f , -S(O)R ^h , -S(O) ₂ R ^h , -NR ^f S(O) ₂ R ^h , -S(O) ₂ NR ^f R ^g , -X ³ OR ^f , -X ³ NR ^f R ^g , -X ³ NR ^f S(O) ₂ R ^h and -X ³ S(O) ₂ NR ^f R ^g , and each X ³ is independently selected from: C _1-4 alkylene, C _2-4 alkenylene and C _2-4 alkynylene, R ^F and R ^g are each independently selected from: hydrogen, C _1-8 alkyl, C _1-8 haloalkyl, C _3-6 cycloalkyl, C _2-8 alkenyl, C _2-8 alkynyl, aryl , heteroaryl, aryl-C _1-4 alkyl and aryloxy-C _1-4 alkyl, or when R ^f and R ^g are connected to the same nitrogen atom, they can combine with the nitrogen atom to form another 0 - a 5-membered or 6-membered ring with 2 heteroatoms as ring atoms, each ^Rh independently selected from: C _1-8 alkyl, C _1-8 haloalkyl, C _3-6 cycloalkyl, C _2-8 Alkenyl, C _2-8 alkynyl, aryl, heteroaryl, aryl-C _1-4 alkyl and aryloxy-C _1-4 alkyl, R ^f , R ^g and ^Rh are also optionally Substituted by 1-3 groups selected from: -OH, -OR ^o , -OC(O)NHR ^o , -OC(O)N(R ^o ) ₂ , -SH, -SR ^o , -S(O )R ^o , -S(O) ₂ R ^o , -SO ₂ NH ₂ , -S(O) ₂ NHR ^o , -S(O) ₂ N(R ^o ) ₂ , -NHS(O) ₂ R ^o , -NR ^o S(O) ₂ R ^o , -C(O)NH ₂ , -C(O)NHR ^o , -C(O)N(R ^o ) ₂ , -C(O)R ^o , -NHC( O)R ^o , -NR ^o C(O)R ^o , -NHC(O)NH ₂ , -NR ^o C(O)NH ₂ , -NR ^o C(O)NHR ^o , -NHC(O)NHR ^o , -NR ^o C(O)N(R ^o ) ₂ , -NHC(O)N(R ^o ) ₂ , -CO ₂ H, -CO ₂ R ^o , -NHCO ₂ R ^o , -NR ^o CO ₂ R ^o , -CN, _-NO2 , _-NH2 , ^-NHRo , -N( ^Ro ) ₂ ^{, -NRoS} (O)NH2 _, and ^-NRoS (O) _2NHRo , where ^Ro is Unsubstituted C _1-6 alkyl. In this group of embodiments, preferred compounds are wherein n is 1, m is 0-2, ^Ar is phenyl substituted by 1-3 ^R groups, HAr is substituted by ^2-3 R groups, preferably is pyrazolyl substituted by 3 R ³ groups, and L ¹ is -CH ₂ - those compounds. Optionally, 2 ^R2 on ^Ar1 combine as described above to form a 5- or 6-membered ring with 0-2 heteroatoms as ring atoms. Other preferred compounds are those wherein ^Ar1 is selected from the substituted phenyl moieties shown in Figures 1A to 1G. In some preferred embodiments are those compounds wherein one ^R3 group is selected from -Y and ^-X3 -Y. More preferably, wherein Y is selected from thienyl, furyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazole group, triazolyl, tetrazolyl, oxadiazolyl, these groups are optionally substituted, or phenyl or naphthyl substituted as described above, or preferably have 1-3 independently selected Those compounds with substituents selected from: halogen, -OR ^f , -NR ^f R ^g , -COR ^f , -CO ₂ R ^f , -CONR ^f R ^g , -NO ₂ , -R ^h , -CN, -X ³ -OR ^f , -X ³ -NR ^f R ^g and -X ³ -NR ^f S(O) ₂ R ^h , wherein R ^f and R ^g are each independently selected from: H, C _1-8 alkyl, C _3-6 cycloalkyl and C _1-8 haloalkyl, each R ^h is independently selected from C _1-8 alkyl, C _3-6 cycloalkyl and C _1-8 haloalkyl.

In another set of embodiments, the compound is represented by formula II, or a pharmaceutically acceptable salt or N-oxide thereof:

In the formula, each of R ^1a , R ^1b , R ^1c , R ^1d , R ^1e , R ^1f , R ^1g and R ^1h represents independently selected from H, C _1-8 alkyl, C _1-8 haloalkyl, C _{3 -6} cycloalkyl, C _2-8 alkenyl and C _2-8 alkynyl, -COR ^a , -CO ₂ R ^a , -CONR ^a R ^b , -NR ^a COR ^b , -SO ₂ R ^a , -X ¹ COR ^a , -X ¹ CO ₂ R ^a , -X ¹ CONR ^a R ^b , -X ¹ NR ^a COR ^b , -X ¹ SO ₂ R ^a , -X ¹ SO ₂ NR ^a R ^b , -X ¹ NR ^a R ^b , -X ¹ OR ^a group, wherein X ¹ is selected from C _1-4 alkylene, C _2-4 alkenylene and C _2-4 alkynylene, R ^a and R ^b are each independently Selected from: hydrogen, C _1-8 alkyl, C _1-8 haloalkyl, C _3-6 cycloalkyl and aryl-C _1-4 alkyl, or when R ^a and R ^b are connected to the same nitrogen atom In combination with this nitrogen atom, a 5- or 6-membered ring is formed having an additional 0-2 heteroatoms as ring atoms, wherein the aliphatic portion of each ^R substituent is optionally replaced by 1-3 groups selected from Group substitution: -OH, -OR ^m , -OC(O)NHR ^m , -OC(O)N(R ^m ) ₂ , -SH, -SR ^m , -S(O)R ^m , -S(O) ₂ R ^m , -SO ₂ NH ₂ , -S(O) ₂ NHR ^m , -S(O) ₂ N(R ^m ) ₂ , -NHS(O) ₂ R ^m , -NR ^m S(O) ₂ R ^m , -C(O)NH ₂ , -C(O)NHR ^m , -C(O)N(R ^m ) ₂ , -C(O)R ^m , -NHC(O)R ^m , -NR ^m C (O)R ^m , -NHC(O)NH ₂ , -NR ^m C(O)NH ₂ , -NR ^m C(O)NHR ^m , -NHC(O)NHR ^m , -NR ^m C(O)N (R ^m ) ₂ , -NHC(O)N(R ^m ) ₂ , -CO ₂ H, -CO ₂ R ^m , -NHCO ₂ R ^m , -NR ^m CO ₂ R ^m , -CN, -NO ₂ , -NH ₂ , -NHR ^m , -N(R ^m ) ₂ , -NR ^m S(O)NH ₂ and -NR ^m S(O) ₂ NHR ^m , wherein each R ^m is independently unsubstituted C _{1- 6} alkyl. The remaining radicals have the meanings described most fully with reference to formula I above. Preferably, Ar ¹ is phenyl, optionally substituted by 1-5 R ² groups; HAr is pyrazolyl, substituted by 1-3 R ³ substituents. More preferably, L ¹ is -CH ₂ -. More preferred are those compounds wherein ^Ar is phenyl substituted with 1-3 independently selected ^R substituents and HAr is pyrazolyl substituted with 1-3, more preferably ³ R substituents. In a more preferred embodiment, ^Ar1 is selected from the substituted phenyl groups shown in Figures 1A to 1G. More preferred are those wherein HAr is selected from the substituted pyrazoles shown in Figures 2A to 2Z, 2AA to 2CC and Figure 3 . Still more preferably, no more than two of R ^1a to R ^1h are not H.

In yet another group of embodiments, there is provided a compound having formula III, or a pharmaceutically acceptable salt or N-oxide thereof:

In the formula, the subscript m is an integer of 0-2; each R ¹ is selected from -CO ₂ H, C _1-4 alkyl and C _1-4 haloalkyl, wherein the aliphatic part is substituted by the following groups if necessary : -OH, -OR ^m , -OC(O)NHR ^m , -OC(O)N(R ^m ) ₂ , -SH, -SR ^m , -S(O)R ^m , -S(O) ₂ R ^m , -SO ₂ NH ₂ , -S(O) ₂ NHR ^m , -S(O) ₂ N(R ^m ) ₂ , -NHS(O) ₂ R ^m , -NR ^m S(O) ₂ R ^m , -C(O)NH ₂ , -C(O)NHR ^m , -C(O)N(R ^m ) ₂ , -C(O)R ^m , -NHC(O)R ^m , -NR ^m C(O )R ^m , -NHC(O)NH ₂ , -NR ^m C(O)NH ₂ , -NR ^m C(O)NHR ^m , -NHC(O)NHR ^m , -NR ^m C(O)N(R ^m ) ₂ , -NHC(O)N(R ^m ) ₂ , -CO ₂ H, -CO ₂ R ^m , -NHCO ₂ R ^m , -NR ^m CO ₂ R ^m , -CN, -NO ₂ , -NH _2. -NHR ^m , -N(R ^m ) ₂ , -NR ^m S(O)NH ₂ and -NR ^m S(O) ₂ NHR ^m , wherein each R ^m is independently unsubstituted C _1-6 alkyl. In some preferred embodiments, R ¹ when present is selected from: methyl, ethyl, isopropyl, -CH ₂ OH, -CH ₂ OCH ₃ , -CH ₂ OCH ₂ CH ₃ , -CH ₂ OCH(CH ₃ ) ₂ , -CH(CH ₃ )OH and -CH(CH ₃ )OCH ₃ , or better yet methyl, -CH ₂ OH and -CH ₂ OCH ₃ . Each of R ^2a , R ^2b , R ^2c , R ^2d and R ^2e is a group independently selected from hydrogen, halogen, -OR ^c , -OC(O)R ^c , -NR ^c R ^d , -SR ^c , -R ^e , -CN, -NO ₂ , -CO ₂ R ^c , -CONR ^c R ^d , -C(O)R ^c , -OC(O)NR ^c R ^d , -NR ^d C(O)R ^c , -NR ^d C(O) ₂ R ^e , -NR ^c -C(O)NR ^c R ^d , -NH-C(NH ₂ )=NH, -NR ^e C(NH ₂ )=NH, -NH- C(NH ₂ )=NR ^e , -NH-C(NHR ^e )=NH, -S(O)R ^e , -S(O) ₂ R ^e , -NR ^c S(O) ₂ R ^e , -S (O) ₂ NR ^c R ^d , -N ₃ , -C(NOR ^c )R ^d , -C(NR ^c W)=NW, -N(W)C(R ^c )=NW, -NR ^c C( S) NR ^c R ^d , -X ² C(NOR ^c )R ^d , -X ² C(NR ^c W )=NW, -X ² N(W)C(R ^c )=NW, -X ² NR ^c C(S)NR ^c R ^d , -X ² OR ^c , -OX ² OR ^c , -X ² OC(O)R ^c , -X ² NR ^c R ^d , -OX ² NR ^c R ^d , -X ² SR ^c , -X ² CN , -X ² NO ₂ , -X ² CO ₂ R ^c , -OX ² CO ₂ R ^c , -X ² CONR ^c R ^d , -OX ² CONR ^c R ^d , -X ² C (O)R ^c , -X ² OC(O)NR ^c R ^d , -X ² NR ^d C(O)R ^c , -X ² NR ^d C(O) ₂ R ^e , -X ² NR ^c C( O) NR ^c R ^d , -X ² NH-C(NH ₂ )=NH, -X ² NR ^e C(NH ₂ )=NH, -X ² NH-C(NH ₂ )=NR ^e , -X ² NH-C(NHR ^e )=NH, -X ² S(O) ^Re , -X ² S(O) ₂ R ^e , -X ² NR ^c S(O) ₂ R ^e , -X ² S(O ) ₂ NR ^c R ^d , -X ² N ³ , -NR ^d -X ² OR ^c , -NR ^d -X ² NR ^c R ^d , -NR ^d -X ² CO ₂ R ^c and -NR ^d -X ² CONR ^c R ^d , wherein each W is selected from R ^c , -CN, -CO ₂ ^Re and -NO ₂ , wherein each X ² is selected from C _1-4 alkylene, C _2-4 alkenylene and C _2-4 alkynylene groups, R ^c and R ^d are each independently selected from: hydrogen, C _1-8 alkyl, C _1-8 haloalkyl, C _3-6 cycloalkyl, C _2-8 alkenes C _2-8 alkynyl, aryl, heteroaryl, aryl-C _1-4 alkyl and aryloxy-C _1-4 alkyl, or, when R ^c and R ^d are connected to the same nitrogen atom , they combine with the nitrogen atom to form a 5-membered or 6-membered ring having an additional 0-2 heteroatoms as ring atoms; each R ^e is independently selected from: C _1-8 alkyl, C _1-8 haloalkyl , C _3-6 cycloalkyl, C _2-8 alkenyl, C _2-8 alkynyl, aryl, heteroaryl, aryl-C _1-4 alkyl and aryloxy-C _1-4 alkyl , R ^c , R ^d and R ^e are each optionally substituted by 1-3 groups selected from the group consisting of -OH, -OR ⁿ , -OC(O)NHR ⁿ , -OC(O)N(R ⁿ ) ₂ , -SH, -SR ⁿ , -S(O)R ⁿ , -S(O) ₂ R ⁿ , -SO ₂ NH ₂ , -S(O) ₂ NHR ⁿ , -S(O) ₂ N( R ⁿ ) ₂ , -NHS(O) ₂ R ⁿ , -NR ⁿ S(O) ₂ R ⁿ , -C(O)NH ₂ , -C(O)NHR ⁿ , -C(O)N(R ⁿ ) ₂ , -C(O)R ⁿ , -NHC(O)R ⁿ , -NR ⁿ C(O)R ⁿ , -NHC(O)NH ₂ , -NR ⁿ C(O)NH ₂ , -NR ⁿ C(O)NHR ⁿ , -NHC(O)NHR ⁿ , -NR ⁿ C(O)N(R ⁿ ) ₂ , -NHC(O)N(R ⁿ ) ₂ , -CO ₂ H, -CO ₂ R ⁿ , -NHCO ₂ R ⁿ , -NR ⁿ CO ₂ R ⁿ , -CN, -NO ₂ , -NH ₂ , -NHR ⁿ , -N(R ⁿ ) ₂ , -NR ⁿ S(O)NH ₂ , and - NR ⁿ S(O) ₂ NHR ⁿ , wherein each R ⁿ is independently an unsubstituted C _1-8 alkyl group such that at least one of R ^2a , R ^2b , R ^2c , R ^2d and R ^2e is not H; R ^3a , R ^3b and R ^3c are each a group selected from the group consisting of hydrogen, halogen, -OR ^f , -OC(O)R ^f , -NR ^f R ^g , -SR ^f , -R ^h , -CN, - NO ₂ , -CO ₂ R ^f , -CONR ^f R ^g , -C(O)R ^f , -OC(O)NR ^f R ^g , -NR ^g C(O)R ^f , -NR ^g C(O) ₂ R ^h , -NR ^f -C(O)NR ^f R ^g , -NH-C(NH ₂ )=NH, -NR ^h C(NH ₂ )=NH, -NH-C(NH ₂ )=NR ^h , -NH-C(NHR ^h )=NH, -S(O)R ^h , -S(O) ₂ R ^h , -NR ^f S(O) ₂ R ^h , -S(O) ₂ NR ^f R ^g , -NR ^f S(O) ₂ NR ^f R ^g , -N ₃ , -C(NOR ^f )R ^g , -C(NR ^f W ^a )=NW ^a , -N(W ^a )C(R ^f ) =NW ^a , -X ³ C(NOR ^f )R ^g , -X ³ C(NR ^f W ^a )=NW ^a , -X ³ N(W ^a )C(R ^f )=NW ^a , -X ³ OR ^f , -X ³ OC(O)R ^f , -X ³ NR ^f R ^g , -X ³ SR ^f , -X ³ CN, -X ³ NO ₂ , -X ³ CO ₂ R ^f , -X ³ CONR ^f R ^g , -X ³ C(O)R ^f , -X ³ OC(O)NR ^f R ^g , -X ³ NR ^g C(O)R ^f , -X ³ NR ^g C(O) ₂ R ^h , -X ³ NR ^f -C(O)NR ^f R ^g , -X ³ NH-C(NH ₂ )=NH, -X ³ NR ^h C(NH ₂ )=NH, -X ³ NH-C(NH ₂ )=NR ^h , -X ³ NH-C(NHR ^h )=NH, -X ³ S(O)R ^h , -X ³ S(O) ₂ R ^h , -X ³ NR ^f S(O) ₂ R ^h , -X ³ S(O) ₂ NR ^f R ^g , -Y, -X ³ Y, -X ³ N ₃ , -OX ³ OR ^f , -OX ³ NR ^f R ^g , -OX ³ CO ₂ R ^f , -OX ³ CONR ^f R ^g , -NR ^g -X ³ OR ^f , -NR ^g -X ³ NR ^f R ^g , -NR ^g -X ³ CO ₂ R ^f and -NR ^g -X ³ CONR ^f R ^g , wherein Y is a 5-membered or 6-membered aryl, heteroaryl or heterocycle, optionally substituted by 1-3 substituents selected from the group consisting of halogen, -OR ^f , -NR ^f R ^g , -R ^h , -SR ^f , -CN, -NO ₂ , -CO ₂ R ^f , -CONR ^f R ^g , -C(O)R ^f , -NR ^g C(O)R ^f , -S(O)R ^h , -S(O) ₂ R ^h , -NR ^f S(O) ₂ R ^h , -S(O) ₂ NR ^f R ^g , -C(NOR ^f )R ^g , -C(NR ^f W ^a )=NW ^a , -N(W ^a )C(R ^f )=NW ^a , -X ³ C(NOR ^f )R ^g , -X ³ C(NR ^f W ^a )=NW ^a , -X ³ N(W ^a ) C(R ^f ) = NW ^a , -X ³ OR ^f , -X ³ NR ^f R ^g , -X ³ NR ^f S(O) ₂ R ^h and -X ³ S(O) ₂ NR ^f R ^g , where W ^a is selected from R ^f , -CN, -CO ₂ R ^h and -NO ₂ , and each X ³ is independently selected from C _1-4 alkylene, C _2-4 alkenylene and C _2-4 alkynylene , and R ^f and R ^g are each independently selected from: hydrogen, C _1-8 alkyl, C _1-8 haloalkyl, C _3-6 cycloalkyl, C _2-8 alkenyl, C _2-8 alkynyl , aryl, heteroaryl, aryl-C _1-4 alkyl and aryloxy-C _1-4 alkyl, or when R ^f and R ^g are connected to the same nitrogen atom, can be combined with the nitrogen atom , forming a 5- or 6-membered ring with an additional 0-2 heteroatoms as ring atoms, each ^Rh independently selected from: C _1-8 alkyl, C _1-8 haloalkyl, C _3-6 cycloalkane C _2-8 alkenyl, C _2-8 alkynyl, aryl, heteroaryl, aryl-C _1-4 alkyl and aryloxy-C _1-4 alkyl, where R ^f , R ^g and ^Rh aliphatic moieties are also optionally substituted with 1-3 groups selected from the group consisting of -OH, -OR ^o , -OC(O)NHR ^o , -OC(O)N(R ^o ) ₂ , - SH, -SR ^o , -S(O)R ^o , -S(O) ₂ R ^o , -SO ₂ NH ₂ , -S(O) ₂ NHR ^o , -S(O) ₂ N(R ^o ) ₂ , -NHS(O) ₂ R ^o , -NR ^o S(O) ₂ R ^o , -C(O)NH ₂ , -C(O)NHR ^o , -C(O)N(R ^o ) ₂ , - C(O)R ^o , -NHC(O)R ^o , -NR ^o C(O)R ^o , -NHC(O)NH ₂ , -NR ^o C(O)NH ₂ , -NR ^o C(O) NHR ^o , -NHC(O)NHR ^o , -NR ^o C(O)N(R ^o ) ₂ , -NHC(O)N(R ^o ) ₂ , -CO ₂ H, -CO ₂ R ^o , -NHCO ₂ R ^o , -NR ^o CO ₂ R ^o , -CN, -NO ₂ , -NH ₂ , -NHR ^o , -N(R ^o ) ₂ , -NR ^o S(O)NH ₂ and -NR ^o S( O) ₂ NHR ^o , wherein each R ^o is independently unsubstituted C _1-6 alkyl, such that at least one of R ^3a , R ^3b and R ^3c is other than H. Optionally, two of R ^3a , R ^3b and R ^3c are connected at adjacent carbon atoms to form a 5-membered or 6-membered ring with 0-3 heteroatoms as ring atoms, and can also be replaced by 0-3 Substituents provided for the aliphatic moiety of R ^f above. In addition, when two of R ^2a , R ^2b , R ^2c , R ^2d and R ^2e are connected to adjacent carbon atoms, they may be optionally combined to form a 5-membered or 6-membered ring having 0-3 heteroatoms as ring atoms , and may also be substituted with 0-3 substituents provided for the aliphatic moiety of ^Rc above.

Within the group of formula III above, certain group embodiments are particularly preferred. In a particularly preferred set of embodiments, the subscript m is 0 or 1 and at least one of R ^2a or R ^2e is hydrogen. More preferably, at least one of R ^3a , R ^3b and R ^3c is selected from halogen, C _1-4 alkyl and C _1-4 haloalkyl, and their aliphatic moieties may be optionally substituted as described above. More preferably, R ^2d is hydrogen, and at least two of R ^3a , R ^3b and R ^3c are selected from halogen, C _1-4 alkyl and C _1-4 haloalkyl, and their aliphatic moieties can be optionally are substituted and the remaining groups are not hydrogen. In a related preferred embodiment, m is 0 or 1, at least one of R ^2a or R ^2e is hydrogen, R ^2d is hydrogen, R ^2c is selected from F, Cl, Br, CN, NO ₂ , CO ₂ CH ₃ , C(O)CH ₃ and S(O) ₂ CH ₃ , at least two of R ^3a , R ^3b and R ^3c are selected from halogen, C _1-4 alkyl and C _1-4 haloalkyl, their aliphatic moieties Can be optionally substituted as described above, the remainder being other than hydrogen. In another group of particularly preferred embodiments, subscript m is 0 or 1; R ^2a and R ^2e are both hydrogen. More preferably, at least one of R ^3a , R ^3b and R ^3c is selected from halogen, C _1-4 alkyl and C _1-4 haloalkyl, and their aliphatic moieties may be optionally substituted as described above. Even better, at least one of R ^3a , R ^3b and R ^3c is selected from halogen, C _1-4 alkyl and C _1-4 haloalkyl, their aliphatic moieties may be optionally substituted as described above, R The remaining groups of ^3a , R ^3b and R ^3c are not hydrogen. In yet another group of particularly preferred embodiments, subscript m is 0 or 1; R ^2b and R ^2e are both hydrogen. More preferably, at least one of R ^3a , R ^3b and R ^3c is selected from halogen, C _1-4 alkyl and C _1-4 haloalkyl, and their aliphatic moieties may be optionally substituted as described above. Even better, at least one of R ^3a , R ^3b and R ^3c is selected from halogen, C _1-4 alkyl and C _1-4 haloalkyl, their aliphatic moieties may be optionally substituted as described above, R The remaining groups of ^3a , R ^3b and R ^3c are not hydrogen.

In other preferred embodiments of formula III, at least one of R ^3a , R ^3b and R ^3c is selected from -Y and -X ³ -Y. Related embodiments are those compounds wherein m is 0 or 1 and at least one of R ^{and R} is hydrogen. In other embodiments, R ^3b is hydrogen, halo or cyano. More preferred is wherein R ^3b is halogen or cyano, and R ¹ when present is selected from -CO ₂ H and C _1-4 alkyl, optionally replaced by -OH, -OR ^m , -S(O) ₂ R ^m , -CO ₂ H and -CO ₂ R ^m substituted those compounds. In still some other embodiments, m is 0 or 1; at least one of R ^2a and R ^2e is hydrogen; at least one of R ^3a , R ^3b and R ^3c is selected from halogen, C _1-4 alkyl and C _{1- 4} Haloalkyl groups whose aliphatic moieties are optionally substituted as described above. More preferably, R ^2d is hydrogen, and at least two of R ^3a , R ^3b and R ^3c are selected from halogen, C _1-4 alkyl and C _1-4 haloalkyl, and their aliphatic moieties can be optionally option is replaced. Still more preferred is wherein R ^2c is selected from F, Cl, Br, CN, NO ₂ , CO ₂ CH ₃ , C(O)CH ₃ and S(O) ₂ CH ₃ , and R ^3a , R ^3b and R ^3c Those compounds that are not hydrogen.

In another group of preferred embodiments of formula III, m is 0 or 1, and R ^2a and R ^2e are each hydrogen. In other embodiments, R ^3b is hydrogen, halo or cyano. Also preferred is wherein R ^3b is halogen or cyano and R ¹ , when present, is selected from C ₁ optionally substituted by -OH, -OR ^m , -S(O) ₂ R ^m , -CO ₂ H and -CO ₂ R ^m Those compounds with _-4 alkyl groups. In other embodiments, m is 0 or 1; R ^2a and R ^2e are each hydrogen; at least one of R ^3a , R ^3b and R ^3c is selected from halogen, C _1-4 alkyl and C _1-4 haloalkyl, which The aliphatic portion of can be optionally substituted as described above. More preferably, none of R ^3a , R ^3b and R ^3c is hydrogen. Preference is also given to those compounds wherein R ^2c is selected from F, Cl, Br, CN, NO ₂ , CO ₂ CH ₃ , C(O)CH ₃ and S(O) ₂ CH ₃ . In a related embodiment, m is 0 or 1, and R ^2b and R ^2e are both hydrogen.

In preferred embodiments of other groups of formula III, the compound has a structural formula selected from:

In the formula, each substituent has the meaning described for formula III. In one group of embodiments, R ^3c and R ^3a are each independently selected from C _1-4 alkyl, C _1-4 haloalkyl and C _3-6 cycloalkyl; R ^3b is hydrogen, halogen or cyano, more Good is halogen. In another set of embodiments, R ^3c and R ^3a are each independently selected from halogen, -NR ^f R ^g , -SR ^f , -CO ₂ R ^f , -Y, and -R ^h , wherein ^Rh is C _{1- 6} alkyl, C _1-6 haloalkyl and C _3-6 cycloalkyl, the aliphatic portion of which is optionally substituted by a group selected from: -OH, -OR ^o , -OC(O)NHR ^o , -OC(O)N(R ^o ) ₂ , -SH, -SR ^o , -S(O)R ^o , -S(O) ₂ R ^o , -SO ₂ NH ₂ , -S(O) ₂ NHR ^o , -S(O) ₂ N(R ^o ) ₂ , -NHS(O) ₂ R ^o , -NR ^o S(O) ₂ R ^o , -C(O)NH ₂ , -C(O)NHR ^o , -C(O)N(R ^o ) ₂ , -C(O)R ^o , -NHC(O)R ^o , -NR ^o C(O)R ^o , -NHC(O)NH ₂ , -NR ^o C (O)NH ₂ , -NR ^o C(O)NHR ^o , -NHC(O)NHR ^o , -NR ^o C(O)N(R ^o ) ₂ , -NHC(O)N(R ^o ) ₂ , -CO ₂ H, -CO ₂ R ^o , -NHCO ₂ R ^o , -NR ^o CO ₂ R ^o , -CN, -NO ₂ , -NH ₂ , -NHR ^o , -N(R ^o ) ₂ , -NR ^o S(O)NH ₂ and -NR ^o S(O) ₂ NHR ^o . In other embodiments, m is zero. For the embodiment wherein m is 1 or 2, R ¹ is preferably -CO ₂ H or C _1-4 alkyl, optionally replaced by -OH, -OR ^m , -S(O) ₂ R ^m , -CO ₂ H and -CO ₂ R ^m substituted. In some preferred embodiments, R ¹ , when present, may be selected from: methyl, ethyl, isopropyl, -CH ₂ OH, -CH ₂ OCH ₃ , -CH ₂ OCH ₂ CH ₃ , -CH ₂ OCH ( CH ₃ ) ₂ , -CH(CH ₃ )OH and -CH(CH ₃ )OCH ₃ , more preferably methyl, -CH ₂ OH and -CH ₂ OCH ₃ .

In another preferred group of formula III, the compound has a structural formula selected from:

In the formula, each substituent has the meaning described for formula III. In one set of embodiments, R ^3c and R ^3a are each independently selected from halogen, cyano, -NO ₂ , -CO ₂ R ^f , -CONR ^f R ^g , -C(O)R ^f , -NR ^f R ^g , -SR ^f , -S(O)R ^h , -S(O) ₂ R ^h , -C(O)Y, -SO ₂ Y, -X ³ Y, Y, C _1-6 alkyl, C _1-6 haloalkyl and C _3-6 cycloalkyl, wherein the alkyl and cycloalkyl substituents may be optionally substituted by groups selected from: -OH, -OR ^o , -OC(O)NHR ^o , -OC(O)N(R ^o ) ₂ , -SH, -SR ^o , -S(O)R ^o , -S(O) ₂ R ^o , -SO ₂ NH ₂ , -S(O) ₂ NHR ^o , -S(O) ₂ N(R ^o ) ₂ , -NHS(O) ₂ R ^o , -NR ^o S(O) ₂ R ^o , -C(O)NH ₂ , -C(O)NHR ^o , -C(O)N(R ^o ) ₂ , -C(O)R ^o , -NHC(O)R ^o , -NR ^o C(O)R ^o , -NHC(O)NH ₂ , -NR ^o C(O)NH ₂ , -NR ^o C(O)NHR ^o , -NHC(O)NHR ^o , -NR ^o C(O)N(R ^o ) ₂ , -NHC(O)N(R ^o ) ₂ , -CO ₂ H, -CO ₂ R ^o , -NHCO ₂ R ^o , -NR ^o CO ₂ R ^o , -CN, -NO ₂ , -NH ₂ , -NHR ^o , -N(R ^o ) ₂ , - NR ^o S(O)NH ₂ and -NR ^o S(O) ₂ NHR ^o ; R ^3b is hydrogen, halogen or cyano. Preferred groups for R ^3a are halogen, cyano, C _1-6 alkyl, C _1-6 haloalkyl, C _3-6 cycloalkyl, -C(O)R ^f , -NR ^f R ^g , -SR ^f , -S(O) ₂ R ^h , -X ³ Y or Y, the aliphatic portion of which may be optionally substituted as described above; and preferred groups for R ^3c are halogen, cyano, -C(O )R ^f , -S(O) ₂ R ^h , C _1-6 alkyl, C _1-6 haloalkyl or C _3-6 cycloalkyl, wherein the alkyl and cycloalkyl substituents are optional as described above Choose to replace. In another set of embodiments, R ^3c and R ^3a are each independently selected from C _1-6 alkyl, optionally substituted by: -OH, -OR ^o , -OC(O)NHR ^o , -OC (O)N(R ^o ) ₂ , -SH, -SR ^o , -S(O)R ^o , -S(O) ₂ R ^o , -SO ₂ NH ₂ , -S(O) ₂ NHR ^o , - S(O) ₂ N(R ^o ) ₂ , -NHS(O) ₂ R ^o , -NR ^o S(O) ₂ R ^o , -C(O)NH ₂ , -C(O)NHR ^o , -C (O)N(R ^o ) ₂ , -C(O)R ^o , -NHC(O)R ^o , -NR ^o C(O)R ^o , -NHC(O)NH ₂ , -NR ^o C(O )NH ₂ , -NR ^o C(O)NHR ^o , -NHC(O)NHR ^o , -NR ^o C(O)N(R ^o ) ₂ , -NHC(O)N(R ^o ) ₂ , -CO ₂ H, -CO ₂ R ^o , -NHCO ₂ R ^o , -NR ^o CO ₂ R ^o , -CN, -NO ₂ , -NH ₂ , -NHR ^o , -N(R ^o ) ₂ , -NR ^o S (O)NH ₂ and -NR ^o S(O) ₂ NHR ^o . In certain embodiments, R ^2c is not hydrogen, and is preferably selected from halogen, cyano and nitro; R ^2b is selected from -SR ^c , -OX ² -OR ^c , -X ² -OR ^c , -R ^e , ^-ORc _, ^-NRcRd , ^-NRdC (O) ^{Rc ,} and ^{-NRcSO2Rd .} In still other embodiments, m is 0. For the embodiment wherein m is 1 or 2, R ¹ is preferably -CO ₂ H or C _1-4 alkyl, optionally replaced by -OH, -OR ^m , -N(R ^m ) ₂ , -S(O ) ₂ R ^m , -CO ₂ H and -CO ₂ R ^m are substituted.

Other preferred compounds of formula III are represented by the formula:

In the formula, R ^2a is not hydrogen; R ^2c is halogen, cyano or nitro; R ^2d is -SR ^c , -OX ² -OR ^c , -X ² -OR ^c , -R ^e , -OR ^c , -NR ^c R ^d , -NR ^d C(O) R ^c and -NR ^c SO ₂ R ^d ; R ^3a is selected from C _1-6 alkyl, C _1-6 haloalkyl and C _3-6 cycloalkyl, optionally Substituted with a group selected from -OH, -OR ^o , -OC(O)NHR ^o , -OC(O)N(R ^o ) ₂ , -SH, -SR ^o , -S(O)R ^o , -S(O) ₂ R ^o , -SO ₂ NH ₂ , -S(O) ₂ NHR ^o , -S(O) ₂ N(R ^o ) ₂ , -NHS(O) ₂ R ^o , -NR ^o S(O) ₂ R ^o , -C(O)NH ₂ , -C(O)NHR ^o , -C(O)N(R ^o ) ₂ , -C(O)R ^o , -NHC(O)R ^o , -NR ^o C(O)R ^o , -NHC(O)NH ₂ , -NR ^o C(O)NH ₂ , -NR ^o C(O)NHR ^o , -NHC(O)NHR ^o , -NR ^o C(O)N(R ^o ) ₂ , -NHC(O)N(R ^o ) ₂ , -CO ₂ H, -CO ₂ R ^o , -NHCO ₂ R ^o , -NR ^o CO ₂ R ^o , - CN, _-NO2 , _-NH2 , ^-NHRo , -N( ^Ro ) ₂ , ^-NRoS (O)NH2 _, and ^-NRoS (O) _2NHRo ; R ^3b is ^hydrogen , F, Cl, Br or cyano; R ^3c is selected from NH ₂ , CF ₃ , SCH ₃ and Y. Also preferred are those compounds wherein each R ¹ when present is selected from —CO ₂ H and C _1-4 alkyl, optionally selected from —OH, —OR ^m , —S(O) ₂ R ^m , —CO ₂ H and -CO ₂ R ^m group substitution.

Those compounds represented by the following formula in related embodiments:

In the formula, R ^2a is not hydrogen; R ^2c is halogen, cyano or nitro; R ^2d is -SR ^c , -OX ² -OR ^c , -X ² -OR ^c , -R ^e , -OR ^c , -NR ^c R ^d , -NR ^d C(O)R ^c and -NR ^c SO ₂ R ^d ; R ^3a is selected from -NR ^f R ^g , -SR ^f , -SO ₂ R ^h , -R ^h , -C(O )R ^f , -Y and -X ³ Y, more preferably -NH ₂ , -CF ₃ , -SCH ₃ and Y; R ^3b is hydrogen, F, Cl, Br or cyano; R ^3c is selected from C _{1- 6} alkyl, C _1-6 haloalkyl and C _3-6 cycloalkyl, optionally substituted by a group selected from: -OH, -OR ^o , -OC(O)NHR ^o , -OC(O) N(R ^o ) ₂ , -SH, -SR ^o , -S(O)R ^o , -S(O) ₂ R ^o , -SO ₂ NH ₂ , -S(O) ₂ NHR ^o , -S(O ) ₂ N(R ^o ) ₂ , -NHS(O) ₂ R ^o , -NR ^o S(O) ₂ R ^o , -C(O)NH ₂ , -C(O)NHR ^o , -C(O) N(R ^o ) ₂ , -C(O)R ^o , -NHC(O)R ^o , -NR ^o C(O)R ^o , -NHC(O)NH ₂ , -NR ^o C(O)NH ₂ , -NR ^o C(O)NHR ^o , -NHC(O)NHR ^o , -NR ^o C(O)N(R ^o ) ₂ , -NHC(O)N(R ^o ) ₂ , -CO ₂ H, -CO ₂ R ^o , -NHCO ₂ R ^o , -NR ^o CO ₂ R ^o , -CN, -NO ₂ , -NH ₂ , -NHR ^o , -N(R ^o ) ₂ , -NR ^o S(O) NH ₂ and -NR ^o S(O) ₂ NHR ^o . Also preferred are those compounds wherein each R ¹ , when present, is selected from —CO ₂ H and C _1-4 alkyl, optionally substituted with a group selected from: —OH, —OR ^m , —S(O) ₂ R ^m , -CO ₂ H and -CO ₂ R ^m . In other preferred embodiments, R ^3b is hydrogen. In other related embodiments, two adjacent R ^3a , R ^3b or R ^3c groups combine to form a 5-membered or 6-membered fused ring, preferably carbocyclic or having 1-2 heteroatoms as the ring atom heterocycle.

Other preferred groups of formula III above are:

First of all, for the compound of formula IIIa, R ^3b is preferably hydrogen, halogen, nitro or cyano, more preferably halogen, preferably fluorine, chlorine or bromine; R ^3c is preferably C _1-6 alkyl, C _{1 -6} haloalkyl or C _3-6 cycloalkyl; R ^2c is halogen, R ^2b is -SR ^c , -OX ² -OR ^c , -X ² -OR ^c , -R ^e , -OR ^c , -NR ^c R ^d , -NR ^c S(O) ₂ R ^e and -NR ^d C (O) R ^c ; wherein R ^c and R ^d are selected from hydrogen, C _1-8 alkyl, C _1-8 haloalkyl, C _{3 -6} cycloalkyl, C _2-8 alkenyl and C _2-8 alkynyl, R ^e is selected from C _1-8 alkyl, C _1-8 haloalkyl, C _3-6 cycloalkyl, C _2-8 Alkenyl and C _2-8 alkynyl, R ^c , R ^d and R ^e are each optionally substituted as described above, or in certain embodiments by 1-3 members selected from OH, O(C _1-8 alkyl), SH, S(C _1-8 alkyl), CN, NO ₂ , NH ₂ , NH(C _1-8 alkyl) and N(C _1-8 alkyl) ₂ .

For the compound of formula IIIb, R ^3b is preferably hydrogen, halogen, nitro or cyano, more preferably halogen, preferably fluorine, chlorine or bromine; R ^3a is preferably C _1-6 alkyl, C _{1- 6} haloalkyl or C _3-6 cycloalkyl; R ^2c is preferably halogen, R ^2b is preferably -SR ^c , -OX ² -OR ^c , -X ² -OR ^c , -R ^e , -OR ^c , -NR ^c R ^d , -NR ^c S(O) ₂ R ^e and -NR ^d C(O) R ^c ; wherein R ^c and R ^d are selected from hydrogen, C _1-8 alkyl, C _1-8 haloalkyl , C _3-6 cycloalkyl, C _2-8 alkenyl and C _2-8 alkynyl, R ^e is selected from C _1-8 alkyl, C _1-8 haloalkyl, C _3-6 cycloalkyl, C _2-8 alkenyl and C _2-8 alkynyl, R ^c , R ^d and R ^e are each optionally substituted as described above, or in certain embodiments by 1-3 members selected from OH, O(C _1-8 alkyl), SH, S(C _1-8 alkyl), CN, NO ₂ , NH ₂ , NH(C _1-8 alkyl) and N(C _1-8 alkyl) ₂ groups replace.

In one group of embodiments of the compound of formula IIIc, R ^3a and R ^3c are each selected from halogen, cyano, -NO ₂ , -CO ₂ R ^f , -CONR ^f R ^g , -C(O)R ^f , -NR ^f R ^g , -SR ^f , -S(O)R ^h , -S(O) ₂ R ^h , -C(O)Y, -SO ₂ Y, -X ³ Y, Y, C _1-6 alkyl , C _1-6 haloalkyl or C _3-6 cycloalkyl, wherein the alkyl and cycloalkyl substituents may be optionally substituted by groups selected from: -OH, -OR ^o , -OC(O) NHR ^o , -OC(O)N(R ^o ) ₂ , -SH, -SR ^o , -S(O)R ^o , -S(O) ₂ R ^o , -SO ₂ NH ₂ , -S(O) ₂ NHR ^o , -S(O) ₂ N(R ^o ) ₂ , -NHS(O) ₂ R ^o , -NR ^o S(O) ₂ R ^o , -C(O)NH ₂ , -C(O) NHR ^o , -C(O)N(R ^o ) ₂ , -C(O)R ^o , -NHC(O)R ^o , -NR ^o C(O)R ^o , -NHC(O)NH ₂ , - NR ^o C(O)NH ₂ , -NR ^o C(O)NHR ^o , -NHC(O)NHR ^o , -NR ^o C(O)N(R ^o ) ₂ , -NHC(O)N(R ^o ) ₂ , -CO ₂ H, -CO ₂ R ^o , -NHCO ₂ R ^o , -NR ^o CO ₂ R ^o , -CN, -NO ₂ , -NH ₂ , -NHR ^o , -N(R ^o ) ₂ , -NR ^o S(O)NH ₂ and -NR ^o S(O) ₂ NHR ^o . More preferably, R ^3a is selected from halogen, cyano, C _1-6 alkyl, C _1-6 haloalkyl, C _3-6 cycloalkyl, -C(O)R ^f , -NR ^f R ^g , - SR ^f , -S(O) ₂ R ^h , -X ³ Y and Y; preferably, R ^3a is halogen, cyano, C _1-6 alkyl, C _1-6 haloalkyl, C _3-6 ring Alkyl, -C(O) ^Rf or _-SO2Rh , the aliphatic portion ^of which may be optionally substituted as described above. R ^3b is hydrogen, F, Cl, Br or cyano. R ^3c is preferably halogen, cyano, -C(O)R ^f , -SO ₂ R ^h , C _1-6 alkyl, C _1-6 haloalkyl or C _3-6 cycloalkyl, wherein the aliphatic part Substitute as above. R ^2c is halogen, cyano or nitro; R ^2b is selected from hydrogen, halogen, -OR ^c , -OC(O)R ^c , -NR ^c R ^d , -SR ^c , -R ^e , -CO ₂ R ^c , -CONR ^c R ^d , -C(O)R ^c , -S(O)Re ^e , -S(O) ₂ R ^e , -NR ^c S(O) ₂ R ^e , -NR ^d C(O) R ^c , -X ² OR ^c , -X ² OC(O)R ^c , -X ² NR ^c R ^d , -X ² SR ^c , -X ² CO ₂ R ^c , -X ² CONR ^c R ^d , - X ² C(O)R ^c , -X ² OC(O)NR ^c R ^d , -X ² NR ^d C(O)R ^c , -X ² NR ^d C(O) ₂ R ^e , -X ² NR ^c C(O)NR ^c R ^d , -X ² S(O)R ^e , -X ² S(O) ₂ R ^e , -X ² NR ^c S(O) ₂ R ^e , -OX ² -OR ^c , -X ² S(O) ₂ NR ^c R ^d and -X ² N ₃ , wherein X ² is C _1-4 alkylene, R ^c and R ^d are each independently selected from hydrogen, C _1-8 alkyl , C _1-8 haloalkyl, C _3-6 cycloalkyl, C _2-8 alkenyl and C _2-8 alkynyl, each R ^e is independently selected from C _1-8 alkyl, C _1-8 haloalkyl , C _3-6 cycloalkyl, C _2-8 alkenyl and C _2-8 alkynyl, R ^c , R ^d and R ^e are each optionally substituted as described for formula III, or 1-3 Substituted by a group selected from: OH, O(C _1-8 alkyl), SH, S(C _1-8 alkyl), CN, NO ₂ , NH ₂ , NH(C _1-8 alkyl) and N(C _1-8 alkyl) ₂ . In certain preferred embodiments, R ^2c is halogen, cyano or nitro; R ^2b is -SR ^c , -OX ² -OR ^c , -X ² -OR ^c , -R ^e , -OR ^c , - NR ^c R ^d , -NR ^c S(O) ₂ ^Re and -NR ^d C(O) R ^c ; wherein R ^c and R ^d are selected from hydrogen, C _1-8 alkyl, C _1-8 haloalkyl, C _3-6 cycloalkyl, C _2-8 alkenyl and C _2-8 alkynyl, R ^e is selected from C _1-8 alkyl, C _1-8 haloalkyl, C _3-6 cycloalkyl, C _{2 -8} alkenyl and C _2-8 alkynyl, each of R ^c , R ^d and R ^e is optionally substituted by 1-3 groups selected from the group consisting of OH, O(C _1-8 alkyl), SH , S(C _1-8 alkyl), CN, NO ₂ , NH ₂ , NH(C _1-8 alkyl) and N(C _1-8 alkyl) ₂ ; R ^3a is C _1-6 alkyl, C _1-6 haloalkyl, C _3-6 cycloalkyl, -C(O)R ^f , -NR ^f R ^g , -SR ^f , -S(O) ₂ R ^h , -X ³ Y or Y; R ^3b is hydrogen, F, Cl, Br or cyano; R ^3c is halogen, cyano, -C(O)R ^f , -SO ₂ R ^h , C _1-6 alkyl, C _1-6 haloalkyl or C _3-6 Cycloalkyl wherein the aliphatic moiety is substituted as described above.

In related preferred embodiments, there is provided a compound of formula IIIc, wherein R ^3c is selected from halogen, cyano, C _1-6 alkyl, C _1-6 haloalkyl, C _3-6 cycloalkyl, -C(O )R ^f , -NR ^f R ^g , -SR ^f , -S(O) ₂ R ^h , -X ³ Y and Y; more preferably, R ^3c is halogen, cyano, C _1-6 alkyl, C _1-6 haloalkyl, C _3-6 cycloalkyl, -C(O)R ^f or -SO ₂ R ^h , their aliphatic moieties may be optionally substituted as described above. R ^3b is hydrogen, F, Cl, Br or cyano; R ^3a is preferably halogen, cyano, -C(O)R ^f , -SO ₂ R ^h , C _1-6 alkyl, C _1-6 haloalkane or C _3-6 cycloalkyl, wherein the aliphatic portion is substituted as described above. R ^2c is halogen, cyano or nitro, preferably halogen; R ^2b is selected from hydrogen, halogen, -OR ^c , -OC(O)R ^c , -NR ^c R ^d , -SR ^c , -R ^e , -CO ₂ R ^c , -CONR ^c R ^d , -C(O)R ^c , -S(O)R ^e , -S(O) ₂ R ^e , -NR ^c S(O) ₂ R ^e , -NR ^d C(O)R ^c , -X ² OR ^c , -X ² OC(O)R ^c , -X ² NR ^c R ^d , -X ² SR ^c , -X ² CO ₂ R ^c , -X ² CONR ^c R ^d , -X ² C(O)R ^c , -X ² OC(O)NR ^c R ^d , -X ² NR ^d C(O)R ^c , -X ² NR ^d C(O) ₂ R ^e , -X ² NR ^c C(O)NR ^c R ^d , -X ² S(O)R ^e , -X ² S(O) ₂ R ^e , -X ² NR ^c S(O) ₂ R ^e , - OX ² -OR ^c , -X ² S(O) ₂ NR ^c R ^d and -X ² N ₃ , wherein X ² is C _1-4 alkylene, R ^c and R ^d are each independently selected from hydrogen, C _1-8 alkyl, C _1-8 haloalkyl, C _3-6 cycloalkyl, C _2-8 alkenyl and C _2-8 alkynyl, each R ^e is independently selected from C _1-8 alkyl, C _1-8 haloalkyl, C _3-6 cycloalkyl, C _2-8 alkenyl and C _2-8 alkynyl, each of R ^c , R ^d and R ^e is optionally substituted as described for formula III, or Substituted by 1-3 groups selected from: OH, O(C _1-8 alkyl), SH, S(C _1-8 alkyl), CN, NO ₂ , NH ₂ , NH(C _{1-8 8} alkyl) and N(C _1-8 alkyl) ₂ . In certain preferred embodiments, R ^2c is halogen, cyano, or nitro; R ^2b is -SR ^c , -OX ² -OR ^c , -X ² -OR ^c , -R ^c , -OR ^c , -NR ^c R ^d , -NR ^c S(O) ₂ R ^e or -NR ^d C(O) R ^c ; R ^3a is selected from C _1-6 alkyl and C _3-6 cycloalkyl; R ^3c is selected from NH ₂ , CF ₃ , SCH ₃ and Y; R ^3b is chlorine or bromine.

For selected compounds of formula IIId, R ^3a and R ^3c are each independently selected from halogen, cyano, -NO ₂ , -CO ₂ R ^f , -CONR ^f R ^g , -C(O)R ^f , -NR ^f R ^g , -SR ^f , -S(O)R ^h , -S(O) ₂ R ^h , -C(O)Y, -SO ₂ Y, -X ³ Y, Y, C _1-6 alkyl, C _1-6 haloalkyl or C _3-6 cycloalkyl, wherein the alkyl and cycloalkyl substituents can be optionally substituted by groups selected from: -OH, -OR ^o , -OC(O)NHR ^o , -OC(O)N(R ^o ) ₂ , -SH, -SR ^o , -S(O)R ^o , -S(O) ₂ R ^o , -SO ₂ NH ₂ , -S(O) ₂ NHR ^o , -S(O) ₂ N(R ^o ) ₂ , -NHS(O) ₂ R ^o , -NR ^o S(O) ₂ R ^o , -C(O)NH ₂ , -C(O)NHR ^o , -C(O)N(R ^o ) ₂ , -C(O)R ^o , -NHC(O)R ^o , -NR ^o C(O)R ^o , -NHC(O)NH ₂ , -NR ^o C(O)NH ₂ , -NR ^o C(O)NHR ^o , -NHC(O)NHR ^o , -NR ^o C(O)N(R ^o ) ₂ , -NHC(O)N(R ^o ) ₂ , -CO ₂ H, -CO ₂ R ^o , -NHCO ₂ R ^o , -NR ^o CO ₂ R ^o , -CN, -NO ₂ , -NH ₂ , -NHR ^o , -N(R ^o ) ₂ , -NR ^o S(O)NH ₂ and -NR ^o S(O) ₂ NHR ^o . More preferably, R ^3a is selected from halogen, cyano, C _1-6 alkyl, C _1-6 haloalkyl, C _3-6 cycloalkyl, -C(O)R ^f , -NR ^f R ^g , - SR ^f , -S(O) ₂ R ^h , -X ³ Y and Y are more preferably selected from NH ₂ , CF ₃ , SCH ₃ , SO ₂ CH ₃ , CN, C(CH ₃ ) ₂ OH and Y. R ^3b is hydrogen, F, Cl, Br or cyano; R ^3c is preferably C _1-6 alkyl, C _1-6 haloalkyl or C _3-6 cycloalkyl, optionally represented by formula III Substituent substitution; R ^2a is preferably not hydrogen, and is selected from halogen, -OR ^c , -OC(O)R ^c , -NR ^c R ^d , -SR ^c , -R ^e , -CO ₂ R ^c , -CONR ^c R ^d , -C(O)R ^c , -S(O)R ^e , -S(O) ₂ R ^e , -C(NOR ^c )R ^d , -C(NR ^c W )=NW, -N (W)C(R ^c )=NW, -X ² C(NOR ^c )R ^d , -X ² C(NR ^c W )=NW, -X ² N(W)C(R ^c )=NW, - X ² OR ^c , -X ² OC(O)R ^c , -X ² NR ^c R ^d , -X ² SR ^c , -X ² CO ₂ R ^c , -X ² CONR ^c R ^d , -X ² C( O)R ^c , -X ² OC(O)NR ^c R ^d , -X ² NR ^d C(O)R ^c , -X ² NR ^d C(O) ₂ R ^e , -X ² NR ^c C(O )NR ^c R ^d , -X ² S(O)R ^e , -X ² S(O) ₂ R ^e , -X ² NR ^c S(O) ₂ R ^e , -X ² S(O) ₂ NR ^c R ^d and -X ² N ₃ ; R ^2c is hydrogen, halogen, cyano or nitro, preferably halogen; R ^2d is selected from hydrogen, halogen, -OR ^c , -OC(O)R ^c , -NR ^c R ^d , -SR ^c , -R ^e , -CO ₂ R ^c , -CONR ^c R ^d , -C(O)R ^c , -S(O)R ^e , -S(O) ₂ R ^e , -NR ^c S(O) ₂ R ^e , -NR ^d C(O)R ^c , -X ² OR ^c , -X ² OC(O)R ^c , -X ² NR ^c R ^d , -X ² SR ^c , - X ² CO ₂ R ^c , -X ² CONR ^c R ^d , -X ² C(O)R ^c , -X ² OC(O)NR ^c R ^d , -X ² NR ^d C(O)R ^c , - X ² NR ^d C(O) ₂ R ^e , -X ² NR ^c C(O)NR ^c R ^d , -X ² S(O)R ^e , -X ² S(O) ₂ R ^e , -X ² NR ^c S(O) ₂ R ^e , -OX ² -OR ^c , -X ² S(O) ₂ NR ^c R ^d and -X ² N ₃ , wherein X ² is C _1-4 alkylene, R ^c and R ^d are each independently selected from hydrogen, C _1-8 alkyl, C _1-8 haloalkyl, C _3-6 cycloalkyl, C _2-8 alkenyl and C _2-8 alkynyl, each R ^e is independently is selected from C _1-8 alkyl, C _1-8 haloalkyl, C _3-6 cycloalkyl, C _2-8 alkenyl and C _2-8 alkynyl, each of R ^c , R ^d and R ^e is for Formula III is also optionally substituted, or substituted by 1-3 groups selected from the following groups: OH, O(C _1-8 alkyl), SH, S(C _1-8 alkyl), CN, NO ₂ , NH ₂ , NH(C _1-8 alkyl) and N(C _1-8 alkyl) ₂ ; not more than one of R ^2a and R ^2d is hydrogen. Preferably, neither R ^2a nor R ^2d is hydrogen. In the most preferred embodiment, R ^2a is not hydrogen; R ^2c is halogen, cyano or nitro; R ^2d is -SR ^c , -OX ² -OR ^c , -X ² -OR ^c , -R ^e , - OR ^c , -NR ^c R ^d , -NR ^c S(O) ₂ R ^e or -NR ^d C(O) R ^c ; R ^3c is selected from C _1-6 alkyl and C _3-6 cycloalkyl; R ^3b is hydrogen, F, Cl, Br or cyano; R ^3a _{is selected from -NRfRg, -SO2Rh} ^{, -Rh , -C} (O) ^Rf , ^-X3Y , _SCH3 and Y , wherein Y is an unsubstituted or substituted 5-membered or 6-membered heteroaryl or heterocyclic group, such as pyridyl, pyrimidyl, thienyl, furyl, _diazolyl, oxazolyl, thiazolyl, pyrazolyl , triazolyl, tetrazolyl, imidazolyl, morpholinyl, pyrrolidinyl, piperidinyl, etc.

In a related and preferred embodiment, there is provided a compound of formula IIId, wherein R ^3a and R ^3c are each independently selected from halogen, cyano, -NO ₂ , -CO ₂ R ^f , -CONR ^f R ^g , -C( O)R ^f , -NR ^f R ^g , -SR ^f , -S(O)R ^h , -S(O) ₂ R ^h , -C(O)Y, -SO ₂ Y, -X ³ Y, Y , C _1-6 alkyl, C _1-6 haloalkyl or C _3-6 cycloalkyl, wherein the alkyl and cycloalkyl substituents may be optionally substituted by groups selected from: -OH, -OR ^o , -OC(O)NHR ^o , -OC(O)N(R ^o ) ₂ , -SH, -SR ^o , -S(O)R ^o , -S(O) ₂ R ^o , -SO ₂ NH ₂ 、-S(O) ₂ NHR ^o 、-S(O) ₂ N(R ^o ) ₂ 、-NHS(O) ₂ R ^o 、-NR ^o S(O) ₂ R ^o 、-C(O)NH ₂ , -C(O)NHR ^o , -C(O)N(R ^o ) ₂ , -C(O)R ^o , -NHC(O)R ^o , -NR ^o C(O)R ^o , -NHC (O)NH ₂ , -NR ^o C(O)NH ₂ , -NR ^o C(O)NHR ^o , -NHC(O)NHR ^o , -NR ^o C(O)N(R ^o ) ₂ , -NHC (O)N(R ^o )) ₂ , -CO ₂ H, -CO ₂ R ^o , -NHCO ₂ R ^o , -NR ^o CO ₂ R ^o , -CN, -NO ₂ , -NH ₂ , -NHR ^o , -N(R ^o ) ₂ , -NR ^o S(O)NH ₂ and -NR ^o S(O) ₂ NHR ^o . More preferably, R ^3c is selected from halogen, cyano, C _1-6 alkyl, C _1-6 haloalkyl, C _3-6 cycloalkyl, -C(O)R ^f , -NR ^f R ^g , - SR ^f , -S(O) ₂ R ^h , -X ³ Y and Y are more preferably selected from NH ₂ , CF ₃ , SCH ₃ , SO ₂ CH ₃ , CN, C(CH ₃ ) ₂ OH and Y. R ^3b is hydrogen, F, Cl, Br or cyano; and R ^3a is preferably C _1-6 alkyl, C _1-6 haloalkyl or C _3-6 cycloalkyl. R ^2a is hydrogen, halogen, -OR ^c , -OC(O)R ^c , -NR ^c R ^d , -SR ^c , -R ^e , -CO ₂ R ^c , -CONR ^c R ^d , -C(O) R ^c , -S(O)R ^e , -S(O) ₂ R ^e , -C(NOR ^c )R ^d , -C(NR ^c W )=NW, -N(W)C(R ^c )= NW, -X ² C(NOR ^c )R ^d , -X ² C(NR ^c W )=NW, -X ² N(W)C(R ^c )=NW, -X ² OR ^c , -X ² OC (O)R ^c , -X ² NR ^c R ^d , -X ² SR ^c , -X ² CO ₂ R ^c , -X ² CONR ^c R ^d , -X ² C(O)R ^c , -X ² OC (O)NR ^c R ^d , -X ² NR ^d C(O)R ^c , -X ² NR ^d C(O) ₂ R ^e , -X ² NR ^c C(O)NR ^c R ^d , -X ² S(O) ^Re _, ^-X2S (O ⁾ _{2Re ,} ^-X2NRcS ( ^O ) _2Re , ^-X2S (O) ^{2NRcRd ,} and ^{-X2N3 ;} R ^2c is hydrogen, halogen, cyano or nitro; R ^2d is selected from hydrogen, halogen, -OR ^c , -OC(O)R ^c , -NR ^c R ^d , -SR ^c , -R ^e , -CO ₂ R ^c , -CONR ^c R ^d , -C(O)R ^c , -S(O)R ^e , -S(O) ₂ R ^e , -NR ^c S(O) ₂ R ^e , -NR ^d C( O)R ^c , -X ² OR ^c , -X ² OC(O)R ^c , -X ² NR ^c R ^d , -X ² SR ^c , -X ² CO ₂ R ^c , -X ² CONR ^c R ^d , -X ² C(O)R ^c , -X ² OC(O)NR ^c R ^d , -X ² NR ^d C(O)R ^c , -X ² NR ^d C(O) ₂ R ^e , -X ² NR ^c C(O)NR ^c R ^d , -X ² S(O)Re ^e , -X ² S(O) ₂ R ^e , -X ² NR ^c S(O) ₂ R ^e , -OX ² - OR ^c , -X ² S(O) ₂ NR ^c R ^d and -X ² N ₃ , wherein X ² is C _1-4 alkylene, R ^c and R ^d are each independently selected from hydrogen, C _1-8 Alkyl, C _1-8 haloalkyl, C _3-6 cycloalkyl, C _2-8 alkenyl and C _2-8 alkynyl, each R ^e is independently selected from: C _1-8 alkyl, C _{1- 8} haloalkyl, C _3-6 cycloalkyl, C _2-8 alkenyl and C _2-8 alkynyl, R ^c , R ^d and R ^e are each optionally substituted as described for formula III, or by 1- Substitution with 3 groups selected from: OH, O(C _1-8 alkyl), SH, S(C _1-8 alkyl), CN, NO ₂ , NH ₂ , NH(C _1-8 alkyl ) and N(C _1-8 alkyl) ₂ ; not more than one of R ^2a and R ^2d is hydrogen. Preferably, neither R ^2a nor R ^2d is hydrogen. In certain preferred embodiments, R ^2a is not hydrogen; R ^2c is halo, cyano, or nitro; R ^2d is -SR ^c , -OX ² -OR ^c , -X ² -OR ^c , -R ^e , - OR ^c , -NR ^c R ^d , -NR ^c S(O) ₂ ^Re or -NR ^d C(O)R ^c ; R ^3c is selected from NH ₂ , CF ₃ , SCH ₃ , C(CH ₃ ) ₂ OH and Y; R ^3b is hydrogen, F, Cl, Br or cyano; R ^3a is selected from C _1-6 alkyl and C _3-6 cycloalkyl, optionally substituted as described above.

Returning to formula III above, a particularly preferred group of compounds are those wherein m is 0 or 1; ^R , when present, is C _1-2 alkyl, optionally substituted by a group selected from: -OH, - OR ^m , -N(R ^m ) ₂ , -S(O) ₂ R ^m , -CO ₂ H and -CO ₂ R ^m ; R ^2a is selected from H, -CH ₃ , halogen, -C(O)CH ₃ , -CO ₂ CH ₃ , -CH ₂ OH, -CH ₂ OCH ₃ , -CH ₂ NH ₂ , -CH(CH ₃ )OH, -CH ₂ NHCH ₃ , -CH ₂ N(CH ₃ ) ₂ , -CH ₂ SO ₂ CH ₃ , -CH(CH ₃ )NH ₂ , -C(=NOH)H, -C(=NOH)CH ₃ , -C(=NOCH ₃ )H, and -C(=NOCH ₃ )CH ₃ ; R ^2b is H; R ^2c is selected from H, F, Cl and Br; R ^2d is selected from OCH ₃ , OCH ₂ CH ₃ , NHCH ₃ , CH ₂ OCH ₃ and CH ₃ ; R ^2e is H, so that R ^2a and At least one of R ^2c is not H; R ^3b is hydrogen, F, Cl, Br or cyano; one of R ^3a and R ^3c is cyclopropyl, CH ₃ , CF ₃ or methyl, optionally replaced by NH ₂ , NHCH _3. Substituted by N(CH ₃ ) ₂ , OH, OCH ₃ , SO ₂ CH ₃ or NHSO ₂ CH ₃ , the other of R ^3a and R ^3c is selected from CF ₃ , Br, methyl, ethyl, isopropyl, -CO ₂ CH ₃ , -CO ₂ Et, -SO ₂ CH ₃ , -C(O)CH ₃ , -CH ₂ OH, -CH(CH ₃ )OH, -SCH ₃ , -C(CH ₃ ) ₂ OH , -NHCH ₃ , -N(CH ₃ ) ₂ , -NH ₂ , substituted phenyl or substituted or unsubstituted pyridyl, pyrimidyl, thienyl, furyl, _diazolyl, oxazolyl, thiazolyl , pyrazolyl, triazolyl, tetrazolyl, imidazolyl, morpholinyl, pyrrolidinyl, piperazinyl and piperidinyl.

Another particularly preferred embodiment of formula III is wherein m is 0 or 1, preferably 0; when R ¹ exists, it is -CO ₂ R ^a , -X ¹ -SO ₂ R ^a or C _1-6 alkyl , those compounds optionally substituted by a group selected from -OH, -OR ^m , -OC(O)NHR ^m , -OC(O)N(R ^m ) ₂ , -SH, -SR ^m , -S (O)R ^m , -S(O) ₂ R ^m , -SO ₂ NH ₂ , -S(O) ₂ NHR ^m , -S(O) ₂ N(R ^m ) ₂ , -NHS(O) ₂ R ^m , -NR ^m S(O) ₂ R ^m , -C(O)NH ₂ , -C(O)NHR ^m , -C(O)N(R ^m ) ₂ , -C(O)R ^m , - NHC(O)R ^m , -NR ^m C(O)R ^m , -NHC(O)NH ₂ , -NR ^m C(O)NH ₂ , -NR ^m C(O)NHR ^m , -NHC(O) NHR ^m , -NR ^m C(O)N(R ^m ) ₂ , -NHC(O)N(R ^m ) ₂ , -CO ₂ H, -CO ₂ R ^m , -NHCO ₂ R ^m , -NR ^m CO ₂ R ^m , -CN, -NO ₂ , -NH ₂ , -NHR ^m , -N(R ^m ) ₂ , -NR ^m S(O)NH ₂ and -NR ^m S(O) ₂ NHR ^m , each of which R ^m is independently unsubstituted C _1-6 alkyl; R ^2a , R ^2b and R ^2e are each hydrogen; R ^2c is halogen or cyano; R ^2d is selected from -SR ^c , -OX ² -OR ^c , -X ² -OR ^c , -R ^e , -OR ^c , -NR ^c R ^d , -NR ^c S(O) ₂ ^Re and -NR ^d C(O)R ^c ; R ^3b is hydrogen, F, Cl , Br or cyano; R ^3a and R ^3c are each independently selected from halogen, cyano, -NO ₂ , -CO ₂ R ^f , -CONR ^f R ^g , -C(O)R ^f , -NR ^f R ^g , -SR ^f , -S(O)R ^h , -S(O) ₂ R ^h , -C(O)Y, -SO ₂ Y, -X ³ Y, Y, C _1-6 alkyl, C ₁ - ₆ haloalkyl or C _3-6 cycloalkyl, wherein the alkyl and cycloalkyl substituents may be optionally substituted with substituents selected from: -OH, -OR ^o , -OC(O)NHR ^o , - OC(O)N(R ^o ) ₂ , -SH, -SR ^o , -S(O)R ^o , -S(O) ₂ R ^o , -SO ₂ NH ₂ , -S(O) ₂ NHR ^o , -S(O) ₂ N(R ^o ) ₂ , -NHS(O) ₂ R ^o , -NR ^o S(O) ₂ R ^o , -C(O)NH ₂ , -C(O)NHR ^o , - C(O)N(R ^o ) ₂ , -C(O)R ^o , -NHC(O)R ^o , -NR ^o C(O)R ^o , -NHC(O)NH ₂ , -NR ^o C( O)NH ₂ , -NR ^o C(O)NHR ^o , -NHC(O)NHR ^o , -NR ^o C(O)N(R ^o ) ₂ , -NHC(O)N(R ^o ) ₂ , - CO ₂ H, -CO ₂ R ^o , -NHCO ₂ R ^o , -NR ^o CO ₂ R ^o , -CN, -NO ₂ , -NH ₂ , -NHR ^o , -N(R ^o ) ₂ , -NR ^o S(O)NH ₂ and -NR ^o S(O) ₂ NHR ^o . In this group of embodiments, compounds that meet the following conditions are more preferred: (a) at least one of R ^3a and R ^3c is C _1-6 alkyl, optionally substituted by 1-3 groups selected from the following groups: -OH , -OR ^o , -OC(O)NHR ^o , -OC(O)N(R ^o ) ₂ , -SH, -SR ^o , -S(O)R ^o , -S(O) ₂ R ^o , - SO ₂ NH ₂ , -S(O) ₂ NHR ^o , -S(O) ₂ N(R ^o ) ₂ , -NHS(O) ₂ R ^o , -NR ^o S(O) ₂ R ^o , -C( O)NH ₂ , -C(O)NHR ^o , -C(O)N(R ^o ) ₂ , -C(O)R ^o , -NHC(O)R ^o , -NR ^o C(O)R ^o , -NHC(O)NH ₂ , -NR ^o C(O)NH ₂ , -NR ^o C(O)NHR ^o , -NHC(O)NHR ^o , -NR ^o C(O)N(R ^o ) ₂ , -NHC(O)N(R ^o ) ₂ , -CO ₂ H, -CO ₂ R ^o , -NHCO ₂ R ^o , -NR ^o CO ₂ R ^o , -CN, -NO ₂ , -NH ₂ , - NHR ^o , -N(R ^o ) ₂ , -NR ^o S(O)NH ₂ and -NR ^o S(O) ₂ NHR ^o ; (b) at least one of R ^3a and R ^3c is -NR ^f R ^g ; (c) at least one of R ^3a and R ^3c is Y, wherein when Y is phenyl, the phenyl is substituted; (d) at least one of R ^3a and R ^3c is Y, wherein Y is unsubstituted or substituted 5-membered or 6-membered heteroaryl or heterocyclic group, such as pyridyl, pyrimidyl, thienyl, furyl, _diazolyl, _azolyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl, morpholinyl, pyrrolidinyl, piperidinyl, etc.; or (e) at least one of R ^3a and R ^3c is -SO ₂ R ^h or -C(O)R ^f . Any substituents not specifically listed are meant to have the fullest meaning for Formula III. Furthermore, all compounds are meant to include pharmaceutically acceptable salts thereof, as well as all N-oxides thereof.

Another particularly preferred embodiment of formula III is wherein m is 0 or 1; R ¹ when present is -CO ₂ R ^a , -X ¹ -SO ₂ R ^a or C _1-6 alkyl, optionally selected from Those compounds substituted from the following groups: -OH, ^-ORm , -OC(O) ^NHRm , -OC(O)N( ^Rm ) ₂ , -SH, ^-SRm , -S(O)R ^m , -S(O) ₂ R ^m , -SO ₂ NH ₂ , -S(O) ₂ NHR ^m , -S(O) ₂ N(R ^m ) ₂ , -NHS(O) ₂ R ^m , -NR ^m S(O) ₂ R ^m , -C(O)NH ₂ , -C(O)NHR ^m , -C(O)N(R ^m ) ₂ , -C(O)R ^m , -NHC(O) R ^m , -NR ^m C(O)R ^m , -NHC(O)NH ₂ , -NR ^m C(O)NH ₂ , -NR ^m C(O)NHR ^m , -NHC(O)NHR ^m , - NR ^m C(O)N(R ^m ) ₂ , -NHC(O)N(R ^m ) ₂ , -CO ₂ H, -CO ₂ R ^m , -NHCO ₂ R ^m , -NR ^m CO ₂ R ^m , -CN, -NO ₂ , -NH ₂ , -NHR ^m , -N(R ^m ) ₂ , -NR ^m S(O)NH ₂ and -NR ^m S(O) ₂ NHR ^m , wherein each R ^m is independently is unsubstituted C _1-6 alkyl; R ^2a is hydrogen, halogen, -OR ^c , -OC(O)R ^c , -NR ^c R ^d , -SR ^c , -R ^c , -CO ₂ R ^c , -CONR ^c R ^d , -C(O)R ^c , -S(O)R ^e , -S(O) ₂ R ^e , -C(NOR ^c )R ^d , -C(NR ^c W)=NW, -N(W)C(R ^c )=NW, -X ² C(NOR ^c )R ^d , -X ² C(NR ^c W )=NW, -X ² N(W)C(R ^c )=NW , -X ² OR ^c , -X ² OC(O)R ^c , -X ² NR ^c R ^d , -X ² SR ^c , -X ² CO ₂ R ^c , -X ² CONR ^c R ^d , -X ² C(O)R ^c , -X ² OC(O)NR ^c R ^d , -X ² NR ^d C(O)R ^c , -X ² NR ^d C(O) ₂ R ^e , -X ² NR ^c C (O)NR ^c R ^d , -X ² S(O) ^Re , -X ² S(O) ₂ R ^e , -X ² NR ^c S(O) ₂ R ^e , -X ² S(O) ₂ NR ^c R ^d or -X ² N ₃ ; R ^2b is hydrogen; R ^2c is halogen or cyano; R ^2d is selected from -SR ^c , -OX ² -OR ^c , -X ² -OR ^c , -R ^e , -OR ^c , -NR ^c R ^d , -NR ^c S(O) ₂ ^Re and -NR ^d C(O)R ^c , or optionally combined with R ^2e , form fused to the benzene ring to which they are each attached 5- or 6-membered rings. R ^3b is hydrogen, F, Cl, Br or cyano; R ^3a and R ^3c are each independently selected from halogen, -NR ^f R ^g , -SR ^f , -CO ₂ R ^f , -C(O)R ^f , -SO ₂ R ^h , -X ³ Y, -Y and -R ^h , wherein R ^h is C _1-6 alkyl, C _1-6 haloalkyl and C _3-6 cycloalkyl, wherein the aliphatic part is also Optionally substituted with 1-3 groups selected from -OH, -OR ^o , -OC(O)NHR ^o , -OC(O)N(R ^o ) ₂ , -SH, -SR ^o , - S(O)R ^o , -S(O) ₂ R ^o , -SO ₂ NH ₂ , -S(O) ₂ NHR ^o , -S(O) ₂ N(R ^o ) ₂ , -NHS(O) ₂ R ^o , -NR ^o S(O) ₂ R ^o , -C(O)NH ₂ , -C(O)NHR ^o , -C(O)N(R ^o ) ₂ , -C(O)R ^o , -NHC(O)R ^o , -NR ^o C(O)R ^o , -NHC(O)NH ₂ , -NR ^o C(O)NH ₂ , -NR ^o C(O)NHR ^o , -NHC(O) )NHR ^o , -NR ^o C(O)N(R ^o ) ₂ , -NHC(O)N(R ^o ) ₂ , -CO ₂ H, -CO ₂ R ^o , -NHCO ₂ R ^o , -NR ^o _CO2Ro , ^-CN , _-NO2 , _-NH2 , ^-NHRo , -N( ^Ro ) ₂ , ^-NRoS (O)NH2 _, and ^-NRoS (O) _2NHRo ^. More preferred in this group of embodiments are compounds that meet the following conditions: (a) at least one of R ^3a and R ^3c is C _1-6 alkyl, optionally substituted by 1-3 groups selected from the following groups: -OH, -OR ^o , -OC(O)NHR ^o , -OC(O)N(R ^o ) ₂ , -SH, -SR ^o , -S(O)R ^o , -S(O) ₂ R ^o , -SO ₂ NH ₂ , -S(O) ₂ NHR ^o , -S(O) ₂ N(R ^o ) ₂ , -NHS(O) ₂ R ^o , -NR ^o S(O) ₂ R ^o , - C(O)NH ₂ , -C(O)NHR ^o , -C(O)N(R ^o ) ₂ , -C(O)R ^o , -NHC(O)R ^o , -NR ^o C(O) R ^o , -NHC(O)NH ₂ , -NR ^o C(O)NH ₂ , -NR ^o C(O)NHR ^o , -NHC(O)NHR ^o , -NR ^o C(O)N(R ^o ) ₂ , -NHC(O)N(R ^o ) ₂ , -CO ₂ H, -CO ₂ R ^o , -NHCO ₂ R ^o , -NR ^o CO ₂ R ^o , -CN, -NO ₂ , -NH ₂ , -NHR ^o , -N(R ^o ) ₂ , -NR ^o S(O)NH ₂ and -NR ^o S(O) ₂ NHR ^o ; (b) at least one of R ^3a and R ^3c is -NR ^f R ^g ; (c) at least one of R ^3a and R ^3c is Y, wherein when Y is phenyl, the phenyl is substituted; (d) at least one of R ^3a and R ^3c is Y, wherein Y is unsubstituted or Substituted 5- or 6-membered heteroaryl or heterocyclic groups, such as pyridyl, pyrimidyl, thienyl, furyl, oxadiazolyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl or (e) at least one of R ^3a and R ^3c is -SO ₂ R ^h or -C(O)R ^f .

In yet another set of embodiments of formula III, two adjacent moieties of R ^3a , R ^3b and R ^3c are joined together to form a 5- or 6-membered ring fused to their respective attached pyrazole moieties. The remainder (R ^3a or R ^{3c ) is} selected from ^-NRfRg , ^-SRf , ^-CO2Rf , -C(O) ^Rf , _{-SO2Rh ,} ^-X3Y , -Y and - R ^b , wherein R ^h is C _1-6 alkyl, C _1-6 haloalkyl and C _3-6 cycloalkyl, wherein the aliphatic part is also optionally substituted by 1-3 groups selected from the following groups: -OH, -OR ^o , -OC(O)NHR ^o , -OC(O)N(R ^o ) ₂ , -SH, -SR ^o , -S(O)R ^o , -S(O) ₂ R ^o , -SO ₂ NH ₂ , -S(O) ₂ NHR ^o , -S(O) ₂ N(R ^o ) ₂ , -NHS(O) ₂ R ^o , -NR ^o S(O) ₂ R ^o , - C(O)NH ₂ , -C(O)NHR ^o , -C(O)N(R ^o ) ₂ , -C(O)R ^o , -NHC(O)R ^o , -NR ^o C(O) R ^o , -NHC(O)NH ₂ , -NR ^o C(O)NH ₂ , -NR ^o C(O)NHR ^o , -NHC(O)NHR ^o , -NR ^o C(O)N(R ^o ) ₂ , -NHC(O)N(R ^o ) ₂ , -CO ₂ H, -CO ₂ R ^o , -NHCO ₂ R ^o , -NR ^o CO ₂ R ^o , -CN, -NO ₂ , -NH ₂ , -NHR ^o , -N(R ^o ) ₂ , -NR ^o S(O)NH ₂ and -NR ^o S(O) ₂ NHR ^o .

Another particularly preferred embodiment of formula III is wherein m is 0 or 1, preferably 0; when R ¹ exists, it is -CO ₂ R ^a , -X ¹ -SO ₂ R ^a or C _1-6 alkyl , those compounds optionally substituted by a group selected from -OH, -OR ^m , -OC(O)NHR ^m , -OC(O)N(R ^m ) ₂ , -SH, -SR ^m , - S(O)R ^m , -S(O) ₂ R ^m , -SO ₂ NH ₂ , -S(O) ₂ NHR ^m , -S(O) ₂ N(R ^m ) ₂ , -NHS(O) ₂ R ^m , -NR ^m S(O) ₂ R ^m , -C(O)NH ₂ , -C(O)NHR ^m , -C(O)N(R ^m ) ₂ , -C(O)R ^m , -NHC(O)R ^m , -NR ^m C(O)R ^m , -NHC(O)NH ₂ , -NR ^m C(O)NH ₂ , -NR ^m C(O)NHR ^m , -NHC(O) )NHR ^m , -NR ^m C(O)N(R ^m ) ₂ , -NHC(O)N(R ^m ) ₂ , -CO ₂ H, -CO ₂ R ^m , -NHCO ₂ R ^m , -NR ^m CO ₂ R ^m , —CN, —NO ₂ , —NH ₂ , —NHR ^m , —N(R ^m ) ₂ , —NR ^m S(O)NH _{2 ,} and —NR ^m S(O) ₂ NHR ^m , where Each R ^m is independently unsubstituted C _1-6 alkyl; R ^2b is selected from hydrogen, halogen, -OR ^c , -OC(O)R ^c , -NR ^c R ^d , -SR ^c , -R ^e , -CO ₂ R ^c , -CONR ^c R ^d , -C(O)R ^c , -S(O)R ^e , -S(O) ₂ R ^e , -NR ^c S(O) ₂ R ^e , -NR ^d C(O)R ^c , -X ² OR ^c , -X ² OC(O)R ^c , -X ² NR ^c R ^d , -X ² SR ^c , -X ² CO ₂ R ^c , -X ² CONR ^c R ^d , -X ² C(O)R ^c , -X ² OC(O)NR ^c R ^d , -X ² NR ^d C(O)R ^c , -X ² NR ^d C(O) ₂ R ^e , -X ² NR ^c C(O)NR ^c R ^d , -X ² S(O)R ^e , -X ² S(O) ₂ R ^e , -X ² NR ^c S(O) ₂ R ^e , - OX ² -OR ^c , -X ² S(O) ₂ NR ^c R ^d and -X ² N ₃ , wherein X ² is C _1-4 alkylene, R ^c and R ^d are each independently selected from hydrogen, C _1-8 alkyl, C _1-8 haloalkyl, C _3-6 cycloalkyl, C _2-8 alkenyl and C _2-8 alkynyl, R ^e is independently selected from C _1-8 alkyl, C _{1 -8} haloalkyl, C _3-6 cycloalkyl, C _2-8 alkenyl and C _2-8 alkynyl, R ^c , R ^d and R ^e are each optionally substituted as described for formula III, or are Substituted by 1-3 groups selected from: OH, O(C _1-8 alkyl), SH, S(C _1-8 alkyl), CN, NO ₂ , NH ₂ , NH(C _1-8 alkyl) and N(C _1-8 alkyl) ₂ . More preferably, R ^2b is hydrogen, R ^2e is hydrogen; R ^2a is hydrogen, halogen, -CN, -C(O)Rc, ^-C ( ^NORc ) ^Rd , -C( ^NRcW )=NW , -N(W)C(R ^c )=NW, -X ² C(NOR ^c )R ^d , -X ² C(NR ^c W )=NW, -X ² N(W)C(R ^c )= NW, -X ² NR ^c R ^d or -R ^e ; R ^2d is selected from -SR ^c , -OX ² -OR ^c , -X ² -OR ^c , -R ^e , -OR ^c , -NR ^c R ^d , -NR ^c S(O) ₂ ^Re and -NR ^d C(O)R ^c ; R ^3b is hydrogen, F, Cl, Br or cyano; R ^3a and R ^3c are each independently selected from halogen, cyano, -NO ₂ , -CO ₂ R ^f , -CONR ^f R ^g , -C(O)R ^f , -NR ^f R ^g , -SR ^f , -S(O)R ^h , -S(O) ₂ R ^h , -C(O)Y, -SO ₂ Y, -X ³ Y, Y, C _1-6 alkyl, C _1-6 haloalkyl or C _3-6 cycloalkyl, wherein alkyl and cycloalkyl are substituted The group may be optionally substituted with a group selected from -OH, -OR ^o , -OC(O)NHR ^o , -OC(O)N(R ^o ) ₂ , -SH, -SR ^o , -S( O)R ^o , -S(O) ₂ R ^o , -SO ₂ NH ₂ , -S(O) ₂ NHR ^o , -S(O) ₂ N(R ^o ) ₂ , -NHS(O) ₂ R ^o , -NR ^o S(O) ₂ R ^o , -C(O)NH ₂ , -C(O)NHR ^o , -C(O)N(R ^o ) ₂ , -C(O)R ^o , -NHC (O)R ^o , -NR ^o C(O)R ^o , -NHC(O)NH ₂ , -NR ^o C(O)NH ₂ , -NR ^o C(O)NHR ^o , -NHC(O)NHR ^o , -NR ^o C(O)N(R ^o ) ₂ , -NHC(O)N(R ^o ) ₂ , -CO ₂ H, -CO ₂ R ^o , -NHCO ₂ R ^o , -NR ^o CO ₂ R ^o , -CN, -NO ₂ , -NH ₂ , -NHR ^o , -N(R ^o ) ₂ , -NR ^o S(O)NH ₂ , and -NR ^o S(O) ₂ NHR ^o . More preferred in this group of embodiments are those compounds that meet the following conditions: (a) at least one of R ^3a and R ^3c is C _1-6 alkyl, optionally substituted by 1-3 groups selected from : -OH, -OR ^o , -OC(O)NHR ^o , -OC(O)N(R ^o ) ₂ , -SH, -SR ^o , -S(O)R ^o , -S(O) ₂ R ^o , -SO ₂ NH ₂ , -S(O) ₂ NHR ^o , -S(O) ₂ N(R ^o ) ₂ , -NHS(O) ₂ R ^o , -NR ^o S(O) ₂ R ^o , -C(O)NH ₂ , -C(O)NHR ^o , -C(O)N(R ^o ) ₂ , -C(O)R ^o , -NHC(O)R ^o , -NR ^o C(O )R ^o , -NHC(O)NH ₂ , -NR ^o C(O)NH ₂ , -NR ^o C(O)NHR ^o , -NHC(O)NHR ^o , -NR ^o C(O)N(R ^o ) ₂ , -NHC(O)N(R ^o ) ₂ , -CO ₂ H, -CO ₂ R ^o , -NHCO ₂ R ^o , -NR ^o CO ₂ R ^o , -CN, -NO ₂ , -NH ₂ , -NHR ^o , -N(R ^o ) ₂ , -NR ^o S(O)NH ₂ and -NR ^o S(O) ₂ NHR ^o ; (b) at least one of R ^3a and R ^3c is -NR ^f R ^g ; (c) at least one of R ^3a and R ^3c is Y, wherein when Y is phenyl, the phenyl is substituted; (d) at least one of R ^3a and R ^3c is Y, wherein Y is unsubstituted Or substituted 5-membered or 6-membered heteroaryl or heterocyclic group, such as pyridyl, pyrimidyl, thienyl, furyl, _diazolyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl Azolyl, imidazolyl, morpholinyl, pyrrolidinyl, piperidinyl, etc.; or (e) at least one of R ^3a and R ^3c is -SO ₂ R ^h or -C(O)R ^f .

Other preferred groups of the above formula III are formulas IIIe to IIIvvv, wherein the substituents are as defined for formula III, and preferred embodiments are provided below. Formulas IIIe through IIIvvv are provided in Figures 5A through 5J. Referring first to formulas IIIe, IIIg, IIIi, IIIk, IIIm, IIIo, IIIq, IIIs, IIIu, IIIw, IIIy, IIIaa, IIIcc, IIIee, IIIgg, IIIii, IIIkk, IIImm, IIIoo, IIIqq, IIIss, IIIuu, IIIww, IIIyy , IIIaaa, IIIccc, IIIeee, IIIggg, IIIiii, IIIkkk, IIImmm, IIIooo, IIIqqq, IIIsss and IIIuuu, R ^2a is preferably hydrogen, halogen, cyano, -NO ₂ , -CO ₂ R ^c , -CONR ^c R ^d , -C(O)R ^c , -S(O)R ^e , -S(O) ₂ R ^e , -R ^c , -C(NOR ^c )R ^d , -C(NR ^c W)=NW, - N(W)C(R ^c )=NW, -X ² C(NOR ^c )R ^d , -X ² C(NR ^c W)=NW, -X ² N(W)C( ^R c )=NW, -X ² NR ^c R ^d , -X ² SR ^c , -X ² CN, -X ² NO ₂ , -X ² CO ₂ R ^c , -X ² CONR ^c R ^d , -X ² C(O)R ^c , -X ² OC(O)NR ^c R ^d , -X ² NR ^d C(O)R ^c , -X ² NR ^d C(O) ₂ R ^e , -X ² NR ^c C(O)NR ^c R ^d , -X ² NH-C(NH ₂ )=NH, -X ² NR ^e C(NH ₂ )=NH, -X ² NH-C(NH ₂ )=NR ^e , -X ² NH-C(NHR ^e )=NH, -X ² S(O)R ^e , -X ² S(O) ₂ R ^e , -X ² NR ^c S(O) ₂ R ^e , -X ² S(O) ₂ NR ^c R ^d or -X ² N ₃ ; R ^2c is halogen, cyano or nitro; R ^2d is -SR ^c , -OX ² -OR ^c , -X ² -OR ^c , -R ^e , -OR ^c , -NR ^c R ^d or -NR ^c SO ₂ R ^d ; R ^3b is preferably hydrogen, halogen, cyano, -NO ₂ , -CO ₂ R ^f , -CONR ^f R ^g , -C(O)R ^f , -S (O)R ^h , -S(O) ₂ R ^h , -R ^h , -X ³ NR ^f R ^g , -X ³ SR ^f , -X ³ CN, -X ³ NO ₂ , -X ³ CO ₂ R ^f , -X ³ CONR ^f R ^g , -X ³ C(O)R ^f , -X ³ OC(O)NR ^f R ^g , -X ³ NR ^g C(O)R ^f , -X ³ NR ^g C (O) ₂ R ^h , -X ³ NR ^f C(O)NR ^f R ^g , -X ³ NH-C(NH ₂ )=NH, -X ³ NR ^h C(NH ₂ )=NH, -X ³ NH-C(NH ₂ )=NR ^h , -X ³ NH-C(NHR ^h )=NH, -X ³ S(O)R ^h , -X ³ S(O) ₂ R ^h , -X ³ NR ^f S(O) ₂ R ^h , -X ³ S(O) ₂ NR ^f R ^g , -X ³ N ₃ , Y or -X ³ Y; R ^3c is preferably halogen, cyano, -NO ₂ , -CO ₂ R ^f , -CONR ^f R ^g , -C(O)R ^f , NR ^f R ^g , SR ^f , -S(O)R ^h , -S(O) ₂ R ^h , -C(O)Y, -SO ₂ Y, -X ³ Y, Y, C _1-6 alkyl, C _1-6 haloalkyl or C _3-6 cycloalkyl, wherein the alkyl and cycloalkyl substituents can optionally be selected from The following groups are substituted: -OH, -OR ^o , -OC(O)NHR ^o , -OC(O)N(R ^o ) ₂ , -SH, -SR ^o , -S(O)R ^o , -S (O) ₂ R ^o , -SO ₂ NH ₂ , -S(O) ₂ NHR ^o , -S(O) ₂ N(R ^o ) ₂ , -NHS(O) ₂ R ^o , -NR ^o S(O ) ₂ R ^o , -C(O)NH ₂ , -C(O)NHR ^o , -C(O)N(R ^o ) ₂ , -C(O)R ^o , -NHC(O)R ^o , - NR ^o C(O)R ^o , -NHC(O)NH ₂ , -NR ^o C(O)NH ₂ , -NR ^o C(O)NHR ^o , -NHC(O)NHR ^o , -NR ^o C( O)N(R ^o ) ₂ , -NHC(O)N(R ^o ) ₂ , -CO ₂ H, -CO ₂ R ^o , -NHCO ₂ R ^o , -NR ^o CO ₂ R ^o , -CN, - NO ₂ , -NH ₂ , -NHR ^o , -N(R ^o ) ₂ , -NR ^o S(O)NH ₂ and -NR ^o S(O) ₂ NHR ^o ; R ⁴ is preferably halogen, -OR ^f , -NR ^f R ^g , -R ^h , -SR ^f , -CN, -NO ₂ , -CO ₂ R ^f , -CONR ^f R ^g , -C(O)R ^f , -NR ^g C(O)R ^f , -S(O)R ^h , -S(O) ₂ R ^h , -NR ^f S(O) ₂ R ^h , -S(O) ₂ NR ^f R ^g , -C(NOR ^f )R ^g , -C(NR ^f W ^a )=NW ^a , -N(W ^a )C(R ^f )=NW ^a , -X ³ OR ^f , -X ³ NR ^f R ^g , -X ³ NR ^f S(O) ₂ R ^h and -X ³ S(O) ₂ NR ^f R ^g ; R ⁵ is connected to ring nitrogen and is preferably hydrogen, -R ^h , -S(O) ₂ R ^h , -X ³ OR ^f , -X ³ NR ^f R ^g , -X ³ NR ^f S(O) ₂ R ^h and -X ³ S(O) ₂ NR ^f R ^g ; m is preferably 0-2; n is preferably 0-3. Also preferred is a group wherein each R ¹ when present is selected from C _1-4 alkyl, optionally selected from -OH, -OR ^m , -S(O) ₂ R ^m , -CO ₂ H and -CO ₂ R ^m Group substitution; those compounds in which at least one R substituent is attached to a ^ring carbon atom adjacent to a ring heteroatom when n is 1 or greater. More preferably, R ^2a is hydrogen, halogen, -CN, -C(O) ^Rc , -C( ^NORc ) ^Rd , -C( ^NRcW )=NW, -N(W)C( ^Rc ) =NW, -X ² C(NOR ^c )R ^d , -X ² C(NR ^c W )=NW, -X ² N(W)C(R ^c )=NW, -X ² NR ^c R ^d or - R ^e ; R ^2c is halogen or cyano; R ⁵ is hydrogen, C _1-4 alkyl or C _3-6 cycloalkyl. More preferably, m is 0 or 1, n is 0 or 1, and R ¹ when present is -CH ₃ . In the most preferred embodiment, R ^2d is -SR ^c , -R ^e or -OR ^c ; R ^3b is hydrogen, halogen, cyano or -NO ₂ ; R ^3c is C _1-6 alkyl, C _{1- 6} haloalkyl or C _3-6 cycloalkyl, which may be optionally substituted as described above; R ⁴ when present is -CH ₃ , -CF ₃ or -CN.

For formulas IIIf, IIIh, IIIj, IIIl, IIIn, IIIp, IIIr, IIIt, IIIv, IIIx, IIIz, IIIbb, IIIdd, IIIff, IIIhh, IIIjj, IIIll, IIInn, IIIpp, IIIrr, IIItt, IIIvv, IIIxx, IIIzz, Compounds of IIIbbb, IIIddd, IIIfff, IIIhhh, IIIjjj, IIIlll, IIInnn, IIIppp, IIIrrr, IIIttt and IIIvvv, R ^2a is preferably hydrogen, halogen, cyano, -NO ₂ , -CO ₂ ^Re , -CONR ^c R ^d , -C(O)R ^c , -S(O)R ^e , -S(O) ₂ R ^e , -R ^c , -C(NOR ^c )R ^d , -C(NR ^c W )=NW, -N(W)C(R ^c )=NW, -X ² C(NOR ^c )R ^d , -X ² C(NR ^c W )=NW, -X ² N(W)C(R ^c )=NW , -X ² NR ^c R ^d , -X ² SR ^c , -X ² CN, -X ² NO ₂ , -X ² CO ₂ R ^c , -X ² CONR ^c R ^d , -X ² C(O)R ^c , -X ² OC(O)NR ^c R ^d , -X ² NR ^d C(O)R ^c , -X ² NR ^d C(O) ₂ R ^e , -X ² NR ^c C(O)NR ^c R ^d , -X ² NH-C(NH ₂ )=NH, -X ² NR ^e C(NH ₂ )=NH, -X ² NH-C(NH ₂ )=NR ^e , -X ² NH-C( NHR ^e )=NH, -X ² S(O)R ^e , -X ² S(O) ₂ R ^e , -X ² NR ^c S(O) ₂ R ^e , -X ² S(O) ₂ NR ^c R ^d or -X ² N ₃ ; R ^2c is halogen, cyano or nitro; R ^2d is -SR ^c , -OX ² -OR ^c , -X ² -OR ^c , -R ^e , -OR ^c , - NR ^c R ^d or -NR ^c SO ₂ R ^d ; R ^3a is preferably halogen, cyano, -NO ₂ , -CO ₂ R ^f , -CONR ^f R ^g , -C(O)R ^f , NR ^f R ^g , SR ^f , -S(O)R ^h , -S(O) ₂ R ^h , -C(O)Y, -SO ₂ Y, -X ³ Y, Y, C _1-6 alkyl, C _{1 -6} haloalkyl or C _3-6 cycloalkyl, wherein the alkyl and cycloalkyl substituents may be substituted by groups selected from: -OH, -OR ^o , -OC(O)NHR ^o , -OC (O)N(R ^o ) ₂ , -SH, -SR ^o , -S(O)R ^o , -S(O) ₂ R ^o , -SO ₂ NH ₂ , -S(O) ₂ NHR ^o , - S(O) ₂ N(R ^o ) ₂ , -NHS(O) ₂ R ^o , -NR ^o S(O) ₂ R ^o , -C(O)NH ₂ , -C(O)NHR ^o , -C (O)N(R ^o ) ₂ , -C(O)R ^o , -NHC(O)R ^o , -NR ^o C(O)R ^o , -NHC(O)NH ₂ , -NR ^o C(O )NH ₂ , -NR ^o C(O)NHR ^o , -NHC(O)NHR ^o , -NR ^o C(O)N(R ^o ) ₂ , -NHC(O)N(R ^o ) ₂ , -CO ₂ H, -CO ₂ R ^o , -NHCO ₂ R ^o , -NR ^o CO ₂ R ^o , -CN, -NO ₂ , -NH ₂ , -NHR ^o , -N(R ^o ) ₂ , -NR ^o S (O)NH ₂ and -NR ^o S(O) ₂ NHR ^o ; R ^3b is preferably hydrogen, halogen, cyano, -NO ₂ , -CO ₂ R ^f , -CONR ^f R ^g , -C(O) R ^f , -S(O)R ^h , -S(O) ₂ R ^h , -R ^h , -X ³ NR ^f R ^g , -X ³ SR ^f , -X ³ CN, -X ³ NO ₂ , - X ³ CO ₂ R ^f , -X ³ CONR ^f R ^g , -X ³ C(O)R ^f , -X ³ OC(O)NR ^f R ^g , -X ³ NR ^g C(O)R ^f , - X ³ NR ^g C(O) ₂ R ^h , -X ³ NR ^f C(O)NR ^f R ^g , -X ³ NH-C(NH ₂ )=NH, -X ³ NR ^h C(NH ₂ )= NH, -X ³ NH-C(NH ₂ )=NR ^h , -X ³ NH-C(NHR ^h )=NH, -X ³ S(O)R ^h , -X ³ S(O) ₂ R ^h , -X ³ NR ^f S(O) ₂ R ^h , -X ³ S(O) ₂ NR ^f R ^g , -X ³ N ₃ , Y or -X ³ Y; R ⁴ is preferably halogen, -OR ^f , -NR ^f R ^g , -R ^h , -SR ^f , -CN, -NO ₂ , -CO ₂ R ^f , -CONR ^f R ^g , -C(O)R ^f , -NR ^g C(O)R ^f , -S(O)R ^h , -S(O) ₂ R ^h , -NR ^f S(O) ₂ R ^h , -S(O) ₂ NR ^f R ^g , -C(NOR ^f )R ^g , - C(NR ^f W ^a )=NW ^a , -N(W ^a )C(R ^f )=NW ^a , -X ³ OR ^f , -X ³ NR ^f R ^g , -X ³ NR ^f S(O) ₂ R ^h and -X ³ S(O) ₂ NR ^f R ^g ; R ⁵ is attached to ring nitrogen and is preferably hydrogen, -R ^h , -S(O) ₂ R ^h , -X ³ OR ^f , -X ³ NR ^f R ^g , -X ³ NR ^f S(O) ₂ R ^h and -X ³ S(O) ₂ NR ^f R ^g ; m is preferably 0-2; n is preferably 0-3. More preferably wherein each R ¹ when present is selected from C _1-4 alkyl, optionally selected from -OH, -OR ^m , -S(O) ₂ R ^m , -CO ₂ H and -CO ₂ R ^m Group substitution; those compounds in which at least one R substituent is attached to a ^ring carbon atom adjacent to a ring heteroatom when n is 1 or greater. More preferably, R ^2a is hydrogen, halogen, -CN, -C(O) ^Rc , -C( ^NORc ) ^Rd , -C( ^NRcW )=NW, -N(W)C( ^Rc ) =NW, -X ² C(NOR ^c )R ^d , -X ² C(NR ^c W )=NW, -X ² N(W)C(R ^c )=NW, -X ² NR ^c R ^d or - R ^e ; R ^2c is halogen or cyano; R ⁵ is hydrogen, C _1-4 alkyl or C _3-6 cycloalkyl. Also preferably, m is 0 or 1, n is 0 or 1, and ^R1 , when present, is _-CH3 . In the most preferred embodiment, R ^2d is -SR ^c , -R ^e or -OR ^c ; R ^3a is halogen, cyano, C _1-6 alkyl, C _1-6 haloalkyl, C _3-6 ring Alkyl, -C(O) ^Rf or _-SO2Rh , the aliphatic portion of which may be optionally substituted as described above; ^R3b is hydrogen, ^halogen , cyano or _-NO2 ; ^R4 when present is -CH ₃ , -CF ₃ , -CN, -C(O)R ^f or -SO ₂ R ^h .

N-linked heteroaryl

In a further preferred group of formula III, the compound has a formula selected from formula IIIwww to IIIdddd, Figure 5K, wherein the substituents have the definitions given for formula III above. First of all, for compounds of formula IIIwww, IIIyyy, IIIaaaa and IIIcccc, R ^2a is preferably hydrogen, halogen, cyano, -NO ₂ , -CO ₂ R ^c , -CONR ^c R ^d , -C(O)R ^c , - S(O)R ^e , -S(O) ₂ R ^e , -R ^c , -C(NOR ^c )R ^d , -C(NR ^c W )=NW, -N(W)C(R ^c )= NW, -X ² C(NOR ^c )R ^d , -X ² C(NR ^c W )=NW, -X ² N(W)C(R ^c )=NW, -X ² NR ^c R ^d , -X ² SR ^c , -X ² CN, -X ² NO ₂ , -X ² CO ₂ R ^c , -X ² CONR ^c R ^d , -X ² C(O)R ^c , -X ² OC(O)NR ^c R ^d , -X ² NR ^d C(O)R ^c , -X ² NR ^d C(O) ₂ R ^e , -X ² NR ^c C(O)NR ^c R ^d , -X ² NH-C(NH ₂ )=NH, -X ² NR ^e C(NH ₂ )=NH, -X ² NH-C(NH ₂ )=NR ^e , -X ² NH-C(NHR ^e )=NH, -X ² S( O)R ^e , -X ² S(O) ₂ R ^e , -X ² NR ^c S(O) ₂ R ^e , -X ² S(O) ₂ NR ^c R ^d or -X ² N ₃ ; R ^2c is halogen, cyano or nitro; R ^2d is -SR ^c , -OX ² -OR ^c , -X ² -OR ^c , -R ^e , -OR ^c , -NR ^c R ^d or -NR ^c SO ₂ R ^d ; R ^3b is preferably hydrogen, halogen, cyano, -NO ₂ , -CO ₂ R ^f , -CONR ^f R ^g , -C(O)R ^f , -S(O)R ^h , -S(O ) ₂ R ^h , -R ^h , -X ³ NR ^f R ^g , -X ³ SR ^f , -X ³ CN, -X ³ NO ₂ , -X ³ CO ₂ R ^f , -X ³ CONR ^f R ^g , -X ³ C(O)R ^f , -X ³ OC(O)NR ^f R ^g , -X ³ NR ^g C(O)R ^f , -X ³ NR ^g C(O) ₂ R ^h , -X ³ NR ^f C(O)NR ^f R ^g , -X ³ NH-C(NH ₂ )=NH, -X ³ NR ^h C(NH ₂ )=NH, -X ³ NH-C(NH ₂ )=NR ^h , -X ³ NH-C(NHR ^h )=NH, -X ³ S(O)R ^h , -X ³ S(O) ₂ R ^h , -X ³ NR ^f S(O) ₂ R ^h , -X ³ S(O) ₂ NR ^f R ^g , -X ³ N ₃ , Y or -X ³ Y; R ^3c is preferably halogen, cyano, -NO ₂ , -CO ₂ R ^f , -CONR ^f R ^g , -C(O)R ^f , -NR ^f R ^g , -SR ^f , -S(O)R ^h , -S(O) ₂ R ^h , -C(O)Y, -SO ₂ Y, -X ³ Y, Y, C _1-6 alkyl, C _1-6 haloalkyl or C _3-6 cycloalkyl, wherein the alkyl and cycloalkyl substituents may be optionally substituted by a group selected from: -OH , -OR ^o , -OC(O)NHR ^o , -OC(O)N(R ^o ) ₂ , -SH, -SR ^o , -S(O)R ^o , -S(O) ₂ R ^o , - SO ₂ NH ₂ , -S(O) ₂ NHR ^o , -S(O) ₂ N(R ^o ) ₂ , -NHS(O) ₂ R ^o , -NR ^o S(O) ₂ R ^o , -C( O)NH ₂ , -C(O)NHR ^o , -C(O)N(R ^o ) ₂ , -C(O)R ^o , -NHC(O)R ^o , -NR ^o C(O)R ^o , -NHC(O)NH ₂ , -NR ^o C(O)NH ₂ , -NR ^o C(O)NHR ^o , -NHC(O)NHR ^o , -NR ^o C(O)N(R ^o ) ₂ , -NHC(O)N(R ^o ) ₂ , -CO ₂ H, -CO ₂ R ^o , -NHCO ₂ R ^o , -NR ^o CO ₂ R ^o , -CN, -NO ₂ , -NH ₂ , - NHR ^o , -N(R ^o ) ₂ , -NR ^o S(O)NH ₂ and -NR ^o S(O) ₂ NHR ^o ; R ⁴ is preferably halogen, -OR ^f , -NR ^f R ^g , - R ^h , -SR ^f , -CN, -NO ₂ , -CO ₂ R ^f , -CONR ^f R ^g , -C(O)R ^f , -NR ^g C(O)R ^f , -S(O)R ^h , -S(O) ₂ R ^h , -NR ^f S(O) ₂ R ^h , -S(O) ₂ NR ^f R ^g , -X ³ OR ^f , -X ³ NR ^f R ^g , -X ³ NR ^f S(O) ₂ R ^h and -X ³ S(O) ₂ NR ^f R ^g , two adjacent R groups can form 5- or 6-membered with ^0-2 additional heteroatoms as ring atoms Saturated or unsaturated ring; m is preferably 0-2; n is preferably 0-3. Also preferred are those wherein R ^{1 ,} when present, is selected from C _1-4 alkyl, optionally selected from -OH, -OR ^m , -S(O) ₂ R ^m , -CO ₂ H and -CO ₂ R ^m Group substitution; those compounds in which at least one R substituent is attached to a ^ring carbon atom adjacent to a ring heteroatom when n is 1 ring greater. More preferably, R ^2a is hydrogen, halogen, -CN, -C(O) ^Rc , -C( ^NORc ) ^Rd , -C( ^NRcW )=NW, -N(W)C( ^Rc ) =NW, -X ² C(NOR ^c )R ^d , -X ² C(NR ^c W )=NW, -X ² N(W)C(R ^c )=NW, -X ² NR ^c R ^d or - R ^e ; R ^2c is halo or cyano. Still more preferably, m is 0 or 1, n is 0 or 1, and ^R1 , when present, is _-CH3 . In the most preferred embodiment, R ^2d is -SR ^c , -R ^e or -OR ^c ; R ^3b is hydrogen, halo, cyano, or -NO ₂ ; R ^3c is halo, cyano, -C(O) R ^f , -SO ₂ R ^h , C _1-6 alkyl, C _1-6 haloalkyl or C _3-6 cycloalkyl, wherein the aliphatic moiety is substituted as described above; R ⁴ when present is - _CH3 , _-CF3 or -CN.

For compounds of formula IIIxxx, IIIzzz, IIIbbbb, IIIdddd, R ^2a is preferably hydrogen, halogen, cyano, -NO ₂ , -CO ₂ R ^c , -CONR ^c R ^d , -C(O)R ^c , -S (O)R ^e , -S(O) ₂ R ^e , -R ^c , -C(NOR ^c )R ^d , -C(NR ^c W )=NW, -N(W)C(R ^c )=NW , -X ² C(NOR ^c )R ^d , -X ² C(NR ^c W )=NW, -X ² N(W)C(R ^c )=NW, -X ² NR ^c R ^d , -X ² SR ^c , -X ² CN, -X ² NO ₂ , -X ² CO ₂ R ^c , -X ² CONR ^c R ^d , -X ² C(O)R ^c , -X ² OC(O)NR ^c R ^d , -X ² NR ^d C(O)R ^c , -X ² NR ^d C(O) ₂ R ^e , -X ² NR ^c C(O)NR ^c R ^d , -X ² NH-C(NH ₂ )=NH, -X ² NR ^e C(NH ₂ )=NH, -X ² NH-C(NH ₂ )=NR ^e , -X ² NH-C(NHR ^e )=NH, -X ² S(O )R ^e , -X ² S(O) ₂ R ^e , -X ² NR ^c S(O) ₂ R ^e , -X ² S(O) ₂ NR ^c R ^d or -X ² N ₃ ; R ² c is halogen, cyano or nitro; R ^2d is -SR ^c , -OX ² -OR ^c , -X ² -OR ^c , -R ^e , -OR ^c , -NR ^c R ^d or -NR ^c SO ₂ R ^d ; R ^3a is preferably halogen, cyano, -NO ₂ , -CO ₂ R ^f , -CONR ^f R ^g , -C(O)R ^f , -NR ^f R ^g , -SR ^f , -S(O )R ^h , -S(O) ₂ R ^h , -C(O)Y, -SO ₂ Y, -X ³ Y, Y, C _1-6 alkyl, C _1-6 haloalkyl or C _3-6 Cycloalkyl, wherein the alkyl and cycloalkyl substituents are optionally substituted with groups selected from the group consisting of -OH, -OR ^o , -OC(O)NHR ^o , -OC(O)N(R ^o ) ₂ , -SH, -SR ^o , -S(O)R ^o , -S(O) ₂ R ^o , -SO ₂ NH ₂ , -S(O) ₂ NHR ^o , -S(O) ₂ N( R ^o ) ₂ , -NHS(O) ₂ R ^o , -NR ^o S(O) ₂ R ^o , -C(O)NH ₂ , -C(O)NHR ^o , -C(O)N(R ^o ) ₂ , -C(O)R ^o , -NHC(O)R ^o , -NR ^o C(O)R ^o , -NHC(O)NH ₂ , -NR ^o C(O)NH ₂ , -NR ^o C(O)NHR ^o , -NHC(O)NHR ^o , -NR ^o C(O)N(R ^o ) ₂ , -NHC(O)N(R ^o ) ₂ , -CO ₂ H, -CO ₂ R ^o , -NHCO ₂ R ^o , -NR ^o CO ₂ R ^o , -CN, -NO ₂ , -NH ₂ , -NHR ^o , -N(R ^o ) ₂ , -NR ^o S(O)NH ₂ , and - NR ^o S(O) ₂ NHR ^o ; R ^3b is preferably hydrogen, halogen, cyano, -NO ₂ , -CO ₂ R ^f , -CONR ^f R ^g , -C(O)R ^f , -S(O )R ^h , -S(O) ₂ R ^h , -R ^h , -X ³ NR ^f R ^g , -X ³ SR ^f , -X ³ CN, -X ³ NO ₂ , -X ³ CO ₂ R ^f , -X ³ CONR ^f R ^g , -X ³ C(O)R ^f , -X ³ OC(O)NR ^f R ^g , -X ³ NR ^g C(O)R ^f , -X ³ NR ^g C(O ) ₂ R ^h , -X ³ NR ^f C(O)NR ^f R ^g , -X ³ NH-C(NH ₂ )=NH, -X ³ NR ^h C(NH ₂ )=NH, -X ³ NH- C(NH ₂ )=NR ^h , -X ³ NH-C(NHR ^h )=NH, -X ³ S(O)R ^h , -X ³ S(O) ₂ R ^h , -X ³ NR ^f S( O) ₂ R ^h , -X ³ S(O) ₂ NR ^f R ^g , -X ³ N ₃ , Y or -X ³ Y; R ⁴ is preferably halogen, -OR ^f , -NR ^f R ^g , - R ^h , -SR ^f , -CN, -NO ₂ , -CO ₂ R ^f , -CONR ^f R ^g , -C(O)R ^f , -NR ^g C(O)R ^f , -S(O)R ^h , -S(O) ₂ R ^h , -NR ^f S(O) ₂ R ^h , -S(O) ₂ NR ^f R ^g , -X ³ OR ^f , -X ³ NR ^f R ^g , -X ³ NR ^f S(O) ₂ R ^h and -X ³ S(O) ₂ NR ^f R ^g , two adjacent R groups can form 5- or 6-membered with ^0-2 additional heteroatoms as ring atoms Saturated or unsaturated ring; m is preferably 0-2; n is preferably 0-3. More preferably, wherein each R ¹ when present is selected from C _1-4 alkyl, optionally selected from -OH, -OR ^m , -S(O) ₂ R ^m , -CO ₂ H and -CO ₂ R group substitution of ^m ; those compounds in which at least one R substituent is attached to a ^ring carbon atom adjacent to a ring heteroatom when n is 1 or greater. More preferably, R ^2a is hydrogen, halogen, -CN, -C(O) ^Rc , -C( ^NORc ) ^Rd , -C( ^NRcW )=NW, -N(W)C( ^Rc ) =NW, -X ² C(NOR ^c )R ^d , -X ² C(NR ^c W )=NW, -X ² N(W)C(R ^c )=NW, -X ² NR ^c R ^d or - R ^e ; R ^2c is halo or cyano. More preferably, m is 0 or 1, n is 0 or 1, and R ¹ when present is -CH ₃ . In the most preferred embodiment, R ^2d is -SR ^c , -R ^e or -OR ^c ; R ^3a is halogen, cyano, -C(O)R ^f , -S(O) ₂ R ^h , C _{1 -6} alkyl, C _1-6 haloalkyl or C _3-6 cycloalkyl, wherein the alkyl and cycloalkyl substituents may be optionally substituted as described above; R ^3b is hydrogen, halogen, cyano or -NO ₂ ; R ⁴ when present is -CH ₃ , -CF ₃ or -CN.

5-membered C-linked and N-linked heterocycles:

In a further preferred group of formula III, the compound has a formula selected from formulas IIIeeee and IIIffff, Figure 5L, wherein the substituents have the definitions given for formula III above. First of all, for the compound of formula IIIeeee, R ^2a is preferably hydrogen, halogen, cyano, -NO ₂ , -CO ₂ R ^c , -CONR ^c R ^d , -C(O)R ^c , -S(O)R ^e , -S(O) ₂ R ^e , -R ^c , -C(NOR ^c )R ^d , -C(NR ^c W)=NW, -N(W)C(R ^c )=NW, -X ² C (NOR ^c )R ^d , -X ² C(NR ^c W )=NW, -X ² N(W)C(R ^c )=NW, -X ² NR ^c R ^d , -X ² SR ^c , -X ² CN, -X ² NO ₂ , -X ² CO ₂ R ^c , -X ² CONR ^c R ^d , -X ² C(O)R ^c , -X ² OC(O)NR ^c R ^d , -X ² NR ^d C(O)R ^c , -X ² NR ^d C(O) ₂ R ^e , -X ² NR ^c C(O)NR ^c R ^d , -X ² NH-C(NH ₂ )=NH, - X ² NR ^e C(NH ₂ )=NH, -X ² NH-C(NH ₂ )=NR ^e , -X ² NH-C(NHR ^e )=NH, -X ² S(O)R ^e ,- X ² S(O) ₂ R ^e , -X ² NR ^c S(O) ₂ R ^e , -X ² S(O) ₂ NR ^c R ^d or -X ² N ₃ ; R ² c is halogen, cyano or nitro; R ^2d is -SR ^c , -OX ² -OR ^c , -X ² -OR ^c , -R ^e , -OR ^c , -NR ^c R ^d or -NR ^c SO ₂ R ^d ; R ³ b Preferably hydrogen, halogen, cyano, -NO ₂ , -CO ₂ R ^f , -CONR ^f R ^g , -C(O)R ^f , -S(O)R ^h , -S(O) ₂ R ^h , -R ^h , -X ³ NR ^f R ^g , -X ³ SR ^f , -X ³ CN, -X ³ NO ₂ , -X ³ CO ₂ R ^f , -X ³ CONR ^f R ^g , -X ³ C (O)R ^f , -X ³ OC(O)NR ^f R ^g , -X ³ NR ^g C(O)R ^f , -X ³ NR ^g C(O) ₂ R ^h , -X ³ NR ^f C( O) NR ^f R ^g , -X ³ NH-C(NH ₂ )=NH, -X ³ NR ^h C(NH ₂ )=NH, -X ³ NH-C(NH ₂ )=NR ^h , -X ³ NH-C(NHR ^h )＝NH, -X ³ S(O)R ^h , -X ³ S(O) ₂ R ^h , -X ³ NR ^f S(O) ₂ R ^h , -X ³ S(O) ) ₂ NR ^f R ^g , -X ³ N ₃ , Y or -X ³ Y; R ^3c is preferably halogen, cyano, -NO ₂ , -CO ₂ R ^f , -CONR ^f R ^g , -C(O )R ^f , -NR ^f R ^g , -SR ^f , -S(O)R ^h , -S(O) ₂ R ^h , -C(O)Y, -SO ₂ Y, -X ³ Y, Y, C _1-6 alkyl, C _1-6 haloalkyl or C _3-6 cycloalkyl, wherein the alkyl and cycloalkyl substituents may be optionally substituted by groups selected from: -OH, -OR ^o , -OC(O)NHR ^o , -OC(O)N(R ^o ) ₂ , -SH, -SR ^o , -S(O)R ^o , -S(O) ₂ R ^o , -SO ₂ NH ₂ , -S(O) ₂ NHR ^o , -S(O) ₂ N(R ^o ) ₂ , -NHS(O) ₂ R ^o , -NR ^o S(O) ₂ R ^o , -C(O)NH ₂ , -C(O)NHR ^o , -C(O)N(R ^o ) ₂ , -C(O)R ^o , -NHC(O)R ^o , -NR ^o C(O)R ^o , -NHC( O)NH ₂ , -NR ^o C(O)NH ₂ , -NR ^o C(O)NHR ^o , -NHC(O)NHR ^o , -NR ^o C(O)N(R ^o ) ₂ , -NHC( O)N(R ^o ) ₂ , -CO ₂ H, -CO ₂ R ^o , -NHCO ₂ R ^o , -NR ^o CO ₂ R ^o , -CN, -NO ₂ , -NH ₂ , -NHR ^o , - N(R ^o ) ₂ , -NR ^o S(O)NH ₂ and -NR ^o S(O) ₂ NHR ^o ; R ⁴ is preferably halogen, -OR ^f , -NR ^f R ^g , -R ^h , - SR ^f , -CN, -NO ₂ , -CO ₂ R ^f , -CONR ^f R ^g , -C(O)R ^f , -NR ^g C(O)R ^f , -S(O)R ^h , -S (O) ₂ R ^h , -NR ^f S(O) ₂ R ^h , -S(O) ₂ NR ^f R ^g , -X ³ OR ^f , -X ³ NR ^f R ^g , -X ³ NR ^f S( O) ₂ R ^h and -X ³ S(O) ₂ NR ^f R ^{g ,} two adjacent R groups can form a 5- or 6-membered saturated or unsaturated group with 0-2 additional heteroatoms as ring atoms ring; m is preferably 0-2; n is preferably 0-3; a, b and c can be N, NR ⁵ , S, SO, SO ₂ , O or C(R ⁴ ) _o , where o can be 0-2; R ⁵ is preferably hydrogen, -R ^h , -S(O) ₂ R ^h , -X ³ OR ^f , -X ³ NR ^f R ^g , -X ³ NR ^f S(O) ₂ R ^h and -X ³ S(O) ₂ NR ^f R ^g , -CO ₂ R ^f , -CONR ^f R ^g , or -C(O)R ^f . More preferably wherein each R ¹ when present is selected from C _1-4 alkyl, optionally selected from -OH, -OR ^m , -S(O) ₂ R ^m , -CO ₂ H and -CO ₂ R ^m Group substitution; when a and c are not C(R ⁴ ) _o , b must be C(R ⁴ ) _o or SO ₂ ; when a and b are not C(R ⁴ ) _o , then c must be C( Those compounds of R ⁴ ) _o or SO ₂ . More preferably, R ^2a is hydrogen, halogen, -CN, -C(O) ^Rc , -C( ^NORc ) ^Rd , -C( ^NRcW )=NW, -N(W)C( ^Rc ) =NW, -X ² C(NOR ^c )R ^d , -X ² C(NR ^c W )=NW, -X ² N(W)C(R ^c )=NW, -X ² NR ^c R ^d or - R ^e ; R ^2c is halo or cyano. Still more preferably, m is 0 or 1, n is 0 or 1, and ^R1 , when present, is _-CH3 . In the most preferred embodiment, R ^2d is -SR ^c , -R ^e or -OR ^c ; R ^3b is hydrogen, halo, cyano, or -NO ₂ ; R ^3c is halo, cyano, -C(O) R ^f , -SO ₂ R ^h , C _1-6 alkyl, C _1-6 haloalkyl or C _3-6 cycloalkyl, wherein the aliphatic moiety is substituted as described above.

For compounds of formula IIIffff, R ^2a is preferably hydrogen, halogen, cyano, -NO ₂ , -CO ₂ R ^c , -CONR ^c R ^d , -C(O)R ^c , -S(O)R ^e , -S(O) ₂ R ^e , -R ^c , -C(NOR ^c )R ^d , -C(NR ^c W)=NW, -N(W)C(R ^c )=NW, -X ² C( NOR ^c ) R ^d , -X ² C(NR ^c W )=NW, -X ² N(W)C(R ^c )=NW, -X ² NR ^c R ^d , -X ² SR ^c , -X ² CN, -X ² NO ₂ , -X ² CO ₂ R ^c , -X ² CONR ^c R ^d , -X ² C(O)R ^c , -X ² OC(O)NR ^c R ^d , -X ² NR ^d C(O)R ^c , -X ² NR ^d C(O) ₂ R ^e , -X ² NR ^c C(O)NR ^c R ^d , -X ² NH-C(NH ₂ )=NH, -X ² NR ^e C(NH ₂ )=NH, -X ² NH-C(NH ₂ )=NR ^e , -X ² NH-C(NHR ^e )=NH, -X ² S(O)R ^e , -X ² S(O) ₂ R ^e , -X ² NR ^c S(O) ₂ R ^e , -X ² S(O) ₂ NR ^c R ^d or -X ² N ₃ ; R ^2c is halogen, cyano or nitrate R ^2d is -SR ^c , -OX ² -OR ^c , -X ² -OR ^c , -R ^e , -OR ^c , -NR ^c R ^d or -NR ^c SO ₂ R ^d ; R ^3a is preferably Halogen, cyano, -NO ₂ , -CO ₂ R ^f , -CONR ^f R ^g , -C(O)R ^f , -NR ^f R ^g , -SR ^f , -S(O)R ^h , -S( O) ₂ R ^h , -C(O)Y, -SO ₂ Y, -X ³ Y, Y, C _1-6 alkyl, C _1-6 haloalkyl or C _3-6 cycloalkyl, wherein the alkyl and cycloalkyl substituents may be optionally substituted with groups selected from -OH, -OR ^o , -OC(O)NHR ^o , -OC(O)N(R ^o ) ₂ , -SH, -SR ^o , -S(O)R ^o , -S(O) ₂ R ^o , -SO ₂ NH ₂ , -S(O) ₂ NHR ^o , -S(O) ₂ N(R ^o ) ₂ , -NHS( O) ₂ R ^o , -NR ^o S(O) ₂ R ^o , -C(O)NH ₂ , -C(O)NHR ^o , -C(O)N(R ^o ) ₂ , -C(O) R ^o , -NHC(O)R ^o , -NR ^o C(O)R ^o , -NHC(O)NH ₂ , -NR ^o C(O)NH ₂ , -NR ^o C(O)NHR ^o , - NHC(O)NHR ^o , -NR ^o C(O)N(R ^o ) ₂ , -NHC(O)N(R ^o ) ₂ , -CO ₂ H, -CO ₂ R ^o , -NHCO ₂ R ^o , -NR ^o CO ₂ R ^o , -CN, -NO ₂ , -NH ₂ , -NHR ^o , -N(R ^o ) ₂ , -NR ^o S(O)NH ₂ , and -NR ^o S(O) ₂ NHR ^o ; R ^3b is preferably hydrogen, halogen, cyano, -NO ₂ , -CO ₂ R ^f , -CONR ^f R ^g , -C(O)R ^f , -S(O)R ^h , -S(O ) ₂ R ^h , -R ^h , -X ³ NR ^f R ^g , -X ³ SR ^f , -X ³ CN, -X ³ NO ₂ , -X ³ CO ₂ R ^f , -X ³ CONR ^f R ^g , -X ³ C(O)R ^f , -X ³ OC(O)NR ^f R ^g , -X ³ NR ^g C(O)R ^f , -X ³ NR ^g C(O) ₂ R ^h , -X ³ NR ^f C(O)NR ^f R ^g , -X ³ NH-C(NH ₂ )=NH, -X ³ NR ^h C(NH ₂ )=NH, -X ³ NH-C(NH ₂ )=NR ^h , -X ³ NH-C(NHR ^h )=NH, -X ³ S(O)R ^h , -X ³ S(O) ₂ R ^h , -X ³ NR ^f S(O) ₂ R ^h , -X ³ S(O) ₂ NR ^f R ^g , -X ³ N ₃ , Y or -X ³ Y; R ⁴ is preferably halogen, -OR ^f , -NR ^f R ^g , -R ^h , -SR ^f , - CN, -NO ₂ , -CO ₂ R ^f , -CONR ^f R ^g , -C(O)R ^f , -NR ^g C(O)R ^f , -S(O)R ^h , -S(O) ₂ R ^h , -NR ^f S(O) ₂ R ^h , -S(O) ₂ NR ^f R ^g , -X ³ OR ^f , -X ³ NR ^f R ^g , -X ³ NR ^f S(O) ₂ R ^h and -X ³ S(O) ₂ NR ^f R ^g , two adjacent R ⁴ groups may form a 5- or 6-membered saturated or unsaturated ring with 0-2 additional heteroatoms as ring atoms; m is preferably 0-2; n is preferably 0-3; a, b and c can be N, NR ⁵ , S, SO, SO ₂ , O or C(R ⁴ ) _o , where o can be 0-2 ; R ⁵ is preferably hydrogen, -R ^h , -S(O) ₂ R ^h , -X ³ OR ^f , -X ³ NR ^f R ^g , -X ³ NR ^f S(O) ₂ R ^h , -X ³ S(O) ₂ NR ^f R ^g , —CO ₂ R ^f , —CONR ^f R ^g , or —C(O)R ^f . Also preferred is a group wherein each R ¹ when present is selected from C _1-4 alkyl, optionally selected from -OH, -OR ^m , -S(O) ₂ R ^m , -CO ₂ H and -CO ₂ R ^m group substitution; when a and c are not C(R ⁴ ) _o , b must be C(R ⁴ ) _o or SO ₂ ; when a and b are not C(R ⁴ ) _o , then c must be C(R ⁴ ) _o or those compounds of SO ₂ . Still more preferably, R ^2a is hydrogen, halogen, -CN, -C(O) ^Rc , -C( ^NORc ) ^Rd , -C( ^NRcW )=NW, -N(W)C( ^Rc )=NW, -X ² C(NOR ^c )R ^d , -X ² C(NR ^c W )=NW, -X ² N(W)C(R ^c )=NW, -X ² NR ^c R ^d or -R ^e ; R ^2c is halogen or cyano. More preferably, m is 0 or 1, n is 0 or 1, and R ¹ when present is -CH ₃ . In the most preferred embodiment, R ^2d is -SR ^c , -R ^e or -OR ^c ; R ^3a is halogen, cyano, -C(O)R ^f , -S(O) ₂ R ^h , C _{1 -6} alkyl, C _1-6 haloalkyl or C _3-6 cycloalkyl, wherein the alkyl and cycloalkyl substituents may be substituted as described above; R ^3b is hydrogen, halogen, cyano or -NO ₂ .

6-membered C-linked and N-linked heterocycles:

In a further preferred group of formula III, the compound has a formula selected from formula IIIgggg and IIIhhhh, Figure 5L, wherein the substituents have the definitions given for formula III above. First of all, for the compound of formula IIIgggg, R ^2a is preferably hydrogen, halogen, cyano, -NO ₂ , -CO ₂ R ^c , -CONR ^c R ^d , -C(O)R ^c , -S(O)R ^e , -S(O) ₂ R ^e , -R ^c , -C(NOR ^c )R ^d , -C(NR ^c W)=NW, -N(W)C(R ^c )=NW, -X ² C (NOR ^c )R ^d , -X ² C(NR ^c W )=NW, -X ² N(W)C(R ^c )=NW, -X ² NR ^c R ^d , -X ² SR ^c , -X ² CN, -X ² NO ₂ , -X ² CO ₂ R ^c , -X ² CONR ^c R ^d , -X ² C(O)R ^c , -X ² OC(O)NR ^c R ^d , -X ² NR ^d C(O)R ^c , -X ² NR ^d C(O) ₂ R ^e , -X ² NR ^c C(O)NR ^c R ^d , -X ² NH-C(NH ₂ )=NH, - X ² NR ^e C(NH ₂ )=NH, -X ² NH-C(NH ₂ )=NR ^e , -X ² NH-C(NHR ^e )=NH, -X ² S(O)R ^e ,- X ² S(O) ₂ R ^e , -X ² NR ^c S(O) ₂ R ^e , -X ² S(O) ₂ NR ^c R ^d or -X ² N ₃ ; R ^2c is halogen, cyano or Nitro; R ^2d is -SR ^c , -OX ² -OR ^c , -X ² -OR ^c , -R ^e , -OR ^c , -NR ^c R ^d or -NR ^c SO ₂ R ^d ; R ^3b is better is hydrogen, halogen, cyano, -NO ₂ , -CO ₂ R ^f , -CONR ^f R ^g , -C(O)R ^f , -S(O)R ^h , -S(O) ₂ R ^h , - R ^h , -X ³ NR ^f R ^g , -X ³ SR ^f , -X ³ CN, -X ³ NO ₂ , -X ³ CO ₂ R ^f , -X ³ CONR ^f R ^g , -X ³ C(O )R ^f , -X ³ OC(O)NR ^f R ^g , -X ³ NR ^g C(O)R ^f , -X ³ NR ^g C(O) ₂ R ^h , -X ³ NR ^f C(O) NR ^f R ^g , -X ³ NH-C(NH ₂ )=NH, -X ³ NR ^h C(NH ₂ )=NH, -X ³ NH-C(NH ₂ )=NR ^h , -X ³ NH- C(NHR ^h )=NH, -X ³ S(O)R ^h , -X ³ S(O) ₂ R ^h , -X ³ NR ^f S(O) ₂ R ^h , -X ³ S(O) ₂ NR ^f R ^g , -X ³ N ₃ , Y or -X ³ Y; R ^3c is preferably halogen, cyano, -NO ₂ , -CO ₂ R ^f , -CONR ^f R ^g , -C(O)R ^f , NR ^f R ^g , SR ^f , -S(O)R ^h , -S(O) ₂ R ^h , -C(O)Y, -SO ₂ Y, -X ³ Y, Y, C _1-6 Alkyl, C _1-6 haloalkyl or C _3-6 cycloalkyl, wherein the alkyl and cycloalkyl substituents may be optionally substituted by groups selected from: -OH, -OR ^o , -OC( O)NHR ^o , -OC(O)N(R ^o ) ₂ , -SH, -SR ^o , -S(O)R ^o , -S(O) ₂ R ^o , -SO ₂ NH ₂ , -S( O) ₂ NHR ^o , -S(O) ₂ N(R ^o ) ₂ , -NHS(O) ₂ R ^o , -NR ^o S(O) ₂ R ^o , -C(O)NH ₂ , -C( O)NHR ^o , -C(O)N(R ^o ) ₂ , -C(O)R ^o , -NHC(O)R ^o , -NR ^o C(O)R ^o , -NHC(O)NH ₂ , -NR ^o C(O)NH ₂ , -NR ^o C(O)NHR ^o , -NHC(O)NHR ^o , -NR ^o C(O)N(R ^o ) ₂ , -NHC(O)N( R ^o ) ₂ , -CO ₂ H, -CO ₂ R ^o , -NHCO ₂ R ^o , -NR ^o CO ₂ R ^o , -CN, -NO ₂ , -NH ₂ , -NHR ^o , -N(R ^o ) ₂ , -NR ^o S(O)NH ₂ and -NR ^o S(O) ₂ NHR ^o ; R ⁴ is preferably halogen, O, -OR ^f , -NR ^f R ^g , -R ^h , -SR ^f , -CN, -NO ₂ , -CO ₂ R ^f , -CONR ^f R ^g , -C(O)R ^f , -NR ^g C(O)R ^f , -S(O)R ^h , -S(O ) ₂ R ^h , -NR ^f S(O) ₂ R ^h , -S(O) ₂ NR ^f R ^g , -X ³ OR ^f , -X ³ NR ^f R ^g , -X ³ NR ^f S(O) ₂ R ^h and -X ³ S(O) ₂ NR ^f R ^g , two adjacent R groups can form a 5- ^membered or 6-membered saturated or unsaturated ring with 0-2 additional heteroatoms as ring atoms; m is preferably 0-2; n is preferably 0-3; a, b, c and d can be N, NR ⁵ , S, SO, SO ₂ , O or C(R ⁴ ) _o , where o can be 0-2; R ⁵ is preferably hydrogen, -R ^h , -S(O) ₂ R ^h , -X ³ OR ^f , -X ³ NR ^f R ^g , -X ³ NR ^f S(O) ₂ R ^h and -X ³ S(O) ₂ NR ^f R ^g , -CO ₂ R ^f , -CONR ^f R ^g , or -C(O)R ^f . Also preferred is a group wherein each R ¹ when present is selected from C _1-4 alkyl, optionally selected from -OH, -OR ^m , -S(O) ₂ R ^m , -CO ₂ H and -CO ₂ R ^m group substitution; when b and d are not C(R ⁴ ) _o , c must be C(R ⁴ ) _o or SO ₂ ; when b and c are not C(R ⁴ ) _o , then d must be C(R ⁴ ) _o or SO ₂ ; when a and d are not C(R ⁴ ) _o , then at least one of a and b must be those compounds of C(R ⁴ ) _o or SO ₂ . More preferably, R ^2a is hydrogen, halogen, -CN, -C(O) ^Rc , -C( ^NORc ) ^Rd , -C( ^NRcW )=NW, -N(W)C( ^Rc ) =NW, -X ² C(NOR ^c )R ^d , -X ² C(NR ^c W )=NW, -X ² N(W)C(R ^c )=NW, -X ² NR ^c R ^d or - R ^e ; R ^2c is halo or cyano. Still more preferably, m is 0 or 1, n is 0 or 1, and ^R1 , when present, is _-CH3 . In the most preferred embodiment, R ^2d is -SR ^c , -R ^e or -OR ^c ; R ^3b is hydrogen, halo, cyano, or -NO ₂ ; R ^3c is halo, cyano, -C(O) R ^f , -SO ₂ R ^h , C _1-6 alkyl, C _1-6 haloalkyl or C _3-6 cycloalkyl, wherein the aliphatic moiety may be substituted as described above.

For compounds of formula IIIhhhh, R ^2a is preferably hydrogen, halogen, cyano, -NO ₂ , -CO ₂ R ^c , -CONR ^c R ^d , -C(O)R ^c , -S(O)R ^e , -S(O) ₂ R ^e , -R ^c , -C(NOR ^c )R ^d , -C(NR ^c W)=NW, -N(W)C(R ^c )=NW, -X ² C( NOR ^c ) R ^d , -X ² C(NR ^c W )=NW, -X ² N(W)C(R ^c )=NW, -X ² NR ^c R ^d , -X ² SR ^c , -X ² CN, -X ² NO ₂ , -X ² CO ₂ R ^c , -X ² CONR ^c R ^d , -X ² C(O)R ^c , -X ² OC(O)NR ^c R ^d , -X ² NR ^d C(O)R ^c , -X ² NR ^d C(O) ₂ R ^e , -X ² NR ^c C(O)NR ^c R ^d , -X ² NH-C(NH ₂ )=NH, -X ² NR ^e C(NH ₂ )=NH, -X ² NH-C(NH ₂ )=NR ^e , -X ² NH-C(NHR ^e )=NH, -X ² S(O)R ^e , -X ² S(O) ₂ R ^e , -X ² NR ^c S(O) ₂ R ^e , -X ² S(O) ₂ NR ^c R ^d or -X ² N ₃ ; R ^2c is halogen, cyano or nitrate R ^2d is -SR ^c , -OX ² -OR ^c , -X ² -OR ^c , -R ^e , -OR ^c , -NR ^c R ^d or -NR ^c SO ₂ R ^d ; R ^3a is preferably Halogen, cyano, -NO ₂ , -CO ₂ R ^f , -CONR ^f R ^g , -C(O)R ^f , NR ^f R ^g , SR ^f , -S(O)R ^h , -S(O) ₂ R ^h , -C(O)Y, -SO ₂ Y, -X ³ Y, Y, C _1-6 alkyl, C _1-6 haloalkyl or C _3-6 cycloalkyl, wherein the alkyl and The cycloalkyl substituent may be optionally substituted with a group selected from -OH, -OR ^o , -OC(O)NHR ^o , -OC(O)N(R ^o ) ₂ , -SH, -SR ^o , -S(O)R ^o , -S(O) ₂ R ^o , -SO ₂ NH ₂ , -S(O) ₂ NHR ^o , -S(O) ₂ N(R ^o ) ₂ , -NHS(O ) ₂ R ^o , -NR ^o S(O) ₂ R ^o , -C(O)NH ₂ , -C(O)NHR ^o , -C(O)N(R ^o ) ₂ , -C(O)R ^o , -NHC(O)R ^o , -NR ^o C(O)R ^o , -NHC(O)NH ₂ , -NR ^o C(O)NH ₂ , -NR ^o C(O)NHR ^o , -NHC (O)NHR ^o , -NR ^o C(O)N(R ^o ) ₂ , -NHC(O)N(R ^o ) ₂ , -CO ₂ H, -CO ₂ R ^o , -NHCO ₂ R ^o , - NR ^o CO ₂ R ^o , -CN, -NO ₂ , -NH ₂ , -NHR ^o , -N(R ^o ) ₂ , -NR ^o S(O)NH ₂ , and -NR ^o S(O) ₂ NHR ^o ; R ^3b is preferably hydrogen, halogen, cyano, -NO ₂ , -CO ₂ R ^f , -CONR ^f R ^g , -C(O)R ^f , -S(O)R ^h , -S(O) ₂ R ^h , -R ^h , -X ³ NR ^f R ^g , -X ³ SR ^f , -X ³ CN, -X ³ NO ₂ , -X ³ CO ₂ R ^f , -X ³ CONR ^f R ^g , - X ³ C(O)R ^f , -X ³ OC(O)NR ^f R ^g , -X ³ NR ^g C(O)R ^f , -X ³ NR ^g C(O) ₂ R ^h , -X ³ NR ^f C(O)NR ^f R ^g , -X ³ NH-C(NH ₂ )=NH, -X ³ NR ^h C(NH ₂ )=NH, -X ³ NH-C(NH ₂ )=NR ^h , -X ³ NH-C(NHR ^h )=NH, -X ³ S(O)R ^h , -X ³ S(O) ₂ R ^h , -X ³ NR ^f S(O) ₂ R ^h , -X ³ S(O) ₂ NR ^f R ^g , -X ³ N ₃ , Y or -X ³ Y; R ⁴ is preferably halogen, -OR ^f , -NR ^f R ⁸ , -R ^h , -SR ^f , -CN , -NO ₂ , -CO ₂ R ^f , -CONR ^f R ^g , -C(O)R ^f , -NR ^g C(O)R ^f , -S(O)R ^h , -S(O) ₂ R ^h 、-NR ^f S(O) ₂ R ^h 、-S(O) ₂ NR ^f R ^g 、-X ³ OR ^f 、-X ³ NR ^f R ^g 、-X ³ NR ^f S(O) ₂ R ^h and -X ³ S(O) ₂ NR ^f R ^g , two adjacent R ⁴ groups can form a 5-membered or 6-membered saturated or unsaturated ring with 0-2 additional heteroatoms as ring atoms; m is better is 0-2; n is preferably 0-3; a, b, c and d can be N, NR ⁵ , S, SO, SO ₂ , O or C(R ⁴ ) _o , where o can be 0-2 ; R ⁵ is preferably hydrogen, -R ^h , -S(O) ₂ R ^h , -X ³ OR ^f , -X ³ NR ^f R ^g , -X ³ NR ^f S(O) ₂ R ^h , -X ³ S(O) ₂ NR ^f R ^g , —CO ₂ R ^f , —CONR ^f R ^g , or —C(O)R ^f . Also preferably wherein each R ¹ when present is selected from C _1-4 alkyl, optionally selected from -OH, -OR ^m , -S(O) ₂ R ^m , -CO ₂ H and -CO ₂ R ^m ; when When b and d are not C(R ⁴ ) _o , c must be C(R ⁴ ) _o or SO ₂ ; when b and c are not C(R ⁴ ) _o , then d must be C(R ⁴ ) _o or SO ₂ ; when a and d are not C(R ⁴ ) _o , then at least one of b and c must be those compounds of C(R ⁴ ) _o or SO ₂ . More preferably, R ^2a is hydrogen, halogen, -CN, -C(O) ^Rc , -C( ^NORc ) ^Rd , -C( ^NRcW )=NW, -N(W)C( ^Rc ) =NW, -X ² C(NOR ^c )R ^d , -X ² C(NR ^c W )=NW, -X ² N(W)C(R ^c )=NW, -X ² NR ^c R ^d or - R ^e ; R ^2c is halo or cyano. More preferably, m is 0 or 1, n is 0 or 1, and R ¹ when present is -CH ₃ . In the most preferred embodiment, R ^2d is -SR ^c , -R ^e or -OR ^c ; R ^3a is halogen, cyano, C _1-6 alkyl, C _1-6 haloalkyl, C _3-6 ring Alkyl, -C(O) ^Rf or _-SO2Rh , the aliphatic portion of which may be optionally substituted as described above; ^R3b is hydrogen ^, halogen, cyano or _-NO2 .

For each group of embodiments of formula III (such as IIIa to IIIhhhh), another preferred embodiment of the present invention is wherein two adjacent R ^3a , R ^3b or R ^3c substituents combine to form 0-3 additional hetero A fused 5- or 6-membered ring of atoms as ring atoms. Also preferred are those embodiments in which the ring is a fused 6-membered ring, preferably a fused benzene, pyridine or piperidine ring.

Various Embodiments of Formula III (eg, Ilia to IIIhhhh) Any substituents not specifically listed above are meant to have the fullest meaning for Formula III. Furthermore, all compounds are meant to include pharmaceutically acceptable salts thereof, and N-oxides thereof.

In another group of preferred embodiments, the compound is selected from the following formulas IVa-IVe:

In the formula, R ¹ and subscript m have the meanings provided above for formula III, R ^2a , R ^2b , R ^2c and R ^2d are each independently selected from the following substituents: hydrogen, halogen, -OR ^c , - OC(O)R ^c , -NR ^c R ^d , -SR ^c , -R ^e , -CN, -NO ₂ , -CO ₂ R ^c , -CONR ^c R ^d , -C(O)R ^c , -OC (O)NR ^c R ^d , -NR ^d C(O)R ^c , -NR ^d C(O) ₂ R ^e , -NR ^c -C(O)NR ^c R ^d , -NH-C(NH ₂ ) =NH, -NR ^e C(NH ₂ )=NH, -NH-C(NH ₂ )=NR ^e , -NH-C(NHR ^e )=NH, -S(O)R ^e , -S(O) ₂ R ^e , -S(O) ₂ NR ^c R ^d , -NR ^c S(O) ₂ R ^e , -NR ^c S(O) ₂ NR ^c R ^d , -N ₃ , -X ² OR ^c , - X ² OC(O)R ^c , -X ² NR ^c R ^d , -X ² SR ^c , -X ² CN, -X ² NO ₂ , -X ² CO ₂ R ^c , -X ² CONR ^c R ^d , -X ² C(O)R ^c , -X ² OC(O)NR ^c R ^d , -X ² NR ^d C(O)R ^c , -X ² NR ^d C(O) ₂ R ^e , -X ² NR ^c C(O)NR ^c R ^d , -X ² NH-C(NH ₂ )=NH, -X ² NR ^e C(NH ₂ )=NH, -X ² NH-C(NH ₂ )=NR ^e , -X ² NH-C(NHR ^e )=NH, -X ² S(O)R ^e , -X ² S(O) ₂ R ^e , -X ² S(O) ₂ NR ^c R ^d , -X ² NR ^c S(O) ₂ R ^e , -X ¹ N ₃ , aryl and heteroaryl, wherein X ² , R ^c , R ^d and R ^e have the meanings given above for compounds of formula I, similarly, R ^3a , R ^3b and R ^3c represent substituents independently selected from the group consisting of hydrogen, halogen, phenyl, thienyl, furyl, pyridyl, pyrimidinyl, pyrazinyl, pyridizinyl, pyrazolyl, imidazolyl, Thiazolyl, _azolyl, isoxazolyl, isothiazolyl, triazolyl, tetrazolyl, _diazolyl, -OR ^f , -OC(O)R ^f , -NR ^f R ^g , -SR ^f , -R ^h , -CN, -NO ₂ , -CO ₂ R ^f , -CONR ^f R ^g , -C(O)R ^f , -OC(O)NR ^f R ^g , -NR ^g C(O)R ^f , -NR ^g C(O) ₂ R ^h , -NR ^f -C(O)NR ^f R ^g , -NH-C(NH ₂ )=NH, -NR ^h C(NH ₂ )=NH, -NH -C(NH ₂ )=NR ^h , -NH-C(NHR ^h )=NH, -S(O)R ^h , -S(O) ₂ R ^h , -S(O) ₂ NR ^f R ^g , - NR ^f S(O) ₂ R ^h , -NR ^f S(O) ₂ NR ^f R ^g , -N ₃ , -X ³ OR ^f , -X ³ OC(O)R ^f , -X ³ NR ^f R ^g , -X ³ SR ^f , -X ³ CN, -X ³ NO ₂ , -X ³ CO ₂ R ^f , -X ³ CONR ^f R ^g , -X ³ C(O)R ^f , -X ³ OC(O )NR ^f R ^g , -X ³ NR ^g C(O)R ^f , -X ³ NR ^g C(O) ₂ R ^h , -X ³ NR ^f -C(O)NR ^f R ^g , -X ³ NH -C(NH ₂ )=NH, -X ³ NR ^h C(NH ₂ )=NH, -X ³ NH-C(NH ₂ )=NR ^h , -X ³ NH-C(NHR ^h )=NH, - X ³ S(O)R ^h , -X ³ S(O) ₂ R ^h , -X ³ S(O) ₂ NR ^f R ^g , -X ³ NR ^f S(O) ₂ R ^h and -X ³ N ₃ , wherein X ³ , R ^f , R ^g and ^Rh have the meanings provided above for formula I, wherein no more than two of R ^3a , R ^3b and R ^3c are hydrogen, preferably, R ^3a , R ^3b and no more than one of R ^3c is hydrogen, more preferably none of R ^3a , R ^3b and R ^3c is hydrogen.

Referring first to the compound of formula IVa, in a particularly preferred embodiment, at least one of R ^3a , R ^3b and R ^3c is selected from halogen and C _1-4 haloalkyl. More preferably, at least one of R ^2b and R ^2d is hydrogen, and at least two of R ^3a , R ^3b and R ^3c are selected from halogen and C _1-4 haloalkyl. In a related preferred embodiment, R ^2c is selected from F, Cl, Br, CN, NO ₂ , CO ₂ CH ₃ , C(O)CH ₃ and S(O) ₂ CH ₃ , R ^3a , R ^3b and R At least two of ^3c are selected from halogen and C _1-4 haloalkyl, and the rest are not hydrogen.

Similarly, certain compounds of formula IVb are preferred. Particularly preferred are compounds of formula IVb in which at least one of R ^3a , R ^3b and R ^3c is selected from halogen and C _1-4 haloalkyl. More preferably, at least one of R ^2b and R ^2d is hydrogen, and at least two of R ^3a , R ^3b and R ^3c are selected from halogen and C _1-4 haloalkyl. In a related preferred embodiment, R ^2c is selected from F, Cl, Br, CN, NO ₂ , CO ₂ CH ₃ , C(O)CH ₃ and S(O) ₂ CH ₃ , and R ^3a , R ^3b and At least two of R ^3c are selected from halogen and C _1-4 haloalkyl, and the rest are not hydrogen.

Referring again to the compound of formula IVc, the preferred embodiment is at least one of R ^2a , R ^2c and R ^2d in the formula, preferably R ^2c is selected from F, Cl, Br, CN, NO ₂ , CO ₂ CH ₃ , C(O)CH ₃ and S(O) ₂ CH ₃ ; at least two of R ^3a , R ^3b and R ^3c are selected from halogen and C _1-4 haloalkyl, and those whose remainder is not hydrogen. In other preferred embodiments, one of R ^2c and R ^2d is selected from F, Cl, Br, CN, NO ₂ , CO ₂ CH ₃ , C(O)CH ₃ and S(O) ₂ CH ₃ , and the other is Aryl or heteroaryl, for example, phenyl, thienyl, furyl, oxazolyl, isoxazolyl, thiazolyl and isothiazolyl, at least two of R ^3a , R ^3b and R ^3c are selected from halogen and C _1-4 haloalkyl, the rest is not hydrogen.

For compounds of formula IVd, a preferred embodiment is that at least one of R ^2a , R ^2b and R ^2d in the formula is selected from F, Cl, Br, CN, NO ₂ , CO ₂ CH ₃ , C(O)CH ₃ and S( O) ₂ CH ₃ , at least two of R ^3a , R ^3b and R ^3c are selected from halogen and C _1-4 haloalkyl, and those whose remainder is not hydrogen. In other preferred embodiments, one of R ^2b and R ^2d is selected from F, Cl, Br, CN, NO ₂ , CO ₂ CH ₃ , C(O)CH ₃ and S(O) ₂ CH ₃ , and the other is Aryl or heteroaryl, for example, phenyl, thienyl, furyl, oxazolyl, isoxazolyl, thiazolyl and isothiazolyl, at least two of R ^3a , R ^3b and R ^3c are selected from halogen and C _1-4 haloalkyl, the rest is not hydrogen.

For the compound of formula IVe, a preferred embodiment is that at least one of R ^2a , R ^2b and R ^2c in the formula is selected from F, Cl, Br, CN, NO ₂ , CO ₂ CH ₃ , C(O)CH ₃ and S(O) ₂ CH ₃ , at least two of R ^3a , R ^3b and R ^3c are selected from halogen and C _1-4 haloalkyl, and those whose remainder is not hydrogen. In other preferred embodiments, one of R ^2b and R ^2c is selected from F, Cl, Br, CN, NO ₂ , CO ₂ CH ₃ , C(O)CH ₃ and S(O) ₂ CH ₃ , and the other is aromatic or heteroaryl, such as phenyl, thienyl, furyl, oxazolyl, isoxazolyl, thiazolyl and isothiazolyl, at least two of R ^3a , R ^3b and R ^3c are selected from halogen and C _{1 -4} haloalkyl, the rest is not hydrogen.

In another group of preferred embodiments, the compound is selected from formulas IVf-IVi:

In the formula, R ¹ and subscript m have the meanings provided above for formula III, R ^2a , R ^2b , R ^2c , R ^2d , R ^3a , R ^3b and R ^3c each have the meanings provided above for formulas IVa-IVe meaning. Furthermore, R ^2e represents a substituent selected from the group provided above for R ^2a in formulas IVa-IVe.

In still other embodiments, compounds of the formulas Va and Vb are provided:

In the formula, R ¹ , subscript m, R ^2a , R ^2b , R ^2c , R ^2d , R ^3a , R ^3b and R ^3c each have the meanings provided above for formulas IVa-IVe.

compound preparation

As provided in the Examples below, the compounds of the present invention can be prepared by component assembly by one skilled in the art. Many compounds were prepared starting with the preparation of an appropriately substituted pyrazole (or other HAr component). Schemes la-Ik illustrate various methods for preparing substituted pyrazoles. In these schemes, non-interfering substituents of -R, ^-Rw , ^-Rx , ^-Ry , and Rz are provided.

Option 1a

Preparation of arylpyrazoles via Suzuki coupling:

Option 1b

    Preparation of arylpyrazoles via Stille coupling:

Option 1c

 Preparation of arylpyrazoles via the Negishi cross-coupling reaction:

Option 1d

Preparation of arylpyrazoles by Kumada-Tamao-Corriu cross-coupling reaction:

Option 1e

Substituted pyrazoles were prepared via Buchwald chemistry:

Option 1f

 Preparation of arylpyrazoles via condensation of 1,3-diketones with hydrazines:

Scheme 1g

 Preparation of heteroarylpyrazoles via condensation of 1,3-diketones with hydrazines:

Scheme 1h

Substituted pyrazoles were prepared by Sonogashira coupling followed by a Diels-Alder reaction to the exocyclic triple bond:

Option 1i

Substituted pyrazoles were prepared by Heck coupling followed by a Diels-Alder reaction on the exocyclic double bond:

Option 1j

Substituted arylpyrazoles were prepared via Ullmann coupling:

Scheme 1k

Preparation of Substituted Aminopyrazoles by Curtis Rearrangement and Reductive Amination:

IV. Pharmaceutical Compositions

In addition to the compounds provided above, compositions that modulate CCR1 activity in humans and animals will generally contain a pharmaceutical carrier or diluent.

The term "composition" herein refers to a product comprising a product containing the specified components in the specified amounts, as well as any combination of products resulting directly or indirectly from the specified components in the specified amounts. "Pharmaceutically acceptable" means that the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not harmful to its recipients.

Pharmaceutical compositions for administering the compounds of the present invention are generally presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy and drug delivery. All methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In brief, the pharmaceutical compositions are made by uniformly and intimately bringing the active ingredient into association with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired shape. In the pharmaceutical composition, the active compound is present in an amount sufficient to produce the desired effect on the disease process or disease symptoms.

The pharmaceutical composition containing the active ingredient may be in a form suitable for oral use, such as a tablet, troche, lozenge, aqueous or oily suspension, dispersible powder or granules, emulsion or self-emulsifying formulation (as in U.S. patent application 2002-0012680), hard or soft capsules, syrups, elixirs, solutions, lozenges, oral gels, chewable gums, chewable tablets, effervescent powders and effervescent tablets. Compositions for oral use can be manufactured by methods known in the art of manufacturing pharmaceutical compositions, and such compositions may contain one or more substances selected from the group consisting of sweeteners, flavoring agents, coloring agents, antioxidants and preservatives. A pharmaceutical preparation of good appearance and palatability is obtained. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients can be, for example, inert diluents such as cellulose, silicon dioxide, aluminum oxide, calcium carbonate, sodium carbonate, dextrose, mannitol, sorbitol, lactose, calcium phosphate or sodium phosphate; granulating and Dispersants such as corn starch or alginic acid; binders such as PVP, cellulose, PEG, starch, gelatin or acacia, and lubricants such as magnesium stearate, stearic acid or talc. Tablets may be uncoated, or may be provided with an enteric or other coating by techniques known in the art to delay disintegration and absorption in the gastrointestinal tract so as to provide sustained activity over an extended period of time. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. Coatings may also be used as described in US Pat. Nos. 4,256,108; 4,166,452 and 4,265,874 to form osmotic therapeutic tablets for controlled release.

Formulations for oral use may be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or in soft gelatin capsules in which the active ingredient is mixed with an aqueous or oily Mix with a medium such as peanut oil, liquid paraffin or olive oil. In addition, emulsions may be prepared with water-immiscible ingredients such as oils and stabilized with surfactants such as mono-diglycerides, PEG esters and the like.

Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and acacia; Wetting agents can be naturally occurring phospholipids, such as lecithin, or condensation products of alkylene oxides with fatty acids, such as polyoxyethylene stearate, or condensation products of ethylene oxide with long-chain fatty alcohols, such as heptadecene Oxycetyl alcohol, or the condensation product of ethylene oxide with partial esters derived from fatty acids and hexitols, such as polyethylene sorbitan monooleate. Aqueous suspensions may also contain one or more preservatives, such as ethyl- or n-propyl-p-hydroxybenzoate, one or more coloring agents, one or more fragrances, and one or more Various sweeteners such as sucrose or saccharin.

Oily suspensions may be prepared by suspending the active ingredient in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such as those mentioned above, and flavoring agents may be added to produce a palatable oral preparation. Antioxidants such as ascorbic acid can also be added to preserve these compositions.

Dispersible powders and granules can be prepared by adding water to form an aqueous suspension in which the active ingredient is in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Examples of suitable dispersing or wetting agents and suspending agents have been mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.

The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, such as olive oil or arachis oil, or a mineral oil, such as liquid paraffin, or a mixture thereof. Suitable emulsifiers may be naturally occurring gums such as acacia or tragacanth, naturally occurring phospholipids such as soybean lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides such as sorbitan monooleate Esters, and condensation products of said partial esters and ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents.

Syrups and elixirs may be prepared with sweetening agents, such as glycerol, propylene glycol, sorbitol or sucrose. Such preparations may contain a demulcent, preservatives and flavoring and coloring agents. Oral solutions can be prepared in admixture with, for example, cyclodextrins, PEG and surfactants.

The pharmaceutical composition may also be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be prepared according to methods known in the art using suitable dispersing or wetting agents and suspending agents (mentioned above). The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

The compounds of this invention may also be administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter and polyethylene glycols. Furthermore, these mixtures can be administered by the ophthalmic route in the form of solutions or ointments. In addition, the compounds can be delivered transdermally by means of iontophoretic transdermal patches and the like. For topical use, creams, ointments, gels, solutions or suspensions, etc., containing the compounds of this invention may be employed. Topical administration herein also includes the use of mouth washes and gargles.

V. Methods of Treating CCR1-Mediated Diseases

In another aspect, the present invention provides a method of treating a CCR1 -mediated condition or disease by administering to a subject suffering from such a disease or condition a therapeutically effective amount of a compound of Formula I above. "Subject" herein includes animals such as mammals, including but not limited to primates (eg, humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, and the like.

In many cell types in mammals such as humans, CCR1 provides a target for interfering with or promoting specific immune cell functions, generally, aspects related to the expression of CCR1. For therapeutic purposes, compounds that inhibit CCR1 are effective in regulating monocytes, macrophages, lymphocytes, granulocytes, NK cells, mast cells, dendritic cells, neutrophils, and certain immune-derived cells (such as osteoclasts) function is particularly effective. Accordingly, the present invention relates to compounds useful for the prevention and/or treatment of various inflammatory and immunomodulatory disorders and diseases (see Saeki et al., Current Pharmaceutical Design 9:1201-1208 (2003)).

For example, compounds of the invention that inhibit one or more functions of CCR1 can be administered to inhibit (ie, reduce or prevent) inflammation or cellular infiltration associated with immune disorders. As a result, one or more inflammatory processes, such as leukocyte extravasation or infiltration, chemotaxis, exocytosis (eg, enzymes, histamine) or release of inflammatory mediators, can be inhibited. For example, infiltration of monocytes into inflammatory sites (eg, joints involved in arthritis, or into the CNS in MS) can be inhibited by the methods of the invention.

Similarly, compounds of the invention that promote one or more functions of CCR1 are administered to stimulate (induce or enhance) an inflammatory response, such as leukocyte extravasation, chemotaxis, exocytosis (e.g., enzyme, histamine) Or the release of inflammatory mediators, which can beneficially stimulate the inflammatory process. For example, monocytes can be recruited to fight bacterial infection.

Diseases and conditions associated with inflammation, immune disorders and infection can be treated using the methods of the invention. In a preferred embodiment, in these diseases or conditions, monocytes, macrophages, lymphocytes, granulocytes, NK cells, mast cells, dendritic cells or certain immune-derived cells (such as osteoclasts) The activity of other immune cells will be suppressed or promoted to regulate inflammatory or autoimmune responses.

In one set of embodiments, modulators of CCR1 function can be used to treat diseases or conditions, including chronic diseases in humans or other species. These diseases or conditions include: (1) allergic diseases, such as anaphylaxis or hypersensitivity, drug allergy, insect sting allergy and food allergy, (2) inflammatory bowel disease, such as Crohn's disease, ulcerative colitis, Enteritis and enteritis, (3) vaginitis, (4) psoriasis and inflammatory skin diseases such as dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, urticaria and pruritus, (5) vasculitis , (6) spondyloarthropathy, (7) scleroderma, (8) asthma and respiratory strain diseases, such as allergic asthma, allergic rhinitis, hypersensitivity lung disease, etc., (9) autoimmune diseases, such as fibromuscular pain, scleroderma, ankylosing spondylitis, juvenile rheumatoid arthritis, Still's disease, polyarticular juvenile rheumatoid arthritis, few-joint juvenile rheumatoid arthritis, polymyalgia rheumatica, rheumatoid arthritis Arthritis, psoriatic arthritis, osteoarthritis, multiple arthritis, multiple sclerosis, systemic lupus erythematosus, type I diabetes, type II diabetes, glomerulonephritis, etc., (10) graft rejection (including allograft rejection and graft-host disease), and (11) other diseases in which unwanted inflammatory responses or immune disturbances are to be suppressed, such as cardiovascular disease including atherosclerosis, myositis neurodegenerative disease ( eg, Alzheimer's disease), encephalitis, meningitis, hepatitis, nephritis, septicemia, sarcoidosis, allergic conjunctivitis, otitis, chronic obstructive pulmonary disease, sinusitis, Behcet's syndrome, and gout , and (12) immune-mediated food allergies, such as Celiac disease.

In another set of embodiments, diseases and conditions are treatable with modulators of CCR1 function. Examples of diseases treatable with modulators of CCR1 function include cancer, cardiovascular diseases, diseases in which angiogenesis or neovascularization plays a role (neoplastic diseases, retinopathy and macular degeneration), infectious diseases (viral infections such as HIV infection and bacterial infections) and immunosuppressive diseases such as organ and skin transplants. The term "organ transplantation" includes bone marrow transplantation and solid organ (eg kidney, liver, lung, heart, pancreas or combinations thereof) transplantation.

Accordingly, the compounds of the present invention are effective in the prevention and treatment of various inflammatory and immunomodulatory disorders and diseases.

Depending on the disease to be treated and the condition of the subject, the compounds of the present invention may be administered orally, parenterally (e.g., intramuscularly, intraperitoneally, intravenously, ICV, intraciscular injection or infusion, subcutaneously, or Implantation), by inhalation spray, nasal, vaginal, rectal, sublingual or topical routes, and can be prepared alone or mixed into suitable dosage unit preparations, which contain conventional non-toxic pharmaceutically acceptable carriers, adjuvant Agents and carriers suitable for various routes of administration.

In the treatment or prevention of conditions requiring modulation of chemokine receptors, suitable dosage levels are generally about 0.001-100 mg per kilogram body weight per day, administered in single or multiple doses. Preferably, dosage levels will be about 0.01-25 mg/kg per day; more preferably about 0.05-10 mg/kg per day. Suitable dosage levels may be about 0.01-25 mg/kg per day, about 0.05-10 mg/kg per day, or about 0.1-5 mg/kg per day. Within this range the dosage may be 0.005-0.05, 0.05-0.5 or 0.5-5.0 mg/kg per day. For oral administration, the composition is preferably provided in the form of a tablet containing 1.0-1000 mg of active ingredient, preferably 1.0, 5.0, 10.0, 15.0, 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0 , 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0 and 1000 mg of active ingredient as doses that can adjust the symptoms of the patient being treated. The compound may be administered 1-4 times a day, preferably once or twice a day.

It should be understood, however, that the specific dosage level and frequency of administration for any particular patient will vary and will depend on a variety of factors, including the activity of the particular compound used, the metabolic stability and duration of action of the compound, the The age, weight, genetic characteristics, health status, sex and diet of the subjects, as well as the mode and time of medication, excretion rate, drug composition, and the severity of the symptoms of the subjects receiving treatment.

Diseases and conditions associated with inflammation, immune disorders, infection and cancer can be treated or prevented using the compounds, compositions and methods of the invention.

The compounds and compositions of the present invention may be combined with other compounds or compositions that are effective in the prevention and treatment of related symptoms or diseases, such as inflammatory or autoimmune disorders, symptoms and diseases, including inflammatory bowel disease , rheumatoid arthritis, osteoarthritis, psoriatic arthritis, polyarticular arthritis, multiple sclerosis, allergic diseases, psoriasis, atopic dermatitis and asthma as well as the aforementioned lesions.

For example, the compounds and compositions of the invention may be used in combination with an anti-inflammatory or analgesic such as an opioid agonist, 5 - lipoxygenase inhibitors, cyclooxygenase inhibitors such as cyclooxygenase-2 inhibitors, interleukin inhibitors such as interleukin-1 inhibitors, NMDA antagonists, nitric oxide inhibitors or nitric oxide synthesis inhibitors, non Steroidal anti-inflammatory drugs, or cytokine-suppressive anti-inflammatory drugs, such as acetaminophen, aspirin, codeine, fentanyl, ibuprofen, indomethacin, ketorolac, morphine, naproxen, Compatibility with compounds such as phenacetin, piroxicam, steroidal analgesics, sufentanil, sulindac (sunlindac), and tenidapa. Similarly, the compounds and compositions of the present invention may be administered with: analgesics as described above; potentiators such as caffeine, H2 antagonists (eg ranitidine), simethicone, aluminum or magnesium hydroxide ; decongestants such as phenylephrine, phenylpropanolamine, pseudoephedrine, oxymetazoline, epinephrine, naphazoline, xylometazoline, prophexadrine, or L-methaephrine; cough suppressants such as codeine , hydrocodone, carametene, pentoxyverine, or dextromethorphan; diuretics; and antihistamines with or without sedating effects.

Similarly, the compounds and compositions of the present invention may be used in combination with other drugs that are used to treat, prevent, inhibit or alleviate diseases or conditions for which the compounds and compositions of the present invention are effective. Such other drugs may be administered simultaneously or sequentially with the compound or composition of the present invention in the amounts and routes normally used. When the compound or composition of the present invention is used simultaneously with one or more other drugs, a pharmaceutical composition containing other drugs other than the compound or composition of the present invention is preferred. Accordingly, the pharmaceutical compositions of the present invention include those that contain, in addition to a compound or composition of the present invention, one or more other active ingredients or therapeutic agents. Examples of other therapeutic agents that can be used in combination with the compounds or compositions of the present invention (either separately or in the same pharmaceutical composition) include, but are not limited to: (a) VLA-4 antagonists, (b) corticosteroids , such as beclomethasone, methylprednisone, betamethasone, prednisone, prednisolone, dexamethasone, fluticasone, hydrocortisone, budesonide, triamcinolone, salmeterol, salmeterol , albuterol, formoterol; (c) immunosuppressants, such as cyclosporine (cyclosporin A, Sandimmune ^_ , Neoral ^_ ), tacrolimus (FK-506, Prograf ^_ ), rapamycin ( Sirolimus, Rapamune ^_ ) and other immunosuppressants of the FK-506 type, and mycophenolate mofetil, such as mycophenolate mofetil (CellCept ^_ ); (d) antihistamines (H1-histamine antagonists) , such as brompheniramine, chlorpheniramine, dexchlorpheniramine, triprolidine, clemastine, diphenhydramine, dipheniramine, tripyramine, hydroxyzine, methazine, promethazine Zine, arimazine, azatadine, cyproheptadine, antazoline, pheniramine, mepyramine, astemizole, terfenadine, loratadine, cetirizine, non Solifenadine, desethyl loratadine, etc.; (e) non-steroidal anti-asthma drugs (such as terbutaline, osinarine, fenoterol, isostarline, salbutamol, bitoterol and pibuterol), theophylline, cromoglycate, atropine, ipratropium bromide, leukotriene antagonists (such as zafirlukast, montelukast, pranlukast, ilalast, porol Bistel and SKB-106, 203), leukotriene biosynthesis inhibitors (zileuton, BAY-1005); (f) non-steroidal anti-inflammatory drugs (NSAIDs), such as propionic acid derivatives (such as aminol Fen, benzoprofen, buprofen, carprofen, fenbufen, fenoprofen, flurprofen, flurbiprofen, ibuprofen, indoprofen, ketoprofen, miprofen, naproxen, oxaprozin, praprofen, pranoprofen, suprofen, tiaprofen and thiaprofen), acetic acid derivatives (such as indomethacin, acemetacin, aclofenac, cyclic Indenac, diclofenac, fenclofenac, fenclofenac, fentic acid, furofenac, ibufenac, isocetac, oxpinac, sulindac, thiopine, tolmetin, zidon mecin and zometac), fenamic acid derivatives (such as flufenamic acid, meclofenamic acid, mefenamic acid, niflumic acid and tolfenamic acid), biphenylcarboxylic acid derivatives (such as diflunis salicyl and flufensal), oxicams (such as isoxicam, piroxicam, sudoxicam, and tenoxicam), salicylates (such as acetylsalicylic acid and sulfasalazine) and Pyrazolones (eg, azapropazone, bezpiperylon, fiprazone, mofebuzone, oxybuzone, and phenylbutazone); (g) cyclooxygenase-2 (COX-2) inhibitors, such as celecoxib ( ^Celebrex_ ) and rofecoxib ( ^Vioxx_ ); (h) phosphodiesterase inhibitors type IV (PDE IV); (i) gold compounds such as auranofin and gold glucosinolate, (j) etanercept ( ^Enbrel_ ), (k) antibody therapy such as orthoclone (OKT3), da(clizumab) ( ^Zenapax_ ), basiliximab ( ^Simulect_ ), and infliximab Anti (Remicade ^_ ), (l) antagonists of other chemokine receptors, especially CCR5, CXCR2, CXCR3, CCR2, CCR3, CCR4, CCR7, CX3CR1 and CXCR6; (m) emollients or emollients, such as petrolatum and lanolin, (n) cuticle softeners (e.g. tazazorotene), (o) vitamin D3 derivatives such as calcipotriene or calcipotriol ( ^Dovonex_ ), (p) PUVA, (q) Dithranol (Drithrocreme ^_ ), (r) acitretin (Tegison ^_ ) and isotretinoin and (s) multiple sclerosis therapeutic agents such as interferon beta-1 beta (Betaseron ^_ ), interferon (beta- 1α ( ^Avonex_ ), azathioprine ( ^Imurek_ , ^Imuran_ ), glatiramer acetate ( ^Capoxone_ ), glucocorticoids (eg prednisolone) and cyclophosphamide, (t)DMARDS such as methotrexate , (u) Other compounds such as 5-aminosalicylic acid and its prodrugs; hydroxychloroquine; D-penicillamine; antimetabolites such as azathioprine, 6-mercaptopurine and methotrexate; DNA synthesis inhibitors agents, such as hydroxyurea; and agents that disrupt microtubules, such as colchicine. The weight ratio of the compound of the invention to the second active ingredient will vary and will depend on the effective dosage of each ingredient. Generally, an effective dose of each can be used. Therefore, for example, when the compound of the present invention is compatible with NSAID, the weight ratio of the compound of the present invention and NSAID is usually about 1000:1-1:1000, preferably about 200:1-1:200. Combinations of the compounds of the present invention and other active ingredients are also generally within the above ranges, but in each case an effective dose of each active ingredient should be used.

VI. Embodiment

The following examples are provided to illustrate the invention, however, these examples are not to be construed as limiting the invention as claimed.

The reagents and solvents used below are commercially available from Aldrich Chemical Co. (Milwaukee, Wisconsin, USA). ¹ H-NMR was recorded on a Varian Mercury 400 MHz NMR spectrophotometer. Significant peaks relative to TMS are provided in the following order: multiplicity (s, singlet; d, doublet; t, triplet; q, quadruplet; m, multimodal) and proton number. Mass spectrometry results are reported as the ratio of mass and charge, followed by the relative abundance of each ion (in parentheses). In the tables, individual m/e values are reported as M+H (or, as indicated, MH) ions, which contain the most common atomic isotopes. In all cases, the isotopic abundances corresponded to the expected molecules. For sample delivery, electrospray ionization (ESI) mass spectrometry analysis was performed using a HP 1100 HPLC on a Hewlett-Packard MSD electrospray mass spectrometer. Typically, analytes are dissolved in methanol at 0.1 mg/ml; 1 microliter is injected as transfer solvent into the mass spectrometer and scanned from 100 Daltons to 1500 Daltons. All compounds were analyzed in positive ESI mode using acetonitrile/water containing 1% formic acid as the transfer solvent. The following compounds were also analyzed in negative ESI mode using 2 mM _NH4OAc in acetonitrile/water as the delivery system.

Compounds within the scope of the present invention can be synthesized as described below using various reactions known to the skilled person. Useful routes to arylpiperazine subunits and heteroaromatic subunits are provided below. In the synthetic instructions, some arylpiperazine and pyrazole precursors were obtained from commercial sources. These commercial sources include Aldrich Chemical Co., Acros Organics, Ryan Scientific Incorporated, Oakwood Products Incorporated, Lancaster Chemicals, Sigma Chemical Co., Lancaster Chemical Co., TCI-America, Alfa Aesar, Davos Chemicals, and GFS Chemicals. Some examples of these commercially available compounds are shown in Figures 4A-4C. Furthermore, standard chemical reagents have been used to link arylpiperazines and heteroaromatic subunits (whether commercially available or prepared as follows) using a suitable optimal linker such as the acetyl unit as described in the text of the invention .

Those skilled in the art will also recognize that other optional methods may be used to synthesize the target compounds of the present invention, and that the routes described in this document are not exclusive but provide a broad range of possible routes to the compounds.

Certain molecules claimed in this patent exist in different enantiomeric and diastereomeric forms and all variants of these compounds are claimed.

Regioisomerism is a common property in organic chemistry, especially for some of the structure types presented here. For the compounds described herein, those skilled in the art will recognize that coupling reactions with heteroaromatic ring systems result in the formation of one detectable regioisomer or mixtures thereof.

Herein, a detailed description of the experimental procedures used to synthesize key compounds will result in the formation of molecules described by the physical data identifying them and their associated structural descriptions.

Both regioisomers sometimes exist in certain compounds of the invention. For example, compounds of formula III can be prepared, wherein the pyrazole moiety can be linked to the rest of the molecule through any nitrogen atom on the pyrazole ring. In these cases, both regioisomer types have demonstrated biological properties and are within the scope of all appended claims, whether explicitly drawn or not.

Those skilled in the art also recognize that acids and bases are often employed during standard work-up procedures in organic chemistry. Salts of compounds are sometimes prepared when the parent compound is itself acidic or basic in the experimental procedures described in this patent.

Example 1

The piperazine ring can be formally attached to the terminal aryl unit in a variety of ways: through aromatic nucleophilic substitution reactions, metal-catalyzed coupling reactions (arylation of secondary amines), ring expansion, rearrangement, and cyclization reactions, among others. Different protection/deprotection strategies can also be employed. Thus, all or only a portion of the final molecular structure may be present at the critical aryl coupling step. Examples of various such aryl coupling methods are listed below.

Scheme A: Metal-catalyzed arylation of secondary amines

Synthesis of (5-chloro-2-piperazin-1-yl-phenyl)-phenyl-methanone

At room temperature, piperazine (3.6g, 42.5mmol), palladium(II) acetate (0.007g, 0.043mmol), sodium tert-butoxide (0.22g, 2.4mmol) and BINAP (0.042g, 0.068mmol) were dissolved in 10 mL of anhydrous Stir in toluene for 15 minutes. Then, a solution of (2-bromo-5-chloro-phenyl)-phenyl-methanone (0.5 g, 1.7 mmol) in 10 mL of anhydrous toluene was added to the above reaction mixture. The reaction mixture was refluxed at 110° C. for 20 hours, filtered through a pad of celite, washed with toluene, concentrated, taken up in ethyl acetate and extracted three times with 1.5 (N) HCl solution. The combined aqueous layers were washed with ether. The aqueous layer was neutralized with 10% aqueous sodium hydroxide solution, then extracted three times with ethyl acetate. The combined ethyl acetate layers were washed with water and saturated saline solution, dried over anhydrous sodium sulfate and concentrated. Purification by flash chromatography (eluting with _CHCl3 -MeOH) afforded the title compound product.

Synthesis of 1-(4-trifluoromethoxy-phenyl)-piperazine

At room temperature, piperazine (0.588g, 6.84mmol), palladium(II) acetate (0.027g, 0.123mmol), sodium tert-butoxide (0.837g, 10.06mmol) and BINAP (0.154g, 0.286mmol) were dissolved in 10 mL of anhydrous Stir in toluene for 15 minutes. A solution of 4-trifluoromethoxybromobenzene (1.5 g, 6.22 mmol) in 10 mL of anhydrous toluene was added to the above reaction mixture. Then, the reaction mixture was refluxed at 110°C for 20 hours. The reaction mixture was filtered through a pad of celite, washed with toluene, concentrated, added ethyl acetate, and extracted three times with 1.5 (N) aqueous HCl. The combined aqueous layers were washed with ether. The aqueous layer was neutralized with 10% aqueous sodium hydroxide solution, then extracted three times with ethyl acetate. The combined ethyl acetate layers were washed with water and saturated saline solution, dried over anhydrous sodium sulfate and concentrated to give the product.

Synthesis of 1-(4-Methanesulfonyl-phenyl)-piperazine

Piperazine (0.98 g, 11.5 mmol), palladium(II) acetate (0.017 g), sodium tert-butoxide (0.37 g, 4.2 mmol) and BINAP (0.049 g) were stirred in 10 mL of anhydrous toluene for 15 minutes at room temperature. A solution of 1-bromo-4-methanesulfonyl-benzene (0.9 g, 3.8 mmol) in 10 mL of anhydrous toluene was added to the above reaction mixture. Then, the reaction mixture was refluxed at 110°C for 20 hours. The reaction mixture was filtered through a pad of celite and washed with toluene. The toluene was concentrated, the reaction mixture was taken up in ethyl acetate and extracted three times with 1.5 (N) HCl solution. The combined aqueous layers were washed with ether. The aqueous layer was neutralized with 10% aqueous sodium hydroxide solution, and then extracted three times with ethyl acetate. The combined ethyl acetate layers were washed with water and saturated brine solution, dried over anhydrous sodium sulfate, concentrated and chromatographed (9/1- _CHCl3 /MeOH) to yield the product.

Synthesis of 1-(4-chloro-3-methoxy-phenyl)-piperazine

Add 5-bromo-2-chloroanisole (1.0 mmol), N-Boc piperazine (1.2 mmol), NaOtBu (1.4 mmol), tris(dibenzylideneacetone)-dipalladium to an oven-dried vial (O) {Pd ₂ dba ₃ } (0.0025 mmol, 0.5 mol%) and BINAP (0.0075 mmol), then the vial was purged with nitrogen and capped tightly. The mixture was heated to 80°C overnight, then cooled to room temperature, taken up in ether, filtered and concentrated. The crude product was purified by flash silica gel column chromatography with ethyl acetate to yield tert-butyl 4-(4-chloro-3-methoxy-phenyl)-piperazine-1-carboxylate.

This product (ca. 1 mmol) was dissolved in dichloromethane (10 mL), and the reaction mixture was cooled to 0°C. TFA: _CH2Cl2 ( ₂ :1) (50% of the total) was slowly added to the reaction mixture and the reaction was allowed to warm to room temperature. When TLC (1:1 ethyl acetate:hexanes) showed complete reaction of the starting material, the solvent was removed and the oily residue was taken up in ethyl acetate (2 x 25 mL) and washed with saturated aqueous NaHCO ₃ . The organic layer was dried over _MgSO4 and the solvent was removed to give the title compound as a yellow oil which solidified on standing. ¹ H NMR (400MHz, CDCl ₃ ) δ7.18-7.22(d, 1H), 6.44-6.48(d, 1H), 6.36-6.42(dd, 1H), 4.8(s, 2H), 6.62-3.8(m , 4H), 3.46-3.6 (m, 4H). ¹³ C NMR (400 MHz, CDCl ₃ ) δ 164, 158.2, 156.4, 148, 119.2, 117, 52.8, 52.2, 48.5, 46.2, 42, 40.4.

Using the key Buchwald coupling, similar reactions were performed to prepare the related phenylpiperazines, some examples follow.

Synthesis of 1-(4-chloro-3-isopropoxy-phenyl)-piperazine

Mix 1-bromo-3-isopropoxy-4-chlorobenzene (prepared by another method) with 1.11g (6mmol) 1-Boc piperazine, 672mg (7.0mmol) sodium tert-butoxide, 93mg (0.15mmol) )rac-2,2'-bis(diphenylphosphine)-1,1'-binaphthyl and 45 mg (0.05 mmol) of tris(dibenzylideneacetone)dipalladium(O) in a flask under _N atmosphere was mixed and the mixture was heated at 85°C for 3.5 hours. The residue formed was partitioned between diethyl ether and a 1/1 mixture of ethyl acetate and water and the phases were separated. The ether/ethyl acetate phase was diluted with 1 volume of hexane, washed twice with 0.5M pH=7 phosphate buffer, once each with 1M NaOH and once with brine. The final organic phase was dried over _Na2SO4 , filtered and concentrated under vacuum to _an oil. This oil was dissolved in ethyl acetate, 10 mL each of 2M HCl in ether and 2M HCl in methanol was added, and the product was isolated by filtration after crystallization. ¹ HNMR (D ₂ O, 400MHz), δ7.23(d, 1H), 6.69(s, 1H), 6.59(d, 1H), 4.53(m, 1H), 3.28(m, 8H), 1.20(d , 6H) ppm.

Synthesis of 1-(4-chloro-3-ethoxy-phenyl)-piperazine

The title compound was obtained in the same manner as above to obtain 1-(4-chloro-3-isopropoxy-phenyl)-piperazine hydrochloride, except that ethanol was added instead of isopropyl in the ether formation reaction. alcohol. ¹ HNMR (D ₂ O, 400MHz), 7.22(d, 1H), 6.64(s, 1H), 6.54(d, 1H), 4.03(q, 2H), 3.29(m, 8H), 1.25(t, 3H )ppm.

Synthesis of 4-piperazin-1-yl-benzoic acid methyl ester

BINAP (230mg, 0.37mmol), palladium(II) acetate (417mg, 0.186mmol), tBuONa (1.25g, 13mmol), N-boc piperazine (1.9g, 10.2mmol) and THF (40mL) were mixed and prepared in Stir at room temperature for 30 minutes under nitrogen atmosphere. A solution of methyl 4-bromobenzoate (2 g, 9.3 mmol) in THF (10 mL) was added dropwise to the mixture and heated at 70° C. for 14 hours. Excess THF was then evaporated and extracted with ethyl acetate. After washing with brine and drying, the ethyl acetate layer was concentrated to give crude product. Flash chromatography on silica gel, eluting with 8% ethyl acetate in petroleum ether, afforded the pure N-BOC protected product. This intermediate (650 mg, 2.01 mmol) was dissolved in methanol (20 mL), then HCl saturated ether (7 mL) was added. The mixture was stirred at room temperature for 14 hours and then concentrated. The concentrated product was washed with petroleum ether to give methyl 4-piperazin-1-yl-benzoate as a white solid.

Synthesis of 1-(2,4-dichloro-phenyl)-piperazine

BINAP (219 mg), palladium(II) acetate (397 mg, 0.176 mmol), tBuONa (1.19 g, 12.3 mmol), piperazine (837 mg, 9.73 mmol) and THF (40 mL) were mixed and stirred at room temperature under a nitrogen atmosphere for 30 minute. A THF (10 mL) solution of 2,4-dichlorobromobenzene (2 g, 8.84 mmol) was added dropwise to the mixture, and heated at 70° C. for 14 hours. Excess THF was then evaporated and extracted with ethyl acetate. After washing with brine and drying, the ethyl acetate layer was concentrated to give crude product. Flash chromatography on silica gel, eluting with 2% MeOH in _CHCl3 , afforded 1-(2,4-dichloro-phenyl)-piperazine.

Synthesis of 1-(4-chloro-phenyl)-3-(R)-methyl-piperazine

Add 1-chloro-4-iodobenzene (1.0g, 0.0041mol) and R(-)-2-methylpiperazine (0.5g, 0.005mol), potassium tert-butoxide (0.705g , 0.0062mol), tris(benzylideneacetone) dipalladium (O) (0.095g, 0.0002mol) and 1,3 bis(2,6-diisopropylphenyl)imidazol-2-ylidene) (0.073 g, 0.0001mol). The flask was evacuated and filled with nitrogen. Anhydrous dioxane (20 mL) was added and stirred at 70 °C overnight. The reaction mixture was diluted with dichloromethane and filtered. The crude compound was purified by column chromatography. The compound was dissolved in ether and sparged with HCl gas to give 1-(4-chloro-phenyl)-3-methyl-piperazine.

Synthesis of 1-(4-chloro-2-fluorophenyl)-piperazine

At room temperature, piperazine (1.5g, 17.8mmol), palladium(II) acetate (0.032g, 0.143mmol), sodium tert-butoxide (0.688g, 10.06mmol) and BINAP (0.18g, 0.286mmol) were dissolved in 10mL without Stir in water toluene for 15 minutes. A solution of 1-bromo-4-chloro-2-fluorobenzene (1.5 g, 7.15 mmol) in 10 mL of anhydrous toluene was added to the reaction mixture. Then, the reaction mixture was refluxed at 110°C for 20 hours. The reaction mixture was filtered through a pad of celite, washed with toluene, then concentrated, the reaction mixture was taken up in ethyl acetate and extracted three times with 1.5 (N) HCl solution. The combined aqueous layers were washed with ether. The aqueous layer was neutralized with 10% aqueous sodium hydroxide solution, then extracted three times with ethyl acetate. The combined ethyl acetate layers were washed with water and saturated saline solution, dried over anhydrous sodium sulfate, and concentrated to give the product as a white solid.

Synthesis of 1-(3-methoxy-phenyl)-3-(S)-methyl-piperazine:

In a 4mL vial mix 467mg (2.5mmol, 1.0eq) 3-bromoanisole, 300mg (2.99mmol, 1.2eq) S-(+)-2-methylpiperazine, 336mg NaOtBu (3.5mmol, 1.4eq ), 50 mg BINAP (0.08 mmol, 0.03 eq), 27 mg Pd2Dba3 (0.03 mmol, 0.01 eq) and 500 μL toluene. The mixture was stirred briefly, then placed in a 90°C oil bath. LC/MS showed complete conversion within 1 hour. Excess 2M HCl/ _Et2O was added to the reaction mixture and the solid was collected by vacuum filtration and dried to give 700 mg of the dihydrochloride salt.

Synthesis of 1-(3-trifluoromethoxy-phenyl)-piperazine:

According to scheme A, 100 ℃, under argon atmosphere, 1-bromo-3-(trifluoromethoxy)-benzene (1.0g, 0.0042mol), piperazine (5.4g, 0.0632mol), potassium tert-butoxide ( 0.72 g, 0.0076 mol), palladium acetate (0.94 g, 0.0002 mol) and diisopropylimidazolium chloride (0.08 g, 0.0002 mol) were heated in 5 mL of dry dioxane for 24 hours. The reaction mixture was cooled to room temperature, quenched with water, and extracted with ethyl acetate. The ethyl acetate phase was washed once each with water and brine and concentrated. The residue was purified by column chromatography to obtain the title compound.

1-(4-chloro-3-methoxyphenyl)-3-(S)-methyl-piperazine:

According to protocol A, 110°C, under argon atmosphere, 5-bromo-2-chloroanisole (0.5g, 0.0023mol), (S)-(+)-2-methylpiperazine (0.35g, 0.0035mol) , palladium acetate (0.026 g, 0.0001 mol), BINAP (0.14 g, 0.00023 mol) and sodium tert-butoxide (0.35 g, 0.0037 mol) were heated in 5 mL of anhydrous toluene for 18 hours. The reaction mixture was quenched with water and extracted with ethyl acetate. The extract was washed with water, brine, and concentrated in vacuo. The product was purified by column chromatography to give an oil.

1-(4-Chloro-3-methoxyphenyl)-3-(R)-methyl-piperazine:

The title compound was prepared following Scheme A using (R)-(+)-2-methylpiperazine as starting material. The isolated product was a low melting solid.

1-(4-fluoro-2-methoxy-phenyl)-piperazine:

-Chloro-3-methoxy-aniline (25 g, 158 mmol) was dissolved in concentrated HCl (160 mL) at 80 °C, and the solution was cooled to -10 °C. Aqueous _NaNO2 (12.04 g, 174.6 mmol) was added dropwise with stirring. After another 20 minutes, _HPF6 (80 mL) was added with stirring while maintaining the temperature at or below 0 °C. After a further 30 minutes, the solid was filtered and washed with cold water and ether-methanol mixture (4:1), and dried overnight in vacuo. At 170°C, the solid was added in batches to mineral oil with stirring. After the addition _was complete, the mixture was cooled to room temperature and 175 mL of 10% _Na2CO3 was added slowly. The mixture was steam distilled, and the distillate was extracted with dichloromethane. The dichloromethane phase was washed _with brine, dried over _Na2SO4 , filtered and concentrated to give 2-chloro-5-fluoroanisole.

Following protocol A, mono-Boc-piperazine (7.64 g, 41.12 mmol), palladium(II) acetate (153 mg, 0.65 mmol), sodium tert-butoxide (4.61 g, 47 mmol) and BINAP (0.853 g, 1.37 mmol) were combined , and stirred in 100 mL of anhydrous toluene for 15 minutes at room temperature under a nitrogen atmosphere. Then, a solution of 2-chloro-5-fluoroanisole (5.5 g, 34.2 mmol) in anhydrous toluene (10 mL) was added, and the mixture was refluxed for 20 hours. After cooling, the reaction mixture was filtered through a pad of celite followed by washing with toluene. The washed toluene was concentrated, and the residue was extracted with ethyl acetate. Ethyl acetate was decanted and concentrated to give a crude material which was used directly in the next step.

The crude compound obtained from the previous step was dissolved in 20 mL of dichloromethane, to which was added 2M HCl in anhydrous ether (20 mL). The reaction mixture was stirred overnight and the solvent was evaporated. The residue was dissolved in water and washed once with ethyl acetate. The aqueous layer was basified to pH 12 with 10% sodium hydroxide solution and extracted three times with ethyl acetate. The combined ethyl acetate layers were washed with water and saturated brine solution, dried over anhydrous sodium sulfate, filtered and concentrated to yield 1-(4-fluoro-2-methoxy-phenyl)-piperazine as a white solid.

Synthesis of 1-[4-chloro-3-(2-ethoxy-ethoxy)-phenyl]-piperazine:

To a solution of 1.11 g (4.24 mmol) of triphenylphosphine in 25 _mL of _CH2Cl2 was added 0.67 mL (4.24 mmol) of diethyl azodicarboxylate at 0 °C following protocol F1 (below). After 10 minutes, 0.80 g (3.86 mmol) 5-bromo-2-chlorophenol was added, followed quickly by 0.38 g (4.24 mmol) 2-ethoxyethanol. The reaction was complete within 3 hours and partitioned between ether and water. The phases were separated and the ether phase was diluted with hexanes and washed twice with 10% aqueous methanol and once with brine. The ether/hexane phase was dried over _Na2SO4 , filtered and concentrated _in vacuo to afford (5-bromo-2-chloro-ethoxy-ethoxy-benzene as a clear oil.

418mg (1.5mmol) (5-bromo-2-chloro-ethoxy-ethoxy-benzene, 335mg (1.8mmol) 1-Boc-piperazine, 202mg (2.1mmol) sodium tert-butoxide, 30mg (0.045 mmol) rac-binap and 14 mg (0.015 mmol) Pd ₂ DBA ₃ were slurried in 0.5 mL of anhydrous toluene, and the mixture was heated at 90° C. for 12 hours. The reaction was partitioned between water and ethyl acetate and carried out The phases were separated. The ethyl acetate phase was washed with brine, dried over _Na2SO4 , filtered and concentrated to _an oil. The oil was chromatographed to obtain 1-[4-chloro-3-(2-ethoxy-ethoxy base)-phenyl]-piperazine.

Additional Example of Synthesis of Arylpiperazines by Metal-Catalyzed Arylation Process (Scheme A)

In addition to the specific examples listed above, a number of other arylpiperazine derivatives were prepared using similar palladium-mediated coupling methods. Specific examples are as follows.

Scheme B: Formation of the piperazine ring by cyclization

Synthesis of 1-(3,4-difluorophenyl)piperazine

3,4-Difluoro-aniline (1 g, 7.7 mmol) was dissolved in anhydrous n-butanol (10 mL) and anhydrous sodium carbonate (3.2 g, 30 mmol) was added thereto, and the reaction mixture was stirred under nitrogen for 1 hour. A solution of bis(2-chloroethyl)amine hydrochloride (1.38 g, 7.7 mmol) in n-BuOH (10 mL) was then added to the mixture by syringe. The reaction was then heated at 120°C for 48 hours. nBuOH was evaporated under vacuum and the residue was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated to give crude product. Purification by flash column chromatography (chloroform/methanol) afforded 1-(3,4-difluoro-phenyl)-piperazine as a beige solid.

Synthesis of 1-(4-bromo-phenyl)-piperazine

4-Bromo-aniline (2 g, 1.162 mmol) was added to anhydrous nBuOH (25 mL), to which was added anhydrous potassium carbonate (4.8 g, 34.8 mmol) under nitrogen, and stirred at room temperature for 1 hour. Then, a solution of bis-(2-chloroethyl)amine hydrochloride 2 (2.49 g, 13.9 mmol) in n-BuOH (10 mL) was added to the mixture by syringe. The reaction was then heated at 100°C for 12 hours. n-BuOH was evaporated in vacuo and the residue was extracted with ethyl acetate. The organic layer was dried over _Na2SO4 and concentrated to give a crude product which was _purified by silica gel column (chloroform/methanol) to give the title compound.

Scheme C: Formation of piperazine rings via ring-opening/cyclization methods

Synthesis of 3-[2-(5-methoxy-2-methyl-phenylamino)-ethyl]-oxazolidin-2-one:

In a flask, add 2.95g (10.3mmol) toluene-4-sulfonic acid 2-(2-oxo-oxazolidin-3-yl)-ethyl ester, 1.56g (11.4mmol) 2-methyl-5- Methoxyaniline, 2.58g (18.7mmol) of potassium carbonate and 22mL of anhydrous dimethylformamide, the mixture was heated at 100°C for 7 hours. The reaction was cooled to room temperature and partitioned between ethyl acetate and water. The phases were separated and the ethyl acetate phase was washed with brine, dried over _Na2SO4 , filtered and concentrated to an oil _. The oil was purified by chromatography (120 mL silica, 60 ethyl acetate/40 hexanes) to give the corresponding product as a clear oil which solidified on drying: ¹ H NMR (DMSO-d6, 400 MHz) 6.81 ( d, 1H), 6.11(s, 1H), 6.04(d, 1H), 4.92(t, 1H), 4.21(t, 2H), 3.65(s, 3H), 3.59(m, 2H), 3.31(m , 2H), 3.23 (m, 2H), 1.95 (s, 3H) ppm.

Synthesis of 1-(5-methoxy-2-methyl-phenyl)-piperazine

To 505 mg (2.0 mmol) of 3-[2-(5-methoxy-2-methyl-phenylamino)-ethyl]-oxazolidin-2-one in the flask was added 2 mL of 48% HBr in acetic acid , 1 mL of acetic acid and 1 mL of anisole, and the mixture was heated at 90° C. for 6 hours. The solution was allowed to cool to room temperature and 5 _{mL CH2Cl2} was added. The product crystallized and was isolated by filtration. The solid was dissolved in 55 mL of ethanol, 201 mg (2 mmol) of triethylamine was added, and the solution was heated under reflux for 3 hours. The solution was then concentrated in vacuo to form a residue which was partitioned between diethyl ether and water. The phases were separated and the aqueous phase was basified with 1M NaOH. Then, the aqueous phase was extracted twice with ethyl acetate. The combined ethyl acetate phases were washed _once with brine, dried over _Na2SO4 , filtered and acidified with 2M HCl in ether. The product was isolated by filtration.

Addition of various piperazines to aryl and heteroaryl halides via aryl-halogen displacement

Direct halogen displacement, with heating if required, can be used to construct the ring systems described here as a complement to the metal-involved methods described above.

Synthesis of 4-piperazin-1-yl-benzoic acid ethyl ester

Concentrated sulfuric acid (20 g) was added dropwise to 4-bromobenzoic acid (25 g) and ethanol (1000 mL). The reaction mixture was heated at 85°C overnight. The reaction was cooled and ethanol was removed by distillation, the reaction mixture was quenched with water and extracted with ethyl acetate. The extract was washed with 10% sodium bicarbonate, water, brine, then concentrated to yield the crude ester. 4-Bromoethyl benzoate (10.0 g, 0.0437 mol) was added to 250 mL of anhydrous DMF, piperazine (37 g, 0.437 mol) was added, followed by 30 g (0.2185 mol) of anhydrous potassium carbonate, 1.0 g TBAI and 1.5 g potassium iodide. The reaction mixture was heated at 135°C overnight. The reaction mixture was quenched with water and extracted with ethyl acetate. The extract was washed with water, then brine, and concentrated to give 4-piperazin-1-yl-benzoic acid ethyl ester as a beige solid.

Synthesis of 1-(4-methoxy-pyridin-2-yl)-piperazine:

To 756 mg (5.29 mmol) of 2-chloro-4-methoxypyridine and 2.27 g (26 mmol) of piperazine in a pressurized flask was added 2.7 mL of dimethylformamide, and the mixture was heated at 115°C for 5 hours. The solution was allowed to cool before opening the flask, and the resulting slurry was partitioned between ethyl acetate and water. The phases were separated and the aqueous phase was back extracted once with ethyl acetate. The combined ethyl acetate phases _were washed once with brine, dried over _Na2SO4 , filtered and the filtrate acidified with 2M HCl in ether. The product was allowed to crystallize overnight and the solid was isolated by filtration to give the product as a white solid: ¹ H NMR (D ₂ O, 400 MHz) 7.72 (d, 1H), 6.61 (d, 1H), 6.48 (s, 1H), 3.88 ( s, 3H), 3.79 (m, 4H), 3.36 (m, 4H) ppm.

Synthesis of 1-(3-methoxy-pyridin-2-yl)-piperazine:

To 966 mg (6.7 mmol) of 2-chloro-6-methoxypyridine and 2.90 g (34 mmol) of piperazine in a pressurized flask was added 3.3 mL of dimethylformamide, and the mixture was heated at 115° C. for 5 hours. The solution was allowed to cool before opening the flask and the resulting slurry was partitioned between ethyl acetate and water. The phases were separated and the aqueous phase was back extracted once with ethyl acetate. The combined ethyl acetate phases were washed once with _brine , dried over _Na2SO4 , filtered and the filtrate acidified with 2M HCl in ether. The product was allowed to crystallize overnight and isolated by filtration to give a white solid: ¹ HNMR (D ₂ O, 400 MHz) 7.73 (t, 1H), 6.52 (d, 1H), 6.31 (d, 1H), 3.81 (s, 3H) , 3.68 (m, 4H), 3.26 (m, 4H) ppm.

Scheme D: Synthesis of piperazines via aryl-halogen displacement and addition of the resulting piperazines to aryl and heteroaryl halides

Synthesis of 2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-piperazin-1-yl-ethanone

0 ℃, to 1.69g (9.1mmol) Boc-piperazine, 2.0g (8.3mmol) (4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid and 1.12g Add 1.73g (9.1mmol) hydrochloride 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide to a solution of (8.3mmol) 1-hydroxybenzotriazole in 20mL of dimethylformamide . The reaction was stirred and allowed to warm to room temperature overnight, then partitioned between ether and water. The phases were separated and the ether phase was washed once each with 1M HCl, water, 1M NaOH and brine. The ether phase was dried over _Na2SO4 , filtered and concentrated to a residue _.

The crude residue was dissolved in 20 mL diethyl ether and 8 mL ethyl acetate, and 20 mL 5M HCl in isopropanol was added. After 1 hour, the mixture was placed in the refrigerator overnight. The product was isolated by filtration to obtain a white solid. ¹ H NMR (DMSO-d6, 400 MHz) 9.21 (br s, 2H), 5.38 (s, 2H), 3.69 (m, 4H), 3.32 (m, 4H), 2.20 (s, 3H) ppm.

Another method for synthesizing 2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-piperazin-1-yl-ethanone

(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid (1.5 g, 6.18 mmol) was added to anhydrous DCM (20 mL) and cooled to 0 °C. To the cold mixture was added N-boc piperazine (1.15 g, 6.18 mmol) followed by T3P (8 g, 12.4 mmol, 50% in EtOAc). The reaction was left at room temperature overnight. The mixture was diluted with CH ₂ Cl ₂ , washed with NaHCO ₃ solution, brine, anhydrous (Na ₂ SO ₄ ), and concentrated to yield a crude product which was washed thoroughly with ether-pet ether to provide 4-[2-(4-Chloro-5methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-piperazine-1-carboxylic acid tert-butyl ester (1.2g, 2.9mmol) . This product was dissolved in methanol (25 mL) cooled to 0°C, and HCl-saturated ether (3 mL) was added thereto. The mixture was stirred at room temperature for 4 hours and then concentrated. Crystallization from MeOH/petroleum ether afforded the product.

Synthesis of 1-[4-(5-bromo-pyrimidin-2-yl)-piperazin-1-yl]-2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazole-1- base)-ethanone (Scheme D)

To 86 mg (0.25 mmol) of 2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-piperazin-1-yl-ethanone hydrochloride in a vial , 76 mg (0.6 mmol) of potassium carbonate and 48 mg (0.3 mmol) of 5-bromo-2-chloropyrimidine were added with 0.7 mL of anhydrous dimethylformamide, and the mixture was heated at 120° C. for 12 hours. The reaction was cooled to room temperature and partitioned between ethyl acetate and water. The phases were separated and the aqueous phase was back extracted once with ethyl acetate. The combined ethyl acetate phases were washed once each with water, 0.5M pH=7 phosphate buffer, water, 1M NaOH and brine. The ethyl acetate phase was dried over _Na2SO4 , filtered and acidified with 2M HCl in ether, and the powdery product precipitated: ¹ H NMR (DMSO-d6, 400 MHz) 8.48 (s, _2H ), 5.37 (s, 2H), 3.81 (m, 2H), 3.72 (m, 2H), 3.57 (m, 4H), 2.18 (s, 3H) ppm; MS (ES) M+H expected = 467.0, found 466.9.

Other compounds of the present invention prepared by aryl-halogen displacement method

Synthesis of 2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(7H-purin-6-yl)piperazin-1-yl]- Ethyl ketone:

The title compound was prepared according to Scheme D, using 6-chloropurine as the heteroaryl halide component: ¹ HNMR (DMSO-d6, 400 MHz) 8.23(s, 1H), 8.14(s, 1H), 5.39(s, 2H), 4.32 (br, 2H), 4.22 (br, 2H), 3.60 (m, 4H), 2.19 (s, 3H) ppm; MS (ES) M+H expected = 429.1, found 429.0.

Synthesis of 2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-(4-quinolin-2-yl-piperazin-1-yl)ethanone:

The title compound was prepared according to Scheme D, using 2-chloroquinoline as the heteroaryl halide component: ¹ HNMR (DMSO-d6, 400 MHz) 8.44(d, 1H), 8.29(br, 1H), 7.91(d, 1H), 7.77(t, 1H), 7.57(d, 1H), 7.48(t, 1H), 5.44(s, 2H), 4.14(br, 2H), 4.01(br, 2H), 3.78(br, 2H ), 3.70 (br, 2H), 2.20 (s, 3H) ppm; MS (ES) M+H expected = 438.1, found 438.0.

Synthesis of 2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(5-chloro-pyridin-2-yl)-piperazine-1- base]-ethanone:

The title compound D was prepared according to Scheme D, using 2,5-dichloropyridine as the heteroaryl halide component: MS(ES) M+H expected = 422.1, found = 422.0; HPLC retention time = 4.75 minutes (Agilent Zorbax SB-C18, 2.1×50mm, 5μ, 35°C), using a 4.5-minute gradient of 20-95% B, with a 1.1-minute wash at 95% B (A = 0.1% formic acid/5% acetonitrile/94.9 % water, B = 0.08% formic acid/99.9% acetonitrile).

Synthesis of 2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-(2,3,5,6-tetrahydro-[1,2']dipyridine Azin-4-yl)-ethanone:

The title compound was prepared according to Scheme D, using 2-chloropyrazine as the heteroaryl halide component: ¹ HNMR (DMSO-d6, 400 MHz) 8.34(s, 1H), 8.09(d, 1H), 7.85(d , 1H), 5.38(s, 2H), 3.68(m, 2H), 3.58(m, 4H), 3.44(m, 2H), 2.19(s, 3H) ppm; MS(ES) M+H expected value = 389.1, found to be 389.0.

Synthesis of 2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(6-methyl-pyridazin-3-yl)-piperazine- 1-yl]-ethanone:

The title compound was prepared according to Scheme D, using 3-chloro-6-pyridazine as the heteroaryl halide component: MS(ES) M+H expected = 403.1, found = 403.0; HPLC retention time = 1.68 min (Agilent Zorbax SB-C18, 2.1×50mm, 5μ, 35°C), using a 4.5-minute gradient from 20-95% B, with a 1.1-minute wash at 95% B (A = 0.1% formic acid/5% acetonitrile/94.9% water, B = 0.08% formic acid/99.9% acetonitrile). Synthesis of 2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(4,6-dimethoxy-[1,3,5] Triazin-2-yl)-piperazin-1-yl]-ethanone:

The title compound was prepared following Scheme D using 2-chloro-4,6-dimethoxytriazine as the heteroaryl halide component: MS(ES) M+H expected = 450.1. Found value = 450.0; HPLC retention time = 4.24 minutes (Agilent Zorbax SB-C18, 2.1 x 50 mm, 5 μ, 35°C) using a 4.5 minute gradient from 20-95% B with a 1.1 minute wash at 95% B ( A = 0.1% formic acid/5% acetonitrile/94.9% water, B = 0.08% formic acid/99.9% acetonitrile).

Synthesis of 2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(2-methylsulfanyl-pyrimidin-4-yl)- Piperazin-1-yl]-ethanone:

The title compound was prepared according to Scheme D, using 4-chloro-2-methylthiopyrimidine as the heteroaryl halide component: ¹ H NMR (DMSO-d6, 400 MHz) 8.16(d, 1H), 6.87(d, 1H), 5.41(s, 2H), 3.90(brm, 4H), 3.62(m, 4H), 2.57(s, 3H), 2.19(s, 3H) ppm; MS(ES) M+Na expected = 435.1 , found a value of 435.0.

Synthesis of 2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(4,6-dimethoxy-pyrimidin-2-yl)- Piperazin-1-yl]-ethanone:

The title compound was prepared following Scheme D, using 2-chloro-4,6-dimethoxypyrimidine as the heteroaryl halide component: MS(ES) M+H expected = 449.1, found = 449.0; HPLC Retention time = 4.92 min (Agilent Zorbax SB-C18, 2.1 x 50 mm, 5 μ, 35°C) with a 4.5 min gradient from 20-95% B, with a 1.1 min wash at 95% B (A = 0.1% formic acid/ 5% acetonitrile/94.9% water, B = 0.08% formic acid/99.9% acetonitrile).

Synthesis of 1-[4-(6-chloro-5-methyl-pyridazin-3-yl)-piperazin-1-yl]-2-(4-chloro-5-methyl-3-trifluoromethyl -pyrazol-1-yl)-ethanone:

The title compound was prepared according to Scheme D, using 3,6-dichloro-4-methylpyridazine as the heteroaryl halide component: MS(ES) M+H expected = 437.1, found = 437.0; HPLC Retention time = 4.17 min (Agilent Zorbax SB-C18, 2.1 x 50 mm, 5 μ, 35°C) with a 4.5 min gradient from 20-95% B, with a 1.1 min wash at 95% B (A = 0.1% formic acid/ 5% acetonitrile/94.9% water, B = 0.08% formic acid/99.9% acetonitrile).

Synthesis of 2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(5-methoxy-1-H-benzimidazole-2- Base)-piperazin-1-yl]-ethanone:

The title compound was prepared according to Scheme D with 2-chloro-5-methoxybenzimidazole as the heteroaryl halide component: MS(ES) M+H expected = 457.1, found = 457.0; HPLC retention time = 2.85 minutes (Agilent Zorbax SB-C18, 2.1 x 50mm, 5μ, 35°C) using a 4.5 minute gradient from 20-95% B with a 1.1 minute wash at 95% B (A = 0.1% formic acid/5% Acetonitrile/94.9% water, B = 0.08% formic acid/99.9% acetonitrile).

Further functionalization after formal formation of the arylpiperazine ring system

Among other selected substituents, the key compounds of the invention also have a halogen atom in the 2- or 4-position. The research carried out on it is described below.

In general, functionalization of aromatic rings within the arylpiperazine ring system can occur before or after the piperazine ring is introduced, as described in the Examples below.

Scheme E: Selected Examples of Halogenation of the Aromatic System Following Linkage of the Piperazine Ring System

Synthesis of 1-(4-bromo-3-methoxy-phenyl)-piperazine hydrochloride:

0°C, add 1.55 g (9.7 mmol) bromine to a solution of 2.33 g (8.8 mmol) 1-(3-methoxyphenyl) piperazine dihydrochloride and 756 mg (9.7 mmol) sodium acetate in 70 mL acetic acid and 15 mL water . After 1 h, the reaction was concentrated in vacuo to an oil which was partitioned between ethyl acetate and 1M NaOH. The phases were separated and the ethyl acetate phase was washed once each with water and brine, dried over _Na2SO4 , filtered and the filtrate was concentrated in vacuo to an oil _. The oil was dissolved in a small amount of methanol and the solution acidified with 2M HCl in ether. The product was isolated by filtration. ¹ H NMR (D ₂ O, 400 MHz) 7.36 (d, 1H), 6.73 (s, 1H), 6.50 (d, 1H), 3.75 (s, 3H), 3.32 (m, 8H) ppm.

Synthesis of 1-(4-bromo-3-methyl-phenyl)-piperazine hydrochloride:

To a solution of 966 mg (4.0 mmol) of 1-(3-methylphenyl)piperazine dihydrochloride in 9 mL of acetic acid and 1 mL of water was added 640 mg (4.0 mmol) of bromine at 0°C. After 1 h, the reaction was concentrated in vacuo to an oil which was partitioned between ethyl acetate and 1M NaOH. The phases were separated and the ethyl acetate phase was washed once each with water and brine, dried over _Na2SO4 , filtered and the filtrate was concentrated in vacuo to an oil _. The oil was dissolved in a small amount of methanol and the solution acidified with 2M HCl in ether. The product was isolated by filtration. ¹ H NMR (D ₂ O, 400 MHz) 7.37 (d, 1H), 6.85 (s, 1H), 6.76 (d, 1H), 3.37 (m, 8H), 2.17 (s, 3H) ppm.

Synthesis of 1-(2-chloro-5-methoxy-phenyl)-piperazine hydrochloride:

To a solution of 5.3 g (20 mmol) 1-(3-methoxyphenyl)piperazine dihydrochloride in 120 mL acetic acid and 30 mL water was added 3.3 g (20 mmol) N-chlorosuccinimide at 0°C. After 5 hours, the reaction was concentrated in vacuo to an oil which was partitioned between ethyl acetate and 1M NaOH. The phases were separated and the ethyl acetate phase was washed once each with water and brine, dried over _Na2SO4 , filtered and the filtrate was concentrated in vacuo to an oil _. The oil was dissolved in a small amount of methanol and the solution acidified with 2M HCl in ether. The product was isolated by filtration. ¹ H NMR (D ₂ O, 400 MHz) 7.28 (d, 1H), 6.66 (m, 3H), 3.70 (s, 3H), 3.32 (m, 4H), 3.20 (m, 4H) ppm.

Synthesis of 1-(2,4-dichloro-5-methoxy-phenyl)-piperazine hydrochloride:

To a solution of 530 mg (2.0 mmol) of 1-(3-methoxyphenyl)piperazine dihydrochloride in 7 mL of acetic acid and 4 mL of water was added 700 mg (4.4 mmol) of N-chlorosuccinimide at 0°C. After 2 hours, the reaction was removed from the ice/water bath and stirred overnight. After 12 hours, the reaction was concentrated in vacuo to an oil which was partitioned between ether and water. The phases were separated and the aqueous phase was basified with 1M NaOH and extracted with ethyl acetate. The ethyl acetate phase was washed once each with water and brine, dried over _Na2SO4 , filtered and the filtrate was concentrated in vacuo to an oil which was dissolved in a small amount of _methanol and the solution acidified with 5M HCl in isopropanol and washed with acetic acid Dilute with ethyl ester for crystallization. The product was isolated by filtration. ¹ H NMR (D ₂ O, 400 MHz) 7.38 (s, 1H), 6.72 (s, 1H), 3.78 (s, 3H), 3.32 (m, 4H), 3.19 (m, 4H) ppm.

Synthesis of 1-(4-chloro-5-methoxy-2-methyl-phenyl)-piperazine

According to protocol E, at 0°C, to 90 mg (0.32 mmol) of 1-(5-methoxy-2-methyl-phenyl)-piperazine hydrochloride in 1.3 mL of acetic acid and 1 mL of water was added 58 mg (0.36 mmol) of N- Chlorosuccinimide. The reaction was allowed to warm to room temperature over 2 hours and after 14 hours was concentrated in vacuo to a dark residue. The residue was partitioned between ether and water and the phases were separated. The aqueous phase was basified to pH>10 with 1M NaOH and extracted twice with ethyl acetate. The combined ethyl acetate phases were washed once with brine, dried over _Na2SO4 , filtered and concentrated to an oil _. The oil was dissolved in methanol, acidified with 2M HCl in ether, and diluted with ether to give the product as a solid.

Synthesis of 1-(4-bromo-3-methoxy-phenyl)-3-(S)-methyl-piperazine:

To 500 mg S-(+)-3-methyl-N1-(4-chloro-3-methoxy)phenylpiperazine (1.79 mmol, 1.0 eq) in 5 mL 1:1 AcOH/DCM was added 91 μL _Br2 (1.79mmol, 1.0eq), resulting in a stirred slurry. LC/MS showed a mixture of polyhalides. The crude mixture was purified by preparative HPLC to afford the title intermediate.

Synthesis of 1-(2,4-dichloro-5-methoxy-phenyl)-3-(S)-methyl-piperazine:

To 500 mg S-(+)-3-methyl-N1-(4-chloro-3-methoxy)phenylpiperazine (1.44 mmol, 1.0 eq) in 2 mL 1:1 AcOH/DCM was added 85 mg NCS (0.64mmol, 0.44eq) to give a stirred slurry. LC/MS showed a mixture of polyhalides. The crude mixture was purified by preparative HPLC to afford the desired intermediate.

Scheme F1: Demethylation/Etherification of Aromatic Precursors to Attach Piperazine Ring Systems to Access Selected Examples of Key Arylpiperazine Moieties

Synthesis of 3-bromo-6-chlorophenol:

5.71 g (25.8 mmol) of 5-bromo _{-2- chloroanisole} was added to a solution of 50 mL of 1 M boron tribromide in CH2Cl2 at 0 °C. After 2 hours, the reaction was allowed to warm to room temperature. After 5 hours, the solution was cooled to 0°C and quenched with methanol. The resulting solution was partitioned between water and ethyl acetate and the phases were separated. The aqueous phase was back extracted once with ethyl acetate. The combined ethyl acetate phases were diluted with 1 volume of ether and extracted twice with 1M NaOH. The combined basic aqueous phases were acidified with 12M HCl and extracted once with ethyl acetate. The final ethyl acetate phase was washed once with brine, dried over MgSO4, filtered, and concentrated to give the phenol as a tan solid. ¹ H NMR (DMSO-d6, 400 MHz) 10.66 (s, 1H), 7.27 (d, 1H), 7.08 (s, 1H), 6.95 (d, 1H) ppm.

Synthesis of 1-bromo-3-isopropoxy-4-chlorobenzene:

To 1.70 g (6.5 mmol) of triphenylphosphine in 25 mL of _CH2Cl2 was added 1.14 _g (6.5 mmol) of diethyl azodicarboxylate at 0 °C. After 10 minutes, 390 mg (6.5 mmol) of isopropanol were added, followed rapidly by 1.03 g (5.0 mmol) of 3-bromo-6-chlorophenol. The reaction was complete within 3 hours and the reaction was partitioned between ether and water. The phases were separated and the ether phase was diluted with hexane, washed twice with 10% aqueous methanol and once with brine. The ether/hexane phase was dried over _Na2SO4 , filtered and concentrated _in vacuo to give the product as a clear oil.

Scheme F2: Other examples of construction of similar ring systems using similar demethylation/etherification methods

Synthesis of 2-chloro-5-bromo-O-(4-methylbenzenesulfonyl)benzyl alcohol:

To 1.0 g of 2-chloro-5-bromobenzyl alcohol (4.5 mmol, 1.0 eq) in 5 mL of anhydrous THF was added 200 mg of a 60% NaH/mineral oil dispersion (5.0 mmol, 1.1 eq) and the resulting slurry was stirred under nitrogen. slurry for 0.5 hours. 900 mg of 4-methylbenzenesulfonyl chloride (4.8 mmol, 1.05 eq) was added and the mixture was stirred overnight for 12 hours. The reaction was poured into 25 mL of aqueous _K2CO3 and the solution was extracted with 2 x 10 _mL of 20% hexane/EtOAc. The aqueous phase was discarded and the combined organic phases were dried in vacuo to obtain a white crystalline solid.

Preparation of benzyl (2-chloro-5-piperazin-1-yl-benzyl)-methyl-carbamate:

To 200 mg 2-chloro-5-bromo-O-(4-methylbenzenesulfonyl)benzyl alcohol (0.53 mmol, 1.0 eq) in 500 μL dry THF was added 230 mg 60% NaH in mineral oil (0.58 mmol, 1.1eq), followed by adding 1.5eq N-Cbz-methylamine. The mixture was heated at 60°C overnight and the crude product was purified by preparative HPLC to afford benzyl (5-bromo-2-chloro-benzyl)-methyl-carbamate.

In 0.5 mL of toluene, 500 mg (5-bromo-2-chloro-benzyl)-methyl-carbamic acid benzyl ester (1.36 mmol), 303 mg (1.63 mmol) N-Boc-piperazine, 182 mg (1.90 mmol) NaOtBu , 27 mg (0.04 mmol) BINAP and 12 mg (0.01 mmol) Pd ₂ Dba ₃ were heated at 90° C. overnight. The crude was purified by preparative HPLC to afford tert-butyl 4-{3-[(benzyloxycarbonyl-methyl-amino)methyl]-4-chloro-phenyl}-piperazine-1-carboxylate.

220mg tert-butyl 4-{3-[(benzyloxycarbonyl-methyl-amino)-methyl]-4-chloro-phenyl}-piperazine-1-carboxylate was dissolved in 2mL 1:2 TFA:di Chloromethane solution. After 0.5 h, the solvent and TFA were removed in vacuo to afford benzyl (2-chloro-5-piperazin-1-yl-benzyl)-methyl-carbamate as an oil.

Other substituted arylpiperazines prepared by this method:

(2-Chloro-5-piperazin-1-yl-phenyl)-tert-butyl carbamate:

To 25 g (0.106 mol) of 4-bromo-1-chloro-2-nitrobenzene in 400 mL of methanol was added 30 g (0.528 mol) of iron powder. The mixture was heated to 50° C., and 45 g (0.8456 mol) of ammonium chloride in 200 mL of water was slowly added. The reaction was heated to 70°C overnight, cooled to room temperature, and filtered through filter paper. The filtrate was concentrated in vacuo, the residue was dissolved in water, and the solution was extracted with ethyl acetate. The ethyl acetate phase was washed once each with water and brine, dried over _Na2SO4 , filtered, and concentrated to give ₅ -bromo-2-chloroaniline.

To 10 g (0.048 mol) of 5-bromo-2-chloroaniline in 300 mL of anhydrous dichloromethane was added 15 g (0.1452 mol) of triethylamine. The reaction was cooled to 0°C and 13 g (0.0581 mol) Boc-anhydride was added. The reaction was warmed to ambient temperature and 6 g (0.048 mol) DMAP was added. After 14 hours, the solvent was removed in vacuo and the residue was purified by chromatography to afford tert-butyl 5-bromo-2-chlorophenylcarbamate as a pale orange solid.

According to scheme A, 5g (0.02mol) tert-butyl 5-bromo-2-chlorophenylcarbamate, 14g (0.1628mol) piperazine, 8.6g (0.025mol) cesium carbonate, 0.1g (0.0025mol) palladium acetate and 0.1 g (0.002 mol) of BINAP was heated in 5 mL of anhydrous toluene at 110° C. for 12 hours. After cooling to ambient temperature, the reaction was quenched with water and the mixture was extracted with ethyl acetate. The ethyl acetate phase was washed with _brine , dried over _Na2SO4 , filtered and concentrated. The residue was purified by 60-120 silica gel using 0.5% methanol in chloroform to give (2-chloro-5-piperazin-1-yl-phenyl)-carbamic acid tert-butyl ester as a low melting solid.

1-(4-Chloro-3-methoxymethyl-phenyl)-piperazine:

0°C, 1 g (0.0045 mol) of 5-bromo-2-chlorobenzyl alcohol in anhydrous THF was added to 0.4 g (0.00032 mol) of sodium hydride in anhydrous THF, and the mixture was stirred at 0°C for 1 hour. 1.28 g (0.009 mol) methyl iodide was added and the reaction was allowed to warm to ambient temperature. After stirring for 12 hours, the reaction was quenched with water and extracted with ethyl acetate. The ethyl acetate phase was washed once each with water and brine, dried over _Na2SO4 , filtered, and _concentrated to give 4-bromo-1-chloro-2-methoxymethyl-benzene.

According to scheme A, in argon atmosphere, 0.98g (0.0041mol) 4-bromo-1-chloro-2-methoxymethyl-benzene, 0.35g (0.0041mol) piperazine, 0.0466g (0.0002mol) palladium acetate, 0.25 g (0.00041 mol) of BINAP and 0.63 g (0.0066 mol, 1.6 eq) of sodium tert-butoxide were heated in 10 mL of anhydrous toluene at 110° C. for 24 hours. The reaction mixture was quenched with water and extracted with ethyl acetate. The extract was _washed once each with water and brine, dried over _Na2SO4 , filtered and concentrated. The residue was purified by chromatography to afford 1-(4-chloro-3-methoxymethyl-phenyl)-piperazine as a low melting solid.

1-(4-Chloro-3-methoxy-phenyl)-2-(R)-methyl-piperazine:

2 g (0.02 mol) R-(-)-2-methylpiperazine, 2.5 g (0.0197 mol) benzyl chloride and 5 g (0.0599 mol) sodium bicarbonate were heated in 25 mL ethanol at 85° C. for 12 hours. After cooling, the reaction was filtered through filter paper and the ethanol was removed in vacuo. The residue was purified by chromatography to afford 1-benzyl-3-(R)-methyl-piperazine as a yellow liquid.

1.2g (0.0054mol) 5-bromo-2-chloroanisole, 1g (0.0054mol) 1-benzyl-3-(R)-methyl-piperazine, 0.06g (0.00027mol) palladium acetate, 0.34 g (0.00054 mol) BINAP and 0.83 g (0.0086 mol) sodium tert-butoxide were heated in anhydrous toluene (5 mL) at 110°C for 48 hours. After cooling, the reaction mixture was quenched with water and extracted with ethyl acetate. The ethyl acetate phase was washed with water and _brine , dried over _Na2SO4 , filtered and concentrated. The residue was purified by chromatography to afford 4-benzyl-1-(4-chloro-3-methoxy-phenyl)-2-(R)-methyl-piperazine as a yellow semisolid.

0.3 g (0.00091 mol, 1 eq) of 4-benzoyl-1-(4-chloro-3-methoxy-phenyl)-2-(R )-methyl-piperazine was cooled to 0 °C. 0.16 g (0.0011 mol) of 1-chloroethyl chloroformate was added dropwise, and the resulting mixture was stirred at 0° C. for 15 minutes. The mixture was then heated at 70°C for 1 hour, after which 1,2-dichloroethane was removed under vacuum. The residue was dissolved in 30 mL methanol and heated at 65°C for 1 hour. Methanol was removed in vacuo, the residue was dissolved in 10 mL of water, and the solution was washed twice with ether. The aqueous phase was basified with solid sodium bicarbonate to pH >9 and extracted with dichloromethane. The dichloromethane phase was _washed with brine, dried over _Na2SO4 , filtered, and concentrated to give 1-(4-chloro-3-methoxy-phenyl)-2-(R)- as a low melting solid. Methyl-piperazine.

1-(4-Chloro-3-methoxy-phenyl)-2-(S)-methyl-piperazine:

This compound follows the same procedure used to synthesize 1-(4-chloro-3-methoxy-phenyl)-2-(R)-methyl-piperazine, using 2-(S)-(+)-methyl Preparation of phenyl-piperazine as starting material afforded the title compound as a light yellow semi-solid.

Synthesis of 2-(R)-benzyloxymethyl-1-(4-chloro-3-methoxy-phenyl)-piperazine:

According to protocol A, 818 mg (3.70 mmol) 5-bromo-2-chloroanisole, 1.15 g (3.88 mmol) 1-benzyl-3-(R)-benzyloxymethyl-piperazine, 0.50 g ( 5.18 mmol) sodium tert-butoxide, 33 mg (0.037 mmol) tris-dibenzylideneacetone-dipalladium(0) and 66 mg (0.11 mmol) rac-Binap were heated in 2 mL of anhydrous toluene at 85°C for 6 hours. The mixture was cooled to room temperature and partitioned between ethyl acetate and water. The phases were separated and the ethyl acetate phase was washed with brine, dried over _Na2SO4 , filtered and concentrated _. The residue was chromatographed to give 4-benzyl-2-(R)-benzyloxymethyl-1-(4-chloro-3-methoxy-phenyl)-piperazine.

1.05 g (2.40 mmol) of 4-benzyl-2-(R)-benzyloxymethyl-1-(4-chloro-3-methoxy-phenyl)-piperidine in 50 mL of dichloromethane The oxazine was cooled to 0°C, and 406 mg (2.88 mmol) of 1-chloroethyl chloroformate was added. After 30 minutes, the mixture was allowed to warm to ambient temperature and heated at 75°C for 3 hours in a sealed vessel. Then, the solution was concentrated in vacuo, the residue was dissolved in 30 mL of methanol, and the solution was heated at 60° C. for 2 hours. The solution was concentrated in vacuo and the residue was partitioned between ethyl acetate and 1M NaOH. _The phases were separated and the ethyl acetate phase was washed with brine, dried over _Na2SO4 , filtered and concentrated to give 2-(R)-benzyloxymethyl-1-(4-chloro-3-methoxy- phenyl)-piperazine.

Synthesis of [4-(4-chloro-3-methoxy-phenyl)-piperazin-2-(S)-yl]-methanol:

Following protocol A, 1.41 g (6.34 mmol) 5-bromo-2-chloroanisole, 2.04 g (6.66 mmol) N ¹ -Boc-2-(R)-benzyloxymethyl-piperazine, 0.85 g ( 8.86 mmol) sodium tert-butoxide, 28 mg (0.032 mmol) tris-dibenzylideneacetone-dipalladium(0) and 58 mg (0.095 mmol) rac-Binap were heated in 3 mL of anhydrous toluene at 90° C. for 6 hours. The mixture was cooled to room temperature and partitioned between ethyl acetate and water. The phases were separated and the ethyl acetate phase was washed with brine, dried over _Na2SO4 , filtered and concentrated _. The residue was chromatographed to give a white foam.

The material purified from above was heated in 25 mL of 48% HBr in acetic acid at 75°C for 1 hour. The reaction was cooled to room temperature, partitioned between ether and water. The phases were separated and the aqueous phase was basified with solid K2CO3 to pH>10 and extracted twice with ethyl acetate. The combined ethyl acetate phases were washed with brine, dried over _{Na2SO4 ,} filtered and concentrated to give [4-(4-chloro-3-methoxy-phenyl)-piperazine-2-( S)-yl]-methanol.

Synthesis of 1-(4-chloro-2-fluoro-5-methoxy-phenyl)-piperazine:

5.0 g (34.1 mmol) of 2-chloro-4-fluorophenol in 75 mL of 10% sodium hydroxide was cooled to 0° C., and 4.0 g (42.6 mmol) of methyl chloroformate were added. After 45 minutes, the solid was removed by filtration to obtain 2-chloro-4-fluoro-phenyl-methyl carbonate.

To 6.0 g (29.3 mmol) of 2-chloro-4-fluoro-phenyl-methyl carbonate in 3 mL of concentrated sulfuric acid was added 6 mL of the nitration mixture at 0°C. After 45 minutes, the reaction was quenched with ice-water and the solid was isolated by filtration to give 2-chloro-4-fluoro-5-nitrophenylmethyl carbonate.

To 7.0 g (28.0 mmol) of 2-chloro-4-fluoro-5-nitrophenyl ester methyl carbonate in 100 mL of methanol was added 75 mL of 0.5M NaOH at 0 °C. After 1 hour, methanol was removed in vacuo, the solution was acidified with 1.5M HCl, and extracted with ethyl acetate. The ethyl acetate phase was washed with water and brine, and concentrated to give 2-chloro-4-fluoro-5-nitrophenol.

To 5.6 g (29.2 mmol) of 2-chloro-4-fluoro-5-nitrophenol in 250 mL of dry acetone was added 21 g (146 mmol) of methyl iodide and 20 g (146 mmol) of potassium carbonate, and the mixture was heated at 55°C for 3 hours , acetone was removed in vacuo and the residue was partitioned between ethyl acetate and water. The phases were separated and the ethyl acetate phase was washed with brine and concentrated to give 2-chloro-4-fluoro-5-nitro-anisole.

To 4.5 g (22.2 mmol) of 2-chloro-4-fluoro-5-nitro-anisole in 75 mL of methanol was added 6 g (11 mmol) of iron powder, the mixture was heated to 50 °C, and 10 g (175 mmol) of ammonium chloride was added 150mL aqueous solution. Reheat the reaction to 70°C and stir for 12 hours. The mixture was cooled to room temperature, filtered through Celite, and the filtrate was concentrated in vacuo. The residue was partitioned between ethyl acetate and water and the phases were separated. The ethyl acetate phase was washed with brine and concentrated to give 4-chloro-2-fluoro-5-methoxy-aniline.

3.0 g (17.1 mmol) of 4-chloro-2-fluoro-5-methoxy-aniline in 23 mL of hydrobromic acid and 23 mL of water was cooled to 0°C. To this solution was added 1.5 g (21.4 mmol) of sodium nitrite in 2 mL of aqueous solution. Add 9 g (36 mmol) of copper bromide in 30 mL of 50% hydrobromic acid. After the addition, the mixture was heated at 55°C for 1 hour. The mixture was cooled and extracted with ethyl acetate. The ethyl acetate phase was washed once each with water and brine, and concentrated to give 5-bromo-2-chloro-4-fluoroanisole.

1.0 g (4.2 mmol) 5-bromo-2-chloro-4-fluoroanisole, 47 mg (0.21 mmol) palladium acetate, 180 mg (0.29 mmol) binap, 0.65 g (6.7 mmol) sodium tert-butoxide and 3.6 g ( 42 mmol) of piperazine was heated in 3 mL of anhydrous toluene at 110° C. for 24 hours. The reaction was partitioned between ethyl acetate and water and the phases were separated. The ethyl acetate phase was washed once each with water and brine and concentrated. The residue was purified by chromatography to afford 1-(4-chloro-2-fluoro-5-methoxy-phenyl)-piperazine.

Synthesis of 1-(4-chloro-3-methoxy-phenyl)-3-methoxymethyl-piperazine:

0°C, to 1.26g (4.90mmol) [4-(4-chloro-3-methoxy-phenyl)-piperazine-2-(S )-yl]-methanol and 779 mg (6.37 mmol) of 2,4,6-collidine were added to 1.18 g (5.40 mmol) of di-tert-butyl dicarbonate. After 2 hours, the reaction was allowed to warm to ambient temperature and stirred for an additional 14 hours. The reaction was partitioned between water and ethyl acetate and the phases were separated. The ethyl acetate phase was washed once each with 1M _NaHSO4 , water, brine, dried over _Na2SO4 , filtered, and concentrated to give 4-(4-chloro-3-methoxy-phenyl)-2- (R)-Hydroxymethyl-piperazine-1-carboxylic acid tert-butyl ester, the product solidified on standing.

0°C, to 122 mg (0.34 mmol) 4-(4-chloro-3-methoxy-phenyl)-2-(R)-hydroxymethyl- tert-Butyl piperazine-1-carboxylate and 57 mg (0.41 mmol) methyl iodide were added to 20 mg (0.48 mmol) 60% sodium hydride in oil. The reaction was allowed to warm to ambient temperature over 10 minutes and after 1 hour the reaction was quenched with water. The mixture was extracted with ethyl acetate and the phases were separated. The ethyl acetate _phase was washed with brine, dried over _Na2SO4 , filtered, and concentrated to give 4-(4-chloro-3-methoxy-phenyl)-2-methoxymethyl- tert-Butyl piperazine-1-carboxylate.

The above oil was dissolved in 1 mL of ethyl acetate and 1 mL of 5M HCl in isopropanol. After 10 hours, the solution was concentrated and the residue was partitioned between 1M NaOH and ethyl acetate. The phases were separated and the ethyl acetate phase was washed with _brine , dried over _Na2SO4 , filtered and concentrated to give 1-(4-chloro-3-methoxy-phenyl)-3-methoxymethyl- Piperazine.

Synthesis of (-)-ol 4-(4-chloro-3-methoxy-phenyl)-piperazine-2-carboxylate:

8.75g (43.4mmol) of 2-piperazinecarboxylic acid and 16.4g (195mmol) of sodium bicarbonate were dissolved in 140mL of water, 140mL of acetonitrile was added, and the mixture was cooled to 0°C. To this solution was added 20.9 g (95.4 mmol) of di-tert-butyl dicarbonate and after 2 hours the mixture was allowed to warm to ambient temperature. After stirring for 12 hours, the mixture was concentrated in vacuo to remove acetonitrile and the mixture was washed with ether. The aqueous solution was acidified with 1M NaHSO4 and extracted with ethyl acetate. The ethyl acetate phase was washed with brine, dried over _Na2SO4 , filtered, and concentrated to give 1,4 _- di-tert-butyl piperazine-1,2,4-tricarboxylate.

13g (39mmol) piperazine-1,2,4-tricarboxylic acid 1,4-di-tert-butyl ester, 13.4g (86mmol) (-)--alcohol and 940mg (7.8mmol) 4-N,N-di A solution of methylamino-pyridine in 200 mL of dichloromethane was cooled to 0° C., and 8.90 g (47 mmol) of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride was added. After 2 hours the solution was allowed to warm to ambient temperature and stirred for an additional 12 hours. The reaction was concentrated in vacuo, the residue was partitioned between ether and water and the phases were separated. The organic phase was washed once each with 1M NaHSO ₄ and brine, dried over Na ₂ SO ₄ , filtered, and concentrated to give a semi-solid.

The semi-solid obtained above was dissolved in 300 mL ethyl acetate, 100 mL dichloromethane and 100 mL 5M HCl in isopropanol. After 20 hours, the solid was isolated by filtration to give piperazine-2-carboxylate 2-(-)-ol dihydrochloride.

1.36g (4.0mmol) piperazine-2 carboxylic acid 2-(-)-_alcohol ester, 803mg (3.63mmol) 5-bromo-2-chloroanisole, 1.09g (11.4mmol) sodium tert-butoxide , 62 mg (0.10 mmol) rac-Binap and 30 mg (0.034 mmol) tris-dibenzylideneacetone dipalladium(0) were slurried in 5 mL toluene, and the mixture was heated at 80° C. for 12 hours. The reaction was partitioned between ethyl acetate and water and the phases were separated. The ethyl acetate phase was washed _once each with water and brine, dried over _Na2SO4 , filtered and concentrated. The residue was chromatographed to give (-)-ol-4-(4-chloro-3-methoxy-phenyl)-piperazine-2-carboxylate.

Synthesis of 1-(4-chloro-3-methoxy-phenyl)-3-(S)-(2-methylsulfonyl-ethyl)-piperazine:

1.00 g (3.99 mmol) of 1-benzyl-3-(S)-(2-methylthio-ethyl)-piperazine and 81 mg (0.8 mmol) of triethylamine in 5 mL of dichloromethane were cooled to At 0°C, 1.05 g (4.79 mmol) of di-tert-butyl dicarbonate was added. After stirring for 2 hours, the solution was allowed to warm to ambient temperature and stirred for an additional 12 hours. The reaction was partitioned between ether and water and the phases were separated. The organic phase was washed with _brine , dried over _Na2SO4 , filtered, and concentrated to give 1-benzyl-3-(S)-(2-methylthio-ethyl)-4-tert-butyl as an oil Oxycarbonylpiperazine.

Dissolve 608 mg (1.74 mmol) of 1-benzyl-3-(S)-(2-methylthio-ethyl)-4-tert-butoxycarbonylpiperazine in 8 mL of dichloromethane, and cool the solution to 0 ℃. To this was added 899 mg (5.21 mmol) m-chloroperbenzoic acid and the mixture was allowed to warm to ambient temperature within 1 hour. The reaction was partitioned between ethyl acetate and water and the phases were separated. The organic phase was _washed with 1M NaOH and brine, dried over _Na2SO4 , filtered, and concentrated to give 1-benzyl-3-(S)-(2-methylsulfonyl-ethyl)- 4-tert-butoxycarbonylpiperazine.

180 mg (0.47 mmol) of 1-benzyl-3-(S)-(2-methylsulfonyl-ethyl)-4-tert-butoxycarbonylpiperazine in 2.5 mL of methanol purged with nitrogen, added 20 mg of 20% carbon-supported Pd(OH)2, and the mixture was stirred for 30 hours under a hydrogen atmosphere. The mixture was purged with nitrogen, filtered through celite, and concentrated to give 3-(S)-(2-methylsulfonyl-ethyl)-4-tert-butoxycarbonylpiperazine as an oil.

96mg (0.33mmol) 3-(S)-(2-methylsulfonyl-ethyl)-4-tert-butoxycarbonylpiperazine, 73mg (0.33mmol) 5-bromo-2-chloroanisole, 6mg (0.01mmol) rac-Binap, 3mg (0.003mmol) tris-benzylideneacetone dipalladium (O) and 44mg (0.46mmol) sodium tert-butoxide were slurried in 0.6mL toluene, and the mixture was heated at 85°C for 8 Hour. The reaction was partitioned between ethyl acetate and water and the phases were separated. The ethyl acetate phase was washed _once each with water and brine, dried over _Na2SO4 , filtered and concentrated. The residue was chromatographed to give tert-butyl 4-(4-chloro-3-methoxy-phenyl)-2-(S)-(2-methanesulfonyl-ethyl)-piperazine-1-carboxylate ester.

30 mg (0.07 mmol) tert-butyl 4-(4-chloro-3-methoxy-phenyl)-2-(S)-(2-methylsulfonyl-ethyl)-piperazine-1-carboxylate Dissolve in 1 mL of ethyl acetate and add 0.5 mL of 5M HCl in isopropanol. After 20 hours, the solid was isolated by filtration to give 1-(4-chloro-3-methoxy-phenyl)-3-(S)-(2-methanesulfonyl-ethyl)-piperene as the hydrochloride salt Zinc.

Synthesis of 1-(4-chloro-3-methylthio-phenyl)-piperazine:

Potassium carbonate (0.5 g, 0.0087 mol) was added to 5-bromo-2-chlorophenol (1.7 g, 0.0087 mol) in 9 mL of water, and the mixture was stirred for 15 minutes, then cooled to 10°C. N,N-Dimethylthiocarbamoyl chloride (1.4 g, 0.0117 mol) in 3 mL THF was added and the reaction was allowed to warm to ambient temperature and stir for 2 hours. The mixture was extracted with ethyl acetate, washed once each with water and brine, and concentrated to afford O-(5-bromo-2-chlorophenyl)dimethylthiocarbamate as a yellow solid.

O-(5-bromo-2-chlorophenyl)dimethylthiocarbamate (1.8 g, 0.0061 mol) in 60 mL of diphenyl ether was heated to 260° C. in a sand bath for 15 hours. The reaction was cooled to ambient temperature and added directly to the silica bed. The column was eluted with petroleum ether to give S-(5-bromo-2-chlorophenyl) dimethylthiocarbamate as a solid.

To S-(5-bromo-2-chlorophenyl) dimethylthiocarbamate (0.5 g, 0.0022 mol) in 10 mL of ethylene glycol was added potassium hydroxide (0.19 g, 0.0033 mol) in 3 mL of water . The reaction was heated to 150°C for 4 hours. The reaction was cooled to room temperature, quenched with water, and extracted with ethyl acetate. The ethyl acetate phase was washed once each with water and brine, and concentrated to give 5-bromo-2-chlorobenzenethiol as a beige solid.

5-Bromo-2-chlorobenzenethiol (0.34 g, 0.0015 mol), methyl iodide (1.1 g, 0.5 mL, 0.0075 mol) and anhydrous potassium carbonate (0.64 g, 0.0045 mol) were heated in 15 mL of dry acetone to 50°C for 9 hours. The solvent was removed in vacuo, the residue was dissolved in ethyl acetate, washed once each with water and brine, and concentrated to give 5-bromo-2-chlorothioanisole as a yellow liquid.

In an argon atmosphere, 5-bromo-2-chlorothioanisole (0.3g, 0.0012mol), piperazine (1.0g, 0.012mol), palladium acetate (0.015g, 0.00006mol), BINAP (0.075g, 0.00012 mol) and sodium tert-butoxide (0.17 g, 0.0018 mol) were heated in 5 mL of anhydrous toluene to 110° C. for 18 hours. The reaction mixture was cooled to room temperature, quenched with water, and extracted with ethyl acetate. The ethyl acetate phase was washed once each with water and brine, and concentrated to a residue. The residue was purified by column chromatography using 2% methanol in chloroform to give 1-(4-chloro-3-methylthio-phenyl)-piperazine as a low melting solid.

5-Chloro-4-methoxy-2-piperazin-1-yl-phenylamine:

Dissolve 17.5g (0.09943mol) of 2,5-dichloroanisole in 4mL of concentrated sulfuric acid, cool the solution to 0°C, and add 18mL of the nitration mixture (add 9mL of concentrated sulfuric acid to 9mL of nitric acid at 0°C). The reaction was allowed to warm to ambient temperature and stirred for 2 hours. The solid was isolated by filtration and washed with petroleum ether to give 2,5-dichloro-4-nitroanisole.

5g (0.0225mol) 2,5-dichloro-4-nitroanisole, 8.3g (0.0450mol) mono-boc piperazine, 7.7g (0.056mol) anhydrous potassium carbonate and 0.2g TBAI in 100mL anhydrous Heat in DMSO at 120°C for 10 hours. After cooling, the reaction mixture was quenched with water and extracted with ethyl acetate. The ethyl acetate phase was washed with water and brine, and concentrated. The residue was purified by chromatography to afford tert-butyl 4-(4-chloro-5-methoxy-2-nitro-phenyl)-piperazine-1-carboxylate.

5.3g (0.0142mol) 4-(4-chloro-5-methoxy-2-nitro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester and 5.4mL (0.07mol ) trifluoroacetic acid overnight. The reaction mixture was basified with 1M NaOH and extracted with dichloromethane. The dichloromethane phase was washed with water and _brine , dried over _Na2SO4 and concentrated to give 4-(4-chloro-5-methoxy-2-nitro-phenyl)-piperazine.

Add 0.4 g of 10% palladium acetate to 3.5 g (0.012 mol) of 4-(4-chloro-5-methoxy-2-nitro-phenyl)-piperazine in 25 mL of methanol and stir at 1 atmosphere The mixture was left for 15 minutes. The reaction mixture was filtered through celite and concentrated. The residue was purified by column chromatography to give 5-chloro-4-methoxy-2-piperazin-1-yl-phenylamine.

Synthesis of 1-(4-oxazol-5-yl-phenyl)-piperazine:

To 4-bromobenzaldehyde (1.0 g, 0.0054 mol) in 20 mL of dry methanol was added TOSMIC reagent (1.2 g, 0.0059 mol) followed by anhydrous potassium carbonate (0.8 g, 0.0058 mol). The reaction mixture was heated to 65°C for 2 hours. The reaction mixture was dissolved in ethyl acetate, washed once each with water and brine, and concentrated. The residue was purified by column chromatography using 10% ethyl acetate in petroleum ether to afford 4-bromo-oxazol-5-yl-benzene.

In an argon atmosphere, 4-bromo-oxazol-5-yl-benzene (0.5g, 0.0023mol), piperazine (1.9g, 0.022mol), palladium acetate (0.026g, 0.00011mol), BINAP (0.14g, 0.00023 mol) and sodium tert-butoxide (0.35 g, 0.0037 mol) were heated in 5 mL of anhydrous toluene to 110° C. for 18 hours. The reaction mixture was cooled to room temperature, quenched with water, and extracted with ethyl acetate. The ethyl acetate phase was washed once each with water and brine and concentrated. The residue was purified by column chromatography using 2% methanol in chloroform to afford 1-(4-oxazol-5-yl-phenyl)-piperazine as a yellow solid.

Scheme G1: General method for the synthesis of aryl bromides from anilines

Synthesis of 4-chloro-2-fluoro-1-bromobenzene

At -10°C bath temperature, sodium nitrite (2.35g, 34.13mmol) solution (40mL) was added dropwise to 4-chloro-2-fluoroaniline (4.5g, 31mmol) in 170mL HBr, and the mixture was stirred at the same temperature Mixture for 30 minutes. Simultaneously, copper sulfate (10.22 g, 24.29 mmol) and sodium bromide (3.79 g, 36.8 mmol) were mixed and the reaction mixture was heated at 60° C. for 30 minutes. Sodium sulfite (2.66 g, 21.2 mmol) was added to the copper sulfate reaction mixture, followed by heating at 95° C. for 30 minutes. The reaction mixture was cooled to room temperature and the solid formed was washed with water to give cuprous bromide as a white solid. The diazonium salt was added portionwise to freshly prepared cuprous bromide in 40 mL of HBr at -10 °C bath temperature, and the reaction mixture was warmed to room temperature. The reaction mixture was heated at 55°C for 20 minutes, cooled and extracted three times with ethyl acetate. The combined organic layers were washed with water and saturated saline solution, dried over sodium sulfate, and concentrated. The crude was purified by column chromatography (5:95 ethyl acetate:petroleum ether) to provide the product as a solid.

Synthesis of (2-bromo-5-chloro-phenyl)-phenyl-methanone

Sodium nitrite (2.5g, 36.28mmol) solution (40mL) was added dropwise to aniline (7g, 30.2mmol) in 100mL HBr at -10°C bath temperature, and the mixture was stirred at the same temperature for 30 minutes to prepare diazo Salt.

Copper sulfate (10.22 g, 24.29 mmol) and sodium bromide (3.79 g, 36.8 mmol) were heated at 60°C for 30 minutes. Then, sodium sulfite (2.66 g, 21.2 mmol) was added to the copper sulfate reaction mixture and heated at 95°C for 30 minutes. The reaction mixture was then cooled to room temperature and the solid formed was washed with water to provide cuprous bromide as a white solid.

The diazonium salt was added portionwise to freshly prepared cuprous bromide in 40 mL of HBr at a bath temperature of -10 °C, and the reaction mixture was warmed to room temperature. Then, the reaction mixture was heated at 55°C for 20 minutes, cooled to room temperature, and extracted three times with ethyl acetate. The combined organic layers were washed with water and saturated saline solution, dried over sodium sulfate, and concentrated. The product was purified by crystallization from DCM/petroleum ether.

Scheme G2: Other examples of ring-like systems constructed using a similar Sandmeyer-type approach

These aforementioned aryl bromides and similar substrates can be used in the various chemistries already described to obtain those arylpiperazines listed below.

Synthesis of Heteroaromatic Ring Systems: Formation of Core Ring Structures

Listed below are chemistries that can be applied to the synthesis of key heteroaryl ring structures. They can be divided into examples of ring formation and ring functionalization reactions.

Scheme H: Synthesis of pyrazoles via addition of hydrazine to α,β-ethynyl ketones

Synthesis of 5-Butyl-3-trifluoromethyl-1H-pyrazole

To 1-hexyne (3.37 mL, 29.4 mmol) in THF (30 mL) was added n-BuLi (2.78M, 10.2 mL, 29.4 mmol). The solution was stirred at -78°C for 30 min, then CF ₃ CO ₂ Et (3.5 mL, 29.35 mL) and BF ₃ -OEt ₂ were added sequentially. The reaction was stirred at -78°C for an additional 2 hours and quenched with saturated _NH4Cl . Then warm to room temperature. THF was removed, the residue was _dissolved in ether, washed with saturated brine solution, dried over _Na2SO4 and reduced. The crude product was dissolved in benzene (25 mL), and hydrazine (29.4 mmol) was added. The reaction mixture was refluxed overnight, then cooled, the solvent was evaporated, _the residue was dissolved in _CH2Cl2 (30 mL), _washed with brine, dried over _Na2SO4 , and concentrated to give the title compound as a colorless oil.

Synthesis of 5-isopropyl-3-trifluoromethyl-1H-pyrazole.

Following Protocol H, 3 _- methylbutyne was treated with n-BuLi, _CF3CO2Et and _BF3 - _OEt2 in THF. Reaction with hydrazine in benzene under similar reaction conditions yields the title compound.

Synthesis of 5-Propyl-3-trifluoromethyl-1H-pyrazole.

Following Protocol _H , 1-pentyne was treated with n-BuLi, _CF3CO2Et and _{BF3- OEt2} in THF. Reaction with hydrazine in benzene under similar reaction conditions gave the title compound.

Synthesis of 5-(3-fluorophenyl)-3-trifluoromethyl-1H-pyrazole.

Following Protocol H, 1 _- ethynyl-3-fluoro-benzene was treated with n-BuLi, _CF3CO2Et and _{BF3- OEt2} in THF. Reaction with hydrazine in benzene under similar reaction conditions gave the title compound.

Other pyrazoles synthesized by this method:

Scheme I: Conventional method for the synthesis of pyrazoles by condensation of hydrazines with β-diketones:

Synthesis of 5-ethyl-3-trifluoromethyl-1H-pyrazole

To a solution of 1,1,1-trifluoro-hexane-2,4-dione (1 g, 5.95 mmol) in absolute ethanol (10 mL) was added NH ₂ NH ₂ .xH ₂ O dropwise at 0°C. The reaction mixture was warmed to room temperature over 1 hour and refluxed overnight. Then ethanol was evaporated, the residue was dissolved in ethyl acetate ₍ 20 mL), washed sequentially with saturated brine solution and water, dried over _Na2SO4 , and concentrated to give the title compound as a colorless oil.

Synthesis of 4-chloro-3-methyl-5-thiophen-2-yl-pyrazole:

To a solution of 2-acetyl-thiophene (5 g, 0.04 mol) in 200 mL THF at -78°C was added 24.5 mL of NaHMDS (0.05 mol) in hexane. After the addition was complete, the reaction was maintained at this temperature for 1 hour. Acetyl chloride (3.4 g, 0.04 mol) was then added dropwise and the reaction mixture was allowed to warm to ambient temperature and stirring was continued for 2 hours. The reaction was quenched with saturated _NH4Cl solution and the THF was removed in vacuo. The aqueous mixture was extracted with ethyl acetate and the phases were separated. _The ethyl acetate layer was washed once each with water and brine, dried over _Na2SO4 , filtered and concentrated. The residue was purified by column chromatography to give the diketone.

The above diketone (1.6 g, 9.5 mmol) was dissolved in ethanol (60 mL) and cooled to 0°C. Hydrazine hydrate (0.6 g, 11.4 mmol) was added dropwise to the solution with stirring. After the addition was complete, the mixture was refluxed overnight. Ethanol was evaporated in vacuo and the residue was dissolved in ethyl acetate. The solution was washed once each with water and _brine , dried over _Na2SO4 , filtered, and concentrated to give 3-methyl-5-thiophen-2-yl-pyrazole.

3-Methyl-5-thiophen-2-yl-pyrazole (1.4 g, 8.5 mmol) was dissolved in 50 mL of chloroform, and N-chlorosuccinimide (1.6 g, 11.9 mmol) was added. The mixture was stirred overnight at ambient temperature. The solution was washed with _brine , dried over _Na2SO4 , filtered and concentrated in vacuo. The residue was purified by chromatography to afford 4-chloro-3-methyl-5-thiophen-2-yl-pyrazole.

Scheme J: Synthesis of pyrazoles via condensation of hydrazines with β-cyanoketones

Synthesis of 5-phenyl-1-pyrazol-3-amine

To 2.0 g (0.0138 mol, 1 eq) of benzoylacetonitrile in 40 mL of absolute ethanol was added 2.0 g (0.0399 mol, 3 eq) of anhydrous hydrazine, and the reaction mixture was stirred at 85°C for 2 hours. Ethanol was removed under vacuum at 50°C. 5-Phenyl-1-pyrazol-3-amine was obtained as a yellow solid, which was washed with petroleum ether (100 mL) and dried in vacuo.

Synthesis of functionalized heteroaromatic ring systems

Chlorination or bromination of pyrazoles

Protocol K: Chlorination of Pyrazoles with NaOCl in Glacial Acetic Acid

Synthesis of 4-chloro-1H-pyrazole.

To a solution of pyrazole (0.5 g, 7.34 mmol) in glacial acetic acid (4 mL) was added NaOCl (0.55 g, 7.34 mmol). The reaction mixture was kept _at room temperature for 18 h, then neutralized with saturated _Na2CO3 solution, extracted with _CH2Cl2 (2 x 25 mL), the combined organic layers were evaporated, then diluted with _NaOH , and _washed with _CH2Cl2 ( 3×20mL) extraction. The organic extracts were combined, dried over _Na2SO4 and evaporated to give the title compound as a white solid _. Synthesis of 4-chloro-3-trifluoromethyl-1H-pyrazole

Following Scheme K, 3-trifluoromethylpyrazole was treated with glacial acetic acid and NaOCl to yield the title compound.

Synthesis of 4-chloro-3-methyl-1H-pyrazole

Following Protocol K, 3-methylpyrazole was treated with glacial acetic acid and NaOCl to yield the title compound.

Synthesis of ethyl 4-chloro-5-propyl-1H-pyrazole-3-carboxylate

Following Scheme K, ethyl 5-propyl-1H-pyrazole-3-carboxylate was treated with glacial acetic acid and NaOCl under similar reaction conditions to yield the title compound.

Scheme L: Chlorination or bromination of pyrazole with N-chlorosuccinimide (NCS) or N-bromosuccinimide (NBS):

Synthesis of 4-chloro-3-methyl-5-trifluoromethyl-1H-pyrazole

3-Methyl-5-trifluoromethylpyrazole or 3,5-bis(trifluoromethyl)pyrazole was added to anhydrous DMF (20 mL), and N-chlorosuccinimide (1.78 g ). The mixture was then heated at 70°C for 22 hours, cooled to room temperature, then water (100 mL) was added, and the mixture was extracted with ethyl acetate (4 x 25 mL). The organic layer was washed _with water and brine, dried over _Na2SO4 . Evaporation of the solvent provided the title compound.

Other halogenated pyrazoles prepared using Scheme L

Synthesis of 4-chloro-5-(4-fluoro-phenyl)-3-trifluoromethyl-1H-pyrazole:

Following Scheme L, 5-(4-fluorophenyl)-3-trifluoromethyl-1-H-pyrazole was treated with NCS in acetonitrile to yield the title compound.

Synthesis of 4-chloro-5-(4-methoxy-phenyl)-3-trifluoromethyl-1H-pyrazole:

Following Protocol L, 5-(4-methoxyphenyl)-3-trifluoromethyl-1-H-pyrazole was treated with NCS in acetonitrile to yield the title compound.

Synthesis of 4-chloro-5-(4-trifluoromethyl-phenyl)-3-trifluoromethyl-1H-pyrazole:

Following Scheme L, 5-(4-trifluoromethyl-phenyl)-3-trifluoromethyl-1-H-pyrazole was treated with NCS in acetonitrile to yield the title compound.

Synthesis of 4-chloro-5-(2-fluoro-phenyl)-3-trifluoromethyl-1H-pyrazole:

Following Scheme L, 5-(2-fluoro-phenyl)-3-trifluoromethyl-1-H-pyrazole was treated with NCS in acetonitrile to yield the title compound.

Synthesis of (4-chloro-5-trifluoromethyl-2H-pyrazol-3-yl)-methanol:

Following Protocol L, (5-trifluoromethyl-2H-pyrazol-3-yl)-methanol was treated with NCS in acetonitrile to yield the title compound.

Synthesis of 4-chloro-5-methoxymethyl-3-trifluoromethyl-1H-pyrazole:

Following Protocol L, 5-methoxymethyl-3-trifluoromethyl-1H-pyrazole was treated with NCS in acetonitrile to yield the title compound.

Synthesis of 4-chloro-5-cyclopropyl-3-trifluoromethyl-1H-pyrazole:

Following Scheme L, 5-cyclopropyl-3-trifluoromethyl-1H-pyrazole was treated with NCS in acetonitrile to yield the title compound.

Synthesis of ethyl 4-chloro-5-thiophen-2-yl-2H-pyrazole-3-carboxylate

Pyrazole (1 eq.) in DMF (0.14M solution) was treated in portions with NCS (1.5 eq.) and heated at 70°C overnight when all NCS was dissolved in the reaction mixture. The reaction mixture was then cooled to room temperature, quenched with water, extracted with ethyl acetate, dried over _MgSO4 . Two products were isolated which contained the title compound. Synthesis of 4-chloro-3,5-diisopropyl-pyrazole

Following protocol L, to a solution of 3,5-diisopropyl-pyrazole (0.5 g, 3.57 mmol) in DMF (10 mL) was added NCS (0.72 g, 5.3 mmol) in portions with vigorous stirring. The reaction mixture was then heated at 80°C for 14 hours and the reaction was quenched with water. It was then extracted with ethyl acetate (2 x 30 mL). The combined organics were washed with brine. The combined organic extracts were dried over _Na2SO4 and finally evaporated to give _the title compound as a colorless oil.

Synthesis of 4-chloro-3-thiophen-2-yl-1H-pyrazole.

Following Protocol L, 3-thiophen-2-yl-1H-pyrazole was treated with NCS in DMF to yield the title compound.

Synthesis of 5-tert-butyl-4-chloro-3-trifluoromethyl-1H-pyrazole

Following Protocol L, 5-tert-butyl-3-trifluoromethyl-1H-pyrazole was treated with NCS in DMF to yield the title compound.

Synthesis of ethyl 4-chloro-3-methyl-1H-pyrazole-5-carboxylate

Following Protocol L, ethyl 3-methyl-2H-pyrazole-5-carboxylate was treated with NCS in DMF to yield the title compound.

Synthesis of ethyl 4-chloro-3-thiophen-2-yl-1H-pyrazole-5-carboxylate

Following Protocol L, ethyl 3-thiophen-2-yl-1H-pyrazole-5-carboxylate was treated with NCS in DMF to yield the title compound.

Synthesis of ethyl 4-chloro-5-(5-chloro-thiophen-2-yl)-2H-pyrazole-3-carboxylate

Following Protocol L, ethyl 3-thiophen-2-yl-1H-pyrazole-5-carboxylate was treated with NCS in DMF to yield the title compound.

Synthesis of 4-chloro-3-(4-fluoro-phenyl)-5-methylthio-1H-pyrazole

Following Scheme L, 3-(4-fluoro-phenyl)-5-methylthio-1H-pyrazole was treated with NCS to yield the title compound.

Synthesis of 5-butyl-4-chloro-3-trifluoromethyl-1H-pyrazole

Following Protocol L, 5-butyl-3-trifluoromethyl-1H-pyrazole was treated with NCS in DMF to yield the title compound.

Synthesis of 4-chloro-5-phenyl-1-pyrazol-3-amine

Following protocol L, to 0.5 g (0.0031 mol, 1 eq) of 5-phenyl-1-pyrazol-3-amine in 25 mL of anhydrous acetonitrile was added 0.4 g (0.0031 mol, 1 eq) of N-chlorosuccinyl in portions imine, and the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with water and brine, and concentrated. The product was purified by a 60-120 silica gel column (1% methanol in chloroform).

Synthesis of 4-bromo-5-phenyl-1-pyrazol-3-amine

Following protocol L, to 0.5 g (0.0031 mol, 1 eq) of 5-phenyl-1-pyrazol-3-amine in 25 mL of anhydrous acetonitrile was added 0.55 g (0.0031 mol, 1 eq) of N-bromosuccinide in portions amine, and the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with water and brine and concentrated. The product was purified by a 60-120 silica gel column (1% methanol in chloroform).

Synthesis of 4-chloro-5-isopropyl-3-trifluoromethylpyrazole

Following protocol L, to 3-trifluoromethyl-5-isopropyl-pyrazole (0.22 g, 1.23 mmol) in _CH3CN (10 mL) was added NCS (0.19 g, 1.43 mmol) in portions with vigorous stirring ). The reaction mixture was then heated at reflux for 14 hours, cooled, the reaction quenched with saturated NaHCO ₃ , extracted with dichloromethane (2 x 30 mL), the combined organic extracts washed with brine, dried over Na ₂ SO ₄ and evaporated to give a white The title compound as a solid. Synthesis of 4-chloro-5-ethyl-3-trifluoromethyl-1H-pyrazole

Following Scheme L, 5-ethyl-3-trifluoromethyl-1H-pyrazole was treated with NCS in _CH3CN to yield the title compound.

Synthesis of 4-chloro-5-propyl-3-trifluoromethyl-1H-pyrazole

Following Scheme L, 5-propyl-3-trifluoromethyl-1H-pyrazole was treated with NCS in _CH3CN to yield the title compound.

Synthesis of 4-chloro-5-(3-fluorophenyl)-3-trifluoromethyl-1H-pyrazole

Following Scheme L, 5-(3-fluorophenyl)-3-trifluoromethyl-1H-pyrazole was treated with NCS in _CH3CN to yield the title compound.

Synthesis of 4-chloro-3,5-bis(trifluoromethyl)-1H-pyrazole

Following Protocol L, 3,5-bis(trifluoromethyl)-1H-pyrazole was treated with NCS in _CH3CN to yield the title compound.

Synthesis of N-(4-chloro-5-methyl-1H-pyrazol-3-yl)-2,2,2-trifluoro-acetamide

Following Protocol L, 2,2,2-trifluoro-N-(5-methyl-1H-pyrazol-3-yl)-acetamide was treated with NCS in _CH3CN to yield the title compound.

Scheme M: General method for the reduction of nitropyrazoles

Synthesis of 3-heptafluoropropyl-5-methyl-1H-pyrazol-4-ylamine

To a suspension of zinc powder (1.5 g) in glacial acetic acid (10 mL) was added dropwise an ice solution of 3-heptafluoropropyl-5-methyl-4-nitro-1H-pyrazole (0.295 g, 1.0 mmol) Acetic acid (5 mL) solution. Then, the reaction mixture was stirred at room temperature for 14 hours. The zinc salt was removed by filtration, and the residue was washed with ethyl acetate. The combined organic extracts were concentrated in vacuo, redissolved in _CHCl3 , washed with _NaHCO3 , water and brine. Finally, the organic layer was dried over _Na2SO4 to give the title compound as a white solid after evaporation of the solvent.

Synthesis of bromo-pyrazoles for aryl-aryl cross-coupling reactions and for metal-involved aminations

The conventional method of trifluoroacetylation of aminopyridine:

Synthesis of 2,2,2-trifluoro-N-(5-methyl-1H-pyrazol-3-yl)-acetamide

To a solution of 3-amino-5-methylpyrazole (0.97 g, 10 mmol) and _Et3N (1.39 mL, 10 mmol) in dioxane (25 mL) was added dropwise trifluoroacetic anhydride (TFAA) at 10 °C (1.39 mL, 10 mmol). The reaction mixture was stirred at this temperature for 1 hour, then slowly warmed to room temperature over 1 hour. Upon completion of the reaction, dioxane was evaporated and the residue was dissolved in water (20 mL) and washed with dichloromethane (30 mL). The organic layer was then dried over _Na2SO4 and concentrated to give _the title compound as a white solid.

Scheme N: Functionalization of Alkyl-Substituted Heteroaryl Ring Systems: Aminomethylation

Synthesis of (5-bromomethyl-4-chloro-3-methyl-pyrazol-1-yl)-ethyl acetate

_Reagents and conditions: i) _BrCH2CO2Et / _K2CO3 / _CH3CN ; ii) NBS/ _AIBN / _CCl4

4-Chloro-3-methyl-5-trifluoromethyl-1H-pyrazole (10 g, 54 mmol) was dissolved in acetonitrile (100 mL), and potassium carbonate (30 g, 0.215 mol) was added. After stirring at room temperature for 1 hour, ethyl bromoacetate (11 g, 65 mmol) was added. After 14 hours at 70°C, the mixture was filtered and the filtrate was concentrated to obtain a crude product which could be recrystallized from petroleum ether.

This intermediate ester (5 g, 0.019 mol) was dissolved in _CCl4 (100 mL), to which was added AIBN (0.053 g, 0.33 mmol) under nitrogen. The mixture is irradiated with a conventional light bulb. The mixture was refluxed, then NBS (3.42 g, 0.019 mol) was added to the mixture in four portions at 15 minute intervals. After the addition was complete, the mixture was refluxed for 3 hours under the light. The reaction mixture was then filtered and the filtrate was washed with water and brine. The organic layer was dried (Na ₂ SO ₄ ), followed by evaporation of the solvent to provide (5-bromomethyl-4-chloro-3-trifluoromethyl-pyrazol-1-yl)-acetic acid ethyl ester.

Scheme O: Synthesis of (5-azidomethyl-4-chloro-3-trifluoromethyl-pyrazol-1-yl)-acetic acid:

To 4.6 g (13.2 mmol) (5-bromomethyl-4-chloro-3-trifluoromethyl-pyrazol-1-yl)-ethyl acetate in 40 mL dry dimethylformamide was added 1.03 g (15.8 mmol) sodium azide. After stirring for 12 hours, the solution was partitioned between ethyl acetate and water. The phases were separated, the aqueous phase _back extracted with ethyl acetate, the combined ethyl acetate phases were washed with water and brine, dried over _Na2SO4 , filtered and concentrated in vacuo to yield an orange oil.

The oil was dissolved in 25 mL THF, 25 mL 1M NaOH was added, and the mixture was vigorously stirred for 3 hours. The tetrahydrofuran was then removed in vacuo and the aqueous solution was washed once with ether. The aqueous phase was acidified with 1M HCl and extracted twice with ethyl acetate. The combined ethyl acetate phases were washed with _brine , dried over _Na2SO4 , filtered and concentrated to yield the title compound as an orange solid.

Coupling of pyrazolyl systems with carboxylic acid equivalents

The following synthesis is an example of this type of chemistry: other examples have been described above (Scheme N).

Synthesis of 4-chloro-3-methyl-5-trifluoromethylpyrazol-1-yl)-acetic acid

_Reagents and _conditions : _BrCH2CO2Et / _K2CO3 / _CH3CN , then LiOH/THF

4-Chloro-3-methyl-5-trifluoromethylpyrazole (10 g, 0.0539 mol) was dissolved in acetonitrile (100 mL), and K ₂ CO ₃ (30 g, 0.213 mol) was added thereto. The mixture was stirred at room temperature for 1 hour, and ethyl bromoacetate (11 g, 0.065 mol) was added slowly. The mixture was then stirred at 70°C for 12 hours. The mixture was filtered and the filtrate was concentrated to give a crude mixture. The crude product was recrystallized from petroleum ether to obtain the corresponding ester.

This ester (14.8 g, 0.0565 mol) was dissolved in THF (100 mL), to which was added an aqueous solution (50 mL) of LiOH (6.9 g). The mixture was stirred at room temperature for 10 hours. Excess THF was evaporated under reduced pressure and the aqueous layer was washed with ethyl acetate to remove any unhydrolyzed material. The aqueous layer was acidified with 1.5N HCl and extracted with ethyl acetate. The ethyl acetate layer was dried and concentrated to obtain crude acid. Recrystallization from ether/petroleum ether afforded the product as a white solid.

Scheme P: Coupling of arylpiperazines with pyrazolyl-acetic acid derivatives - compounds prepared by HATU-involved couplings:

Synthesis of 2-(5-azidomethyl-4-chloro-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(4-chlorophenyl)-piperazin-1-yl] - ethyl ketone:

To 2.71g (13.7mmol) 1-(4-chlorophenyl)piperazine and 3.58g (12.5mmol) (5-azidomethyl-4-chloro-3- Trifluoromethyl-pyrazol-1-yl)-acetic acid was added with 4.36 mL (31.2 mmol) of triethylamine. The solution was cooled to 0°C, and 5.21g (13.7mmol) of hexafluorophosphate O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea ( HATU). After 2 hours, the reaction was diluted with 2 volumes of water and the solvent was decanted from the resulting oil. The oil was dissolved in methanol and a small amount of water was added to crystallize the oil. The product was isolated as a white solid by filtration: ¹ H NMR (DMSO-d6, 400 MHz) 7.23 (d, 2H), 6.97 (d, 2H), 5.48 (s, 2H), 4.62 (s, 2H), 3.60 (m , 4H), 3.24 (m, 2H), 3.12 (m, 2H) ppm; MS (ES) M+H expected = 462.1, found = 462.0.

Synthesis of 2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(2,5-dimethyl-phenyl)-piperazine-1 -yl]-ethanone

To 38 mg (0.20 mmol) 1-(2,5-dimethylphenyl) piperazine and 53 mg (0.22 mmol) (4-chloro-5-methyl-3 -trifluoromethyl-pyrazol-1-yl)-acetic acid was added 62 mg (0.6 mmol) triethylamine, followed by 84 mg (0.22 mmol) hexafluorophosphate O-(7-azabenzotriazole-1- base)-N,N,N',N'-tetramethylurea (HATU). After 6 hours, the reaction was partitioned between ethyl acetate and water and the phases were separated. The aqueous phase was back-extracted once with ethyl acetate, and the combined ethyl acetate phases were washed once each with 0.5M phosphate buffer at pH=7, water, 1M NaOH, water, and brine. The ethyl acetate phase was then dried over _Na2SO4 , filtered, and concentrated in vacuo to a residue _. The residue was dissolved in a small amount of 5M HCl in isopropanol and precipitated by diluting the solution with ethyl acetate. The product was isolated by filtration as a white solid: ¹ H NMR (DMSO-d 6400 MHz) 7.07 (d, 1H), 6.90 (s, 1H), 6.82 (d, 1H), 5.39 (s, 2H), 3.66 (m, 4H ), 2.98(m, 2H), 2.89(m, 2H), 2.26(s, 3H), 2.24(s, 3H), 2.20(s, 3H) ppm; MS(ES) M+H expected value = 415.1, Found as 415.1.

Examples of additional compounds prepared by HATU-involved couplings:

Synthesis of 2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(3-methoxy-phenyl)-piperazin-1-yl ]-Ethanone:

The title compound was prepared according to Scheme P using 1-(3-methoxyphenyl)piperazine and (4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid as The components were coupled to give the product as a white solid: ¹ H NMR (DMSO-d6, 400 MHz) 7.15 (t, 1H), 6.65 (d, 1H), 6.60 (s, 1H), 6.47 (d, 1H), 5.38 (s, 2H), 3.72 (s, 3H), 3.65 (m, 4H), 3.28 (m, 2H), 3.19 (m, 2H), 2.18 (s, 3H) ppm; MS(ES) M+H expected Value = 417.1, found value = 417.1.

Synthesis of 2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(4-chloro-phenyl)-2-(R)-methyl -piperazin-1-yl]-ethanone:

The title compound was prepared according to coupling scheme P involving HATU using 1-(4-chlorophenyl)-3-(R)-methylpiperazine and (4-chloro-5-methyl-3-trifluoro Methyl-pyrazol-1-yl)-acetic acid as coupling component afforded the product as a white solid: ¹ H NMR (CDCl ₃ , 300 MHz) 7.25 (d, 2H), 6.83 (d, 2H), 4.91 (m ,3H), 4.28(m,1H), 3.80-3.10(m,4H), 2.86(m,1H), 2.71(m,1H), 2.29(s,3H), 1.40(m,3H)ppm; MS (ES) M+H expected = 435.1, found 435.0.

Synthesis of 2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-(4-o-tolyl-piperazin-1-yl)-ethanone:

The title compound was prepared according to coupling scheme P involving HATU using 1-(2-methylphenyl)piperazine and (4-chloro-5-methyl-3-trifluoromethyl-pyrazole-1- base)-acetic acid as a coupling component to give the product as a solid: ¹ H NMR (DMSO-d6, 400 MHz) 7.14 (m, 2H), 6.98 (m, 2H), 5.37 (s, 2H), 3.60 (m, 4H), 2.89 (m, 2H), 2.81 (m, 2H), 2.27 (s, 3H), 2.20 (s, 3H) ppm; MS (ES) M+H expected = 401.1, found = 401.1.

Synthesis of 2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(4-chloro-phenyl)-2-(S)-methyl -piperazin-1-yl]-ethanone:

The title compound was prepared according to coupling scheme P involving HATU using 1-(4-chlorophenyl)-3-(S)-methylpiperazine and (4-chloro-5-methyl-3-trifluoro Methyl-pyrazol-1-yl)-acetic acid as coupling component afforded the product as a solid: ¹ H NMR (CDCl ₃ , 300 MHz) 7.25 (d, 2H), 6.83 (d, 2H), 4.91 (m, 3H), 4.28(m, 1H), 3.80-3.10(m, 4H), 2.86(m, 1H), 2.71(m, 1H), 2.29(s, 3H), 1.40(m, 3H) ppm; MS( ES) M+H expected = 435.1, found = 435.0.

Synthesis of 2-(4-chloro-3-trifluoromethyl-5-methyl-pyrazol-1-yl)-1-[4-(5-fluoro-2-methoxy-phenyl)-piperazine -1-yl]-ethanone

The title compound was prepared according to coupling scheme P involving HATU using 1-(2-methoxy-5-fluorophenyl)piperazine and (4-chloro-5-methyl-3-trifluoromethyl- Pyrazol-1-yl)-acetic acid as coupling component afforded the product as a solid: ¹ H NMR (DMSO-d6, 400 MHz) 6.93 (m, 1H), 6.77 (m, 3H), 5.36 (s, 2H) , 3.77(s, 3H), 3.59(m, 4H), 3.07(m, 2H), 2.98(m, 2H), 2.19(s, 3H) ppm; MS(ES) M+H expected 435.1, found 435.0.

Synthesis of 2-{4-chloro-3-methyl-5-trifluoromethyl-pyrazol-1-yl}-1-[4-(3-methylthioalkyl-phenyl)-piperazine-1 -yl]-ethanone

The title compound was prepared following coupling scheme P with HATU participation using 1-(3-methylthiophenyl)piperazine and (4-chloro-5-methyl-3-trifluoromethyl-pyrazole-1 -yl)-acetic acid as coupling component afforded the product as a solid: ¹ H NMR (DMSO-d6, 400 MHz) 7.21(t, 1H), 6.98(s, 1H), 6.91(d, 1H), 6.81(d , 1H), 5.39(s, 2H), 3.68(m, 4H), 3.34(m, 2H), 3.24(m, 2H), 2.44(s, 3H), 2.19(s, 3H)ppm; MS(ES ) M+H expected 433.1, found 433.0.

Synthesis of 1-[4-(4-bromo-phenyl)-piperazin-1-yl]-2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)- Ethyl ketone:

The title compound was prepared following coupling scheme P with HATU participation using 1-(4-bromophenyl)piperazine and (4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl )-acetic acid as the coupling component to give the product as a solid: ¹ H NMR (DMSO-d6, 400 MHz) 7.36 (d, 2H), 6.92 (d, 2H), 5.37 (s, 2H), 3.60 (m, 4H ), 3.24 (m, 2H), 3.14 (m, 2H), 2.18 (s, 3H) ppm; MS (ES) M+H expected = 465.0, found = 465.0.

Synthesis of 2-(4-chloro-3-trifluoromethyl-5-methyl-pyrazol-1-yl)-1-[4-(2,3-dimethyl-phenyl)piperazine-1- base]-ethanone

The title compound was prepared according to coupling scheme P involving HATU using 1-(2,3-dimethylphenyl)piperazine and (4-chloro-5-methyl-3-trifluoromethyl-pyrazole -1-yl)-acetic acid as coupling component afforded the product as a solid: ¹ H NMR (DMSO-d6, 400 MHz) 7.04 (t, 1H), 6.99 (m, 2H), 5.38 (s, 2H), 3.64 (m, 4H), 2.89 (m, 2H), 2.81 (m, 2H), 2.21 (m, 9H) ppm; MS(ES) M+H expected 415.1, found 415.1.

Synthesis of 2-(4-chloro-3-trifluoromethyl-5-methyl-pyrazol-1-yl)-1-[4-(2-chloro-5-methoxy-phenyl)-piperazine -1-yl]-ethanone

The title compound was prepared according to coupling scheme P involving HATU using 1-(2-chloro-5-methoxyphenyl)piperazine and (4-chloro-5-methyl-3-trifluoromethyl- Pyrazol-1-yl)-acetic acid as coupling component afforded the product as a solid: ¹ H NMR (DMSO-d6, 400 MHz) 7.31 (d, 1H), 6.65 (m, 2H), 5.37 (s, 2H) , 3.73 (s, 3H), 3.62 (m, 4H), 3.02 (m, 2H), 2.96 (m, 2H), 2.19 (s, 3H) ppm; MS(ES) M+H expected = 451.1, found Value = 451.0.

Synthesis of 1-[4-(4-bromo-3-methoxy-phenyl)-piperazin-1-yl]-2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazole -1-yl)-ethanone:

The title compound was prepared according to coupling scheme P involving HATU using 1-(4-bromo-3-methoxyphenyl)piperazine and (4-chloro-5-methyl-3-trifluoromethyl- Pyrazol-1-yl)-acetic acid as coupling component afforded the product as a solid: ¹ H NMR (DMSO-d6, 400 MHz) 7.34 (d, 1H), 6.71 (s, 1H), 6.52 (d, 1H) , 5.39(s, 2H), 3.82(s, 3H), 3.62(m, 4H), 3.30(m, 2H), 3.20(m, 2H), 2.19(s, 3H) ppm; MS(ES) M+ H expected = 495.0, found = 495.0.

Synthesis of 2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(2,4-dichloro-phenyl)-piperazine-1- base]-ethanone:

The title compound was prepared according to coupling scheme P involving HATU using 1-(2,4-dichlorophenyl)piperazine and (4-chloro-5-methyl-3-trifluoromethyl-pyrazole- 1-yl)-acetic acid as the coupling component afforded the product as a solid: ¹ H NMR (DMSO-d6, 400 MHz) 7.56 (s, 1H), 7.36 (d, 1H), 7.15 (d, 1H), 5.37 ( s, 2H), 3.61 (m, 4H), 3.01 (m, 2H), 2.94 (m, 2H), 2.19 (s, 3H) ppm; MS(ES) M+H expected 455.0, found = 454.9 .

Synthesis of 2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(4-methoxy-pyridin-2-yl)-piperazine- 1-yl]-ethanone:

The title compound was prepared according to coupling scheme P involving HATU using 1-(4-methoxy-pyridin-2-yl)-piperazine and (4-chloro-5-methyl-3-trifluoromethyl -pyrazol-1-yl)-acetic acid as a coupling component afforded the product as a solid: ¹ H NMR (DMSO-d6, 400 MHz) 7.92 (d, 1H), 6.67 (s1H), 6.63 (d, 1H), 5.42(s, 2H), 3.96(s, 3H), 3.88(m, 2H), 3.73(m, 4H), 3.62(m, 2H), 2.19(s, 3H)ppm; MS(ES)M+H Expected = 418.1, Found = 418.0.

Synthesis of 2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(3,4-dimethyl-phenyl)-piperazine-1 -yl]-ethanone:

The title compound was prepared according to coupling scheme P with HATU participation, using 1-(3,4-dimethylphenyl)-piperazine and (4-chloro-5-methyl-3-trifluoromethyl-pyridine Azol-1-yl)-acetic acid as coupling component afforded the product as a solid: ¹ H NMR (DMSO-d6, 400 MHz) 7.03 (d, 1H), 6.94 (br s, 1H), 6.84 (brs, 1H) , 5.38(s, 2H), 3.68(m, 4H), 3.25(m, 2H), 3.15(m, 2H), 2.18(s, 6H), 2.14(s, 3H) ppm; MS(ES) M+ H expected = 415.1, found = 415.1.

Synthesis of 2-(4-chloro-3-trifluoromethyl-5-methyl-pyrazol-1-yl)-1-[4-(4-trifluoromethoxy-phenyl)-piperazine-1 -yl]-ethanone

The title compound was prepared according to coupling scheme P involving HATU using 1-(4-trifluoromethoxyphenyl)-piperazine and (4-chloro-5-methyl-3-trifluoromethyl-pyridine Azol-1-yl)-acetic acid as coupling component afforded the product as a solid: ¹ H NMR (DMSO-d6, 400 MHz) 7.20 (d, 2H), 7.04 (d, 2H), 5.38 (s, 2H), 3.60 (m, 4H), 3.27 (m, 2H), 3.17 (m, 2H), 2.18 (s, 3H) ppm; MS (ES) M+H expected = 471.1, found = 471.0.

Synthesis of 2-(4-chloro-3-trifluoromethyl-5-methyl-pyrazol-1-yl)-1-[4-(2,4-dichloro-5-methoxy-phenyl) -Piperazin-1-yl]-ethanone

The title compound was prepared according to coupling scheme P involving HATU using 1-(2,4-dichloro-5-methoxyphenyl)-piperazine and (4-chloro-5-methyl-3-tri Fluoromethyl-pyrazol-1-yl)-acetic acid as coupling component afforded the product as a solid: ¹ H NMR (DMSO-d6, 400 MHz) 7.50 (s, 1H), 6.84 (s, 1H), 5.37 ( s, 2H), 3.85(s, 3H), 3.62(m, 4H), 3.07(m, 2H), 3.00(m, 2H), 2.19(s, 3H) ppm; MS(ES) M+H expected value = 485.1, found value = 485.0.

Synthesis of 2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(4-nitro-phenyl)-piperazin-1-yl] Ethyl ketone:

The title compound was prepared following coupling scheme P with HATU participation using 1-(4-nitrophenyl)-piperazine and (4-chloro-5-methyl-3-trifluoromethyl-pyrazole-1 -yl)-acetic acid as the coupling component afforded the product as a yellow solid: ¹ H NMR (DMSO-d6, 400 MHz) 8.05 (d, 2H), 7.01 (d, 2H), 5.38 (s, 2H), 3.62 ( m, 6H), 3.52 (m, 2H), 2.19 (s, 3H) ppm; MS (ES) M+H expected = 432.1, found = 432.0.

Synthesis of 2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(4-chloro-2-methoxy-phenyl)-piperazine -1-yl]-ethanone

The title compound was prepared according to coupling scheme P involving HATU using 1-(4-chloro-2-methoxyphenyl)-piperazine and (4-chloro-5-methyl-3-trifluoromethyl -pyrazol-1-yl)-acetic acid as a coupling component afforded the product as a solid: ¹ H NMR (DMSO-d6, 400 MHz) 7.02 (s, 1H), 6.93 (m, 2H), 5.36 (s, 2H ), 3.82(s, 3H), 3.60(m, 4H), 3.03(m, 2H), 2.95(m, 2H), 2.19(s, 3H) ppm; MS(ES) M+H expected value = 451.1, Found value = 451.0.

Synthesis of 1-[4-(4-bromo-3-methyl-phenyl)-piperazin-1-yl]-2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazole- 1-yl)-ethanone:

The title compound was prepared according to coupling scheme P involving HATU using 1-(4-bromo-3-methylphenyl)-piperazine and (4-chloro-5-methyl-3-trifluoromethyl- Pyrazol-1-yl)-acetic acid as coupling component afforded the product as a solid: ¹ H NMR (DMSO-d6, 400 MHz) 7.38 (d, 1H), 7.01 (s, 1H), 6.78 (d, 1H) , 5.38(s, 2H), 3.60(m, 4H), 3.26(m, 2H), 3.16(m, 2H), 2.28(s, 3H), 2.19(s, 3H) ppm; MS(ES) M+ H expected = 479.0, found = 478.9.

Synthesis of 1-[4-(4-acetyl-phenyl)-piperazin-1-yl]-2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl) - ethyl ketone:

The title compound was prepared following coupling scheme P with HATU participation using 1-(4-acetyl-phenyl)piperazine and (4-chloro-5-methyl-3-trifluoromethyl-pyrazole-1 -yl)-acetic acid as a coupling component afforded the product as a solid: ¹ H NMR (DMSO-d6, 400 MHz) 7.80 (d, 1H), 6.98 (d, 2H), 5.38 (s, 2H), 3.61 (m , 4H), 3.48 (m, 2H), 3.39 (m, 2H), 2.46 (s, 3H), 2.19 (s, 3H) ppm; MS (ES) M+H expected = 429.1, found = 429.0.

Synthesis of 2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(3,4-dichloro-phenyl)-piperazine-1- base]-ethanone:

The title compound was prepared according to coupling scheme P involving HATU using 1-(3,4-dichlorophenyl)piperazine and (4-chloro-5-methyl-3-trifluoromethyl-pyrazole- 1-yl)-acetic acid as coupling component afforded the product as a solid: ¹ H NMR (DMSO-d6, 400 MHz) 7.40 (d, 1H), 7.16 (s, 1H), 6.95 (d, 1H), 5.37 ( s, 2H), 3.59 (m, 4H), 3.31 (m, 2H), 3.21 (m, 2H), 2.18 (s, 3H) ppm; MS(ES) M+H expected = 455.0, found = 455.0 .

Synthesis of 2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(3-chloro-phenyl)-piperazin-1-yl]- Ethyl ketone:

The title compound was prepared following coupling scheme P with HATU participation using 1-(3-chlorophenyl)piperazine and (4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl )-acetic acid as the coupling component to give the product as a solid: ¹ H NMR (DMSO-d6, 400 MHz) 7.23(t, 1H), 7.19(s, 1H), 6.90(d, 1H), 6.79(d, 1H ), 5.37(s, 2H), 3.58(m, 4H), 3.29(m, 2H), 3.19(m, 2H), 2.18(s, 3H) ppm; MS(ES) M+H expected value = 421.1, Found value = 421.0.

Synthesis of 2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-(4-m-tolyl-piperazin-1-yl)-ethanone

The title compound was prepared according to the coupling scheme P participated by HATU using 1-(3-methylphenyl)piperazine and (4-chloro-5-methyl-3-trifluoromethyl-pyrazole-1- base)-acetic acid as a coupling component to give the product as a solid: ¹ H NMR (DMSO-d6, 400 MHz) 7.17 (t, 1H), 6.97 (br, 2H), 6.77 (d, 1H), 5.39 (s, 2H), 3.68(m, 4H), 3.31(m, 2H), 3.22(m, 2H), 2.27(s, 3H), 2.19(s, 3H) ppm; MS(ES) M+H expected = 401.1 , found value = 401.1.

Synthesis of 1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazole -1-yl)-ethanone:

The title compound was prepared according to coupling scheme P involving HATU using 1-(4-chloro-3-methoxyphenyl)piperazine and (4-chloro-5-methyl-3-trifluoromethyl- Pyrazol-1-yl)-acetic acid as coupling component afforded the product as a solid: ¹ H NMR (DMSO-d6, 400 MHz) 7.21 (d, 1H), 6.74 (s, 1H), 6.56 (d, 1H) , 5.39(s, 2H), 3.82(s, 3H), 3.63(m, 4H), 3.30(m, 2H), 3.19(m, 2H), 2.19(s, 3H) ppm; MS(ES) M+ H expected = 451.1, found 451.0.

Synthesis of 4-{4-[2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-piperazin-1-yl}-benzoic acid methyl ester :

The title compound was prepared according to coupling scheme P involving HATU using 4-piperazin-1-yl-benzoic acid methyl ester and (4-chloro-5-methyl-3-trifluoromethyl-pyrazole-1 -yl)-acetic acid as the coupling component afforded the product as a solid: ¹ H NMR (DMSO-d6, 400 MHz) 7.78 (d, 2H), 6.98 (d, 2H), 5.38 (s, 2H), 3.71 (s , 3H), 3.60 (m, 4H), 3.46 (m, 2H), 3.37 (m, 2H), 2.19 (s, 3H) ppm; MS (ES) M+H expected = 445.1, found 445.0.

Synthesis of 2-(4-chloro-3,5-dimethyl-pyrazol-1-yl)-1-(4-pyridin-4-yl-piperazin-1-yl)-ethanone

The title compound was prepared according to coupling scheme P involving HATU using 1-(4-pyridyl)piperazine and (4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl) - Acetic acid as the coupling component affords the product as a solid: ¹ H NMR (DMSO-d6, 400 MHz) 8.28 (d, 2H), 7.18 (d, 2H), 5.41 (s, 2H), 3.83 (m, 2H) , 3.72 (m, 4H), 3.63 (m, 2H), 2.18 (s, 3H) ppm; MS (ES) M+H expected = 388.1, found = 388.0.

Synthesis of 2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(5-methoxy-2-methyl-phenyl)-piper Azin-1-yl]-ethanone

The title compound was prepared according to coupling scheme P involving HATU using 1-(3-methoxy-5-methylphenyl)piperazine and (4-chloro-5-methyl-3-trifluoromethyl -pyrazol-1-yl)-acetic acid as a coupling component afforded the product as a solid: ¹ H NMR (DMSO-d6, 400 MHz) 7.06 (d, 1H), 6.56 (m, 2H), 5.38 (s, 2H ), 3.69(s, 3H), 3.62(m, 4H), 2.92(m, 2H), 2.84(m, 2H), 2.20(s, 3H) ppm; MS(ES) M+H expected value = 431.1, Found value = 431.1.

Synthesis of 2-(4-chloro-3-trifluoromethyl-5-methyl-pyrazol-1-yl)-1-(4-phenyl-piperazin-1-yl)-ethanone:

The title compound was prepared according to coupling scheme P participated by HATU using 1-phenylpiperazine and (4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid as coupling Components, the product was obtained as a solid: ¹ HNMR (DMSO-d6, 400 MHz) 7.32 (m4H), 7.02 (m, 1H), 5.40 (s, 2H), 3.74 (m, 4H), 3.39 (m, 2H) , 3.29 (m, 2H), 2.19 (s, 3H) ppm; MS (ES) M+H expected = 387.1, found 387.1.

Synthesis of 1-[4-(4-chloro-3-ethoxy-phenyl)-piperazin-1-yl]-2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazole -1-yl)-ethanone:

The title compound was prepared according to coupling scheme P involving HATU using 1-(4-chloro-3-ethoxyphenyl)piperazine and (4-chloro-5-methyl-3-trifluoromethyl- Pyrazol-1-yl)-acetic acid as coupling component afforded the product as a solid: ¹ H NMR (DMSO-d6, 400 MHz) 7.20 (d, 1H), 6.66 (s, 1H), 6.48 (d, 1H) , 5.38(s, 2H), 4.08(q, 2H), 3.61(m, 4H), 3.25(m, 2H), 3.16(m, 2H), 2.18(s, 3H), 1.33(t, 3H)ppm ; MS(ES) M+H expected = 465.1, found 465.0.

Synthesis of 2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-(4-pyridin-2-yl-piperazin-1-yl)-ethanone:

The title compound was prepared following coupling scheme P with HATU participation using 1-(2-pyridyl)piperazine and (4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl) - Acetic acid as the coupling component affords the product as a solid: ¹ H NMR (DMSO-d6, 400 MHz) 8.11 (d, 1H), 7.53 (t, 1H), 6.85 (d, 1H), 6.65 (t, 1H) , 5.37 (s, 2H), 3.59-3.50 (m, 8H), 2.18 (s, 3H) ppm; MS (ES) M+H expected = 388.1, found = 388.0.

Synthesis of 2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-(4-p-tolyl-piperazin-1-yl)-ethanone:

The title compound was prepared according to coupling scheme P involving HATU using 1-(4-methylphenyl)piperazine and (4-chloro-5-methyl-3-trifluoromethyl-pyrazole-1- base)-acetic acid as a coupling component to give the product as a solid: ¹ H NMR (DMSO-d6, 400 MHz) 7.20 (m, 4H), 5.40 (s, 2H), 3.79 (m, 4H), 3.37 (m, 2H), 3.28 (m, 2H), 2.49 (s, 3H), 2.19 (s, 3H) ppm; MS (ES) M+H expected = 401.1, found 401.0.

Synthesis of 1-[(4-methylsulfonyl-phenyl)-piperazin-1-yl]-2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)- ethyl ketone

The title compound was prepared following coupling scheme P with HATU participation using 1-(4-methanesulfonyl-phenyl)-piperazine and (4-chloro-5-methyl-3-trifluoromethyl-pyrazole -1-yl)-acetic acid as coupling component afforded the product as a solid: ¹ H NMR (DMSO-d6, 400 MHz) 7.69 (d, 2H), 7.08 (d, 2H), 5.38 (s, 2H), 3.59 (m, 4H), 3.49(m, 2H), 3.38(m, 2H), 3.09(s, 3H), 2.19(s, 3H)ppm; MS(ES) M+H expected = 465.1, found = 465.0.

Synthesis of 2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(4-chloro-phenyl)-piperazin-1-yl]- ethyl ketone.

The title compound was prepared according to coupling scheme P involving HATU using 1-(4-chlorophenyl)-piperazine and (4-chloro-5-methyl-3-trifluoromethyl-pyrazole-1- base)-acetic acid as coupling component to give the product as a solid: ¹ H NMR (CDCl ₃ , 400 MHz) 7.22 (d, 2H), 6.83 (d, 2H), 4.99 (s, 2H), 3.77 (m, 2H ), 3.72 (m, 2H), 3.19 (m, 2H), 3.16 (m, 2H), 2.28 (s, 3H) ppm; MS (ES) M+Na expected = 443.0, found 443.0.

Synthesis of 2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(4-methoxy-phenyl)-piperazin-1-yl ]-Ethanone.

The title compound was prepared according to coupling scheme P involving HATU using 1-(4-methoxyphenyl)-piperazine and (4-chloro-5-methyl-3-trifluoromethyl-pyrazole- 1-yl)-acetic acid as coupling component afforded the product as a solid: ¹ H NMR (CDCl ₃ , 400 MHz) 6.88 (m, 4H), 5.00 (s, 2H), 3.78 (m, 3H), 3.76 (m , 2H), 3.70 (m, 2H), 3.08 (m, 4H), 2.30 (s, 3H) ppm; MS (ES) M+Na expected = 439.0, found 439.0.

Synthesis of 4-{4-[2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-piperazin-1-yl}-benzonitrile

The title compound was prepared according to the coupling scheme P participated by HATU using 1-(4-cyanophenyl)-piperazine and (4-chloro-5-methyl-3-trifluoromethyl-pyrazole-1 -yl)-acetic acid as coupling component afforded the product as a solid: ¹ H NMR (CDCl ₃ , 400 MHz) 7.44 (d, 2H), 6.77 (d, 2H), 4.90 (s, 2H), 3.67 (m, 4H), 3.29 (m, 4H), 2.22 (s, 3H) ppm; MS (ES) M+Na expected = 434.0, found 434.0.

Synthesis of 2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(2-fluoro-phenyl)-piperazin-1-yl]- ethyl ketone

The title compound was prepared according to coupling scheme P involving HATU using 1-(2-fluorophenyl)-piperazine and (4-chloro-5-methyl-3-trifluoromethyl-pyrazole-1- base)-acetic acid as coupling component to give the product as a solid: ¹ H NMR (CDCl ₃ , 400 MHz) 7.02 (m, 4H), 5.00 (s, 2H), 3.80 (m, 2H), 3.70 (m, 2H ), 3.53 (m, 2H), 3.25 (m, 2H), 2.30 (s, 3H) ppm; MS (ES) M+Na expected = 427.0, found 427.0.

Synthesis of 2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(2-methoxy-phenyl)-piperazin-1-yl ]-Ethanone

The title compound was prepared according to coupling scheme P involving HATU using 1-(2-methoxyphenyl)-piperazine and (4-chloro-5-methyl-3-trifluoromethyl-pyrazole- 1-yl)-acetic acid as coupling component afforded the product as a solid: ¹ H NMR (CDCl ₃ , 400 MHz) 6.62 (m, 1H), 6.48 (m, 3H), 5.01 (s, 2H), 3.73 (s , 3H), 3.61 (m, 4H), 3.43 (m, 2H), 2.31 (s, 3H) ppm; MS (ES) M+H expected = 439.0, found 439.1.

Synthesis of 2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(3-trifluoromethyl-phenyl)-piperazine-1- base]-ethanone.

The title compound was prepared according to the coupling scheme P participated by HATU using 1-(3-trifluoromethylphenyl)-piperazine and (4-chloro-5-methyl-3-trifluoromethyl-pyrazole -1-yl)-acetic acid as coupling component afforded the product as a solid: ¹ H NMR (CDCl ₃ , 400 MHz) 7.38 (m, 1H), 7.11 (m, 3H), 5.00 (s, 2H), 3.79 ( m,2H), 3.73(m,2H), 3.27(m,2H), 3.23(m,2H), 2.30(s,3H)ppm; MS(ES) M+H expected = 455.0, found 455.0 .

Synthesis of 2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-(4-pyrimidin-2-yl-piperazin-1-yl)-ethanone:

The title compound was prepared following coupling scheme P with HATU participation using 1-(2-pyrimidinyl)-piperazine and (4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl )-acetic acid as a coupling component, the product was obtained as a solid: MS(ES) M+H expected value = 389.1, found value = 389.0; HPLC retention time = 3.99 minutes (Agilent Zorbax SB-C18, 2.1 × 50mm, 5μ, 35° C.) with a 4.5 minute gradient of 20-95% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.08% formic acid/99.9% acetonitrile).

Synthesis of 1-[4-(4-chloro-3-isopropoxy-phenyl)-piperazin-1-yl]-2-(4-chloro-5-methyl-3-trifluoromethyl-pyridine Azol-1-yl)-ethanone

The title compound was prepared according to the coupling scheme P participated by HATU using 1-(4-chloro-3-isopropoxy-phenyl)-piperazine and (4-chloro-5-methyl-3-trifluoro Methyl-pyrazol-1-yl)-acetic acid as coupling component afforded the product as a solid: ¹ H NMR (DMSO-d6, 400 MHz) 7.21(d, 1H), 6.71(s, 1H), 6.53(d , 1H), 5.38(s, 2H), 4.66(m, 1H), 3.58(m, 4H), 3.25(m, 2H), 3.15(m, 2H), 2.18(s, 3H), 1.26(d, 6H) ppm; MS(ES) M+H expected = 479.1, found = 479.0.

Synthesis of 2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(3,4-difluoro-phenyl)piperazin-1-yl ]-Ethanone

The title compound was prepared according to the coupling scheme P participated by HATU using 1-(3,4-difluorophenyl)-piperazine and (4-chloro-5-methyl-3-trifluoromethyl-pyrazole -1-yl)-acetic acid as the coupling component gave the product as a solid: ¹ H NMR (DMSO-d6, 400 MHz, without F-decoupling) 7.25 (q, 1H), 7.04 (m, 1H), 6.74 ( d, 1H), 5.37(s, 2H), 3.57(m, 4H), 3.24(m, 2H), 3.12(m, 2H), 2.18(s, 3H) ppm; MS(ES) M+H expected value = 423.1, found to be 423.0.

Synthesis of 2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(6-methoxy-pyridin-2-yl)-piperazine- 1-yl]-ethanone

The title compound was prepared according to coupling scheme P involving HATU using 1-(6-methoxy-pyridin-2-yl)-piperazine and (4-chloro-5-methyl-3-trifluoromethyl -pyrazol-1-yl)-acetic acid as a coupling component afforded the product as a solid: ¹ H NMR (DMSO-d6, 400 MHz) 7.45 (t, 1H), 6.34 (d, 1H), 6.05 (d, 1H ), 5.37(s, 2H), 3.77(s, 3H), 3.50(m, 6H), 3.34(m, 2H), 2.18(s, 3H) ppm; MS(ES) M+H expected value = 418.1, Found value = 418.0.

Synthesis of 4-{4-[2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-piperazin-1-yl}-N,N- Dimethyl-benzenesulfonamide:

The title compound was prepared according to coupling scheme P involving HATU using N,N-dimethyl-4-piperazin-1-yl-benzenesulfonamide and (4-chloro-5-methyl-3-trifluoro Methyl-pyrazol-1-yl)-acetic acid as coupling component afforded the product as a solid: ¹ H NMR (DMSO-d6, 400 MHz) 7.54(d, 2H), 7.08(d, 2H), 5.38(s , 2H), 3.62 (m, 4H), 3.48 (m, 2H), 3.37 (m, 2H), 2.19 (s, 3H) ppm; MS (ES) M+H expected = 494.1, found = 494.0.

Synthesis of 1-[4-(4-chloro-3-methyl-phenyl)-piperazin-1-yl]-2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazole- 1-yl)-ethanone

The title compound was prepared according to coupling scheme P involving HATU using 1-(4-chloro-3-methylphenyl)-piperazine and (4-chloro-5-methyl-3-trifluoromethyl- Pyrazol-1-yl)-acetic acid as coupling component afforded the product as a solid: ¹ H NMR (DMSO-d6, 400 MHz) 7.25 (d, 1H), 7.05 (s, 1H), 6.90 (d, 1H) , 5.38(s, 2H), 3.64(m, 4H), 3.27(m, 2H), 3.17(m, 2H), 2.26(s, 3H), 2.19(s, 3H) ppm; MS(ES) M+ H expected = 435.1, found = 435.0.

Synthesis of 2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(3-hydroxy-phenyl)-piperazin-1-yl]- ethyl ketone

The title compound was prepared according to coupling scheme P involving HATU using 1-(3-hydroxyphenyl)-piperazine and (4-chloro-5-methyl-3-trifluoromethyl-pyrazole-1- base)-acetic acid as a coupling component to give the product as a solid: ¹ H NMR (DMSO-d6, 400 MHz) 7.10 (t, 1H), 6.66 (m, 2H), 6.45 (d, 1H), 5.39 (s, 2H), 3.74 (m, 4H), 3.33 (br, 2H), 3.24 (br, 2H), 2.19 (s, 3H) ppm; MS (ES) M+H expected = 403.1, found 403.0.

Synthesis of 2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(4-trifluoromethyl-phenyl)-piperazine-1- base]-ethanone

The title compound was prepared according to the coupling scheme P participated by HATU using 1-(4-trifluoromethylphenyl)-piperazine and (4-chloro-5-methyl-3-trifluoromethyl-pyrazole -1-yl)-acetic acid as a coupling component afforded the product as a solid: ¹ H NMR (DMSO-d6, 400 MHz) 7.50 (d, 2H), 7.07 (d, 2H), 5.38 (s, 2H), 3.60 (m, 4H), 3.41 (m, 2H), 3.31 (m, 2H), 2.19 (s, 3H) ppm; MS (ES) M+H expected = 455.1, found = 455.0.

Synthesis of 2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-(3-methyl-4-m-tolyl-piperazin-1-yl) - ethyl ketone:

The title compound was prepared according to coupling scheme P involving HATU using 1-(3-methylphenyl)-2-methyl-piperazine and (4-chloro-5-methyl-3-trifluoromethyl -pyrazol-1-yl)-acetic acid as a coupling component afforded the product as a solid: ¹ H NMR (DMSO-d6, 400 MHz) 7.68 (br, 1H), 7.17 (br, 1H), 6.71 (br, 2H ), 5.41(m, 2H), 4.08(m, 4H), 3.70(m, 2H), 3.50(br m, 2H), 2.30(s, 3H), 2.18(s, 3H), 1.01(m, 3H ) ppm; MS(ES) M+H expected = 415.1, found = 415.1.

Synthesis of 1-[4-(4-chloro-3-methoxy-phenyl)-2-(S)-methyl-piperazin-1-yl]-2-(4-chloro-5-methyl- 3-Trifluoromethyl-pyrazol-1-yl)-ethanone:

The title compound was prepared according to coupling scheme P involving HATU using 1-(4-chloro-3-methoxyphenyl)-3-(S)-methyl-piperazine and (4-chloro-5- Methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid as a coupling component afforded the product as a solid: ¹ H NMR (DMSO-d6, 400 MHz, 95° C.) δ 7.16 (d, 1H ), 6.62(s, 1H), 6.48(d, 1H), 5.26(br, 2H), 3.65(m, 1H), 3.53(m, 1H), 3.01(m, 4H), 2.84(m, 1H) , 2.21 (s,3H), 1.29 (d,3H) ppm; MS (ES) M+H expected = 465.1, found = 465.0.

Synthesis of 1-[4-(4-chloro-3-methylthio-phenyl)-piperazin-1-yl]-2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazole -1-yl)-ethanone:

The title compound was prepared according to the coupling scheme P participated by HATU using 1-(4-chloro-3-methylthio-phenyl)-piperazine and (4-chloro-5-methyl-3-trifluoromethane yl-pyrazol-1-yl)-acetic acid as the coupling component to give the product as a solid: ¹ H NMR (DMSO-d6, 400 MHz) δ7.27 (m, 1H), 6.81 (m, 2H), 5.40 ( s, 2H), 3.64(m, 4H), 3.31(m, 2H), 3.21(m, 2H), 2.50(s, 3H), 2.92(s, 3H) ppm; MS(ES) M+H expected value = 467.0, found value = 467.0.

Synthesis of 1-[4-(3-trifluoromethoxy-phenyl)-piperazin-1-yl]-2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazole-1 -yl)-ethanone:

The title compound was prepared according to coupling scheme P involving HATU using 1-(3-trifluoromethoxy-phenyl)-piperazine and (4-chloro-5-methyl-3-trifluoromethyl- Pyrazol-1-yl)-acetic acid as a coupling component afforded the product as a solid: ¹ H NMR (DMSO-d6, 400 MHz) δ 7.33 (t, 1H), 6.99 (m, 1H), 6.90 (s, 1H), 6.76(m, 1H), 5.39(s, 2H), 3.62(m, 4H), 3.33(m, 2H), 3.23(m, 2H), 2.19(s, 3H)ppm; MS(ES) M+H expected = 471.0, found = 471.0.

Synthesis of 2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(4-oxazol-5-yl-phenyl)-piperazine- 1-yl]-ethanone:

The title compound was prepared according to coupling scheme P involving HATU using 1-(4-oxazol-5-yl-phenyl)-piperazine and (4-chloro-5-methyl-3-trifluoromethyl -pyrazol-1-yl)-acetic acid as a coupling component afforded the product as a solid: ¹ H NMR (DMSO-d6, 400 MHz) δ 8.34 (s, 1H), 7.59 (d, 2H), 7.48 (s, 1H), 7.07(d, 2H), 5.40(s, 2H), 3.63(m, 4H), 3.35(m, 2H), 3.25(m, 2H), 2.20(s, 3H)ppm; MS(ES) M+H expected = 454.0, found = 454.0.

Synthesis of 1-[4-(3-chloro-4-methoxy-naphthalen-1-yl)-piperazin-1-yl]-2-(4-chloro-5-methyl-3-trifluoromethyl -pyrazol-1-yl)-ethanone:

The title compound was prepared according to coupling scheme P participated by HATU using 1-[4-(3-chloro-4-methoxy-naphthalen-1-yl)-piperazine and (4-chloro-5-methyl -3-Trifluoromethyl-pyrazol-1-yl)-acetic acid as a coupling component to give the product as a solid: ¹ H NMR (DMSO-d6, 400 MHz) δ8.22 (m, 1H), 8.07 (m , 1H), 7.64(m, 2H), 7.13(s, 1H), 5.43(s, 2H), 3.91(s, 3H), 3.73(m, 4H), 3.10(m, 2H), 3.01(m, 2H), 2.21 (s,3H) ppm; MS(ES) M+H expected = 501.0, found = 501.0.

Synthesis of 2-(5-azidomethyl-4-chloro-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(4-chloro-3-methoxy-phenyl)- Piperazin-1-yl]-ethanone:

The title compound was prepared according to coupling scheme P involving HATU using 1-[4-(4-chloro-3-methoxy-phenyl)-piperazine and (5-azidomethyl-4-chloro- 3-Trifluoromethyl-pyrazol-1-yl)-acetic acid as coupling component afforded the product as a solid: ¹ H NMR (DMSO-d6, 400 MHz) δ 7.21(d, 1H), 6.71(d, 1H), 6.53(dd, 1H), 5.50(s, 2H), 4.64(s, 2H), 3.80(s, 3H), 3.62(m, 4H), 3.29(m, 2H), 3.18(m, 2H ) ppm; MS(ES) M+H expected = 492.0, found = 492.0.

Synthesis of 1-[4-(5-bromo-6-methoxy-pyridin-2-yl)-piperazin-1-yl]-2-(4-chloro-5-methyl-3-trifluoromethyl -pyrazol-1-yl)-ethanone:

The title compound was prepared following coupling scheme P involving HATU using 1-(5-bromo-6-methoxy-pyridin-2-yl)-piperazine and (4-chloro-5-methyl-3- Trifluoromethyl-pyrazol-1-yl)-acetic acid as coupling component afforded the product as a solid: ¹ H NMR (DMSO-d6, 400 MHz) 7.69 (d, 1H), 6.37 (d, 1H), 5.39 (s, 2H), 3.87 (s, 3H), 3.62 (m, 4H), 3.55 (m, 4H), 2.20 (s, 3H) pm; MS(ES) M+H expected = 496.0, found = 496.0.

Synthesis of 1-[4-(4-chloro-5-methoxy-2-methyl-phenyl)-piperazin-1-yl]-2-(4-chloro-5-methyl-3-trifluoro Methyl-pyrazol-1-yl)-ethanone:

The title compound was prepared according to coupling scheme P involving HATU using 1-(4-chloro-5-methoxy-2-methyl-phenyl)-piperazine and (4-chloro-5-methyl- 3-Trifluoromethyl-pyrazol-1-yl)-acetic acid as coupling component gave the product as a solid: MS(ES) M+H expected = 465.0, found = 465.0; HPLC retention time = 5.27 min (Agilent Zorbax SB-C18, 2.1×50mm, 5μ, 35°C), using a 4.5-minute gradient of 20-95% B, with a 1.1-minute wash at 95% B (A = 0.1% formic acid/5% acetonitrile/94.9 % water, B = 0.08% formic acid/99.9% acetonitrile).

Synthesis of 1-[4-(5-chloro-4-methoxy-pyridin-2-yl)-piperazin-1-yl]-2-(4-chloro-5-methyl-3-trifluoromethyl -pyrazol-1-yl)-ethanone:

The title compound was prepared according to coupling scheme P involving HATU using 1-(5-chloro-4-methoxy-pyridin-2-yl)-piperazine and (4-chloro-5-methyl-3- Trifluoromethyl-pyrazol-1-yl)-acetic acid as coupling component afforded the product as a solid: ¹ H NMR (DMSO-d6, 400 MHz) δ 8.13 (m, 1H), 6.92 (m, 1H) , 5.38(s, 2H), 3.91(s, 3H), 3.62(m, 4H), 3.29(m, 2H), 3.21(m, 2H), 2.19(s, 3H) ppm; MS(ES) M+ H expected = 452.0, found = 452.0.

Synthesis of 1-[4-(3-tert-butoxycarbonylamino-4-chloro-phenyl)-piperazin-1-yl]-2-(4-chloro-5-methyl-3-trifluoromethyl -pyrazol-1-yl)-ethanone:

The title compound was prepared according to the coupling scheme P participated by HATU using 1-(3-tert-butoxycarbonylamino-4-chloro-phenyl)-piperazine and (4-chloro-5-methyl-3- Trifluoromethyl-pyrazol-1-yl)-acetic acid as coupling component afforded the product as a solid: ¹ H NMR (DMSO-d6, 400 MHz) δ 8.43 (s, 1H), 7.25 (s, 1H) , 7.21(m, 1H), 6.78(m, 1H), 5.39(s, 1H), 3.62(m, 4H), 3.22(m, 2H), 3.13(m, 2H), 2.19(s, 3H), 1.45 (s, 9H) ppm; MS(ES) M+H expected = 536.0, found = 536.0.

Synthesis of 1-{4-[4-chloro-3-(2-ethoxy-ethoxy)-phenyl]-piperazin-1-yl}-2-(4-chloro-5-methyl-3 -Trifluoromethyl-pyrazol-1-yl)-ethanone:

The title compound was prepared according to coupling scheme P participated by HATU using 1-[4-chloro-3-(2-ethoxy-ethoxy)-phenyl]-piperazine and (4-chloro-5- Methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid as coupling component afforded the product as a solid: ¹ H NMR (CDCl ₃ , 400 MHz) δ 7.22 (d, 1H), 6.57 ( s, 1H), 6.45(d, 1H), 4.99(s, 2H), 4.17(t, 2H), 3.84(t, 2H), 3.77(t, 2H), 3.71(t, 2H), 3.64(q, 2H), 3.16 (m, 4H), 2.30 (s, 3H), 1.25 (t, 3H) ppm; MS (ES) M+H expected = 449.0, found = 449.0.

Synthesis of 1-[4-(2-amino-4-chloro-5-methoxy-phenyl)-piperazin-1-yl]-2-(4-chloro-5-methyl-3-trifluoromethyl Base-pyrazol-1-yl)-ethanone:

The title compound was prepared according to coupling scheme P involving HATU using 1-(2-amino-4-chloro-5-methoxy-phenyl)-piperazine and (4-chloro-5-methyl-3 -Trifluoromethyl-pyrazol-1-yl)-acetic acid as coupling component afforded the product as a solid: ¹ H NMR (CDCl ₃ , 400 MHz) δ 6.79 (s, 1H), 6.59 (s, 1H) , 5.00 (s, 2H), 3.82 (s, 3H), 3.70 (m, 4H), 2.92 (m, 4H), 2.31 (s, 3H) ppm; MS(ES) M+H expected = 449.0, found Value = 449.0.

Synthesis of 1-[4-(4-chloro-2-fluoro-5-methoxy-phenyl)-piperazin-1-yl]-2-(4-chloro-5-methyl-3-trifluoromethyl Base-pyrazol-1-yl)-ethanone:

The title compound was prepared according to the coupling scheme P participated by HATU using 1-(4-chloro-2-fluoro-5-methoxy-phenyl)-piperazine and (4-chloro-5-methyl-3 -Trifluoromethyl-pyrazol-1-yl)-acetic acid as coupling component afforded the product as a solid: ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.11 (d, 1H), 6.50 (d, 1H) , 5.02(s, 2H), 3.87(s, 3H), 3.83-3.74(m, 4H), 3.14-3.08(m, 4H), 2.31(s, 3H) MS(ES)(M+H) expected value = 469.1, found value = 469.0.

Synthesis of 1-[4-(4-bromo-3-methoxy-phenyl)-2-(S)-methyl-piperazin-1-yl]-2-(4-bromo-5-methyl- 3-Trifluoromethyl-pyrazol-1-yl)-ethanone:

The title compound was prepared according to coupling scheme P involving HATU using 1-(4-bromo-3-methoxy-phenyl)-3-(S)-methyl-piperazine and (4-bromo-5 -Methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid as coupling component afforded the product as a solid: ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.37 (d, 1H), 6.42 (s, 1H), 6.37(d, 1H), 5.00(s, 2H), 3.89(s, 3H), 3.60-2.90(m, 7H), 2.32(s, 3H), 1.41(d, 3H); HPLC retention time = 7.25 minutes (Agilent Zorbax SB-C18, 2.1 x 50mm, 5μ, 35°C) with an initial no-gradient time of 2.0 followed by a 5.0-minute gradient of 20-95% B at 95% B in 1.1 minutes (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.08% formic acid/99.9% acetonitrile), finally at 95% B with 2.5 min no gradient time.

Synthesis of 1-[4-(2,4-dichloro-5-methoxy-phenyl)-piperazin-1-yl]-2-(4-bromo-5-methyl-3-trifluoromethyl -pyrazol-1-yl)-ethanone:

The title compound was prepared according to coupling scheme P involving HATU using 1-(2,4-dichloro-5-methoxy-phenyl)-piperazine and (4-bromo-5-methyl-3- Trifluoromethyl-pyrazol-1-yl)-acetic acid as coupling component afforded the product as a solid: ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.38 (s, 1H), 6.55 (s, 1H), 5.02 (s, 2H), 3.89 (s, 3H), 3.82-3.73 (m, 4H), 3.08-3.02 (m, 4H), 2.33 (s, 3H); HPLC retention time = 7.72 minutes (Agilent Zorbax SB- C18, 2.1 x 50mm, 5μ, 35°C) with an initial no-gradient time of 2.0, followed by a 5.0-minute gradient of 20-95% B with a 1.1-minute wash at 95% B (A = 0.1% formic acid/5% Acetonitrile/94.9% water, B = 0.08% formic acid/99.9% acetonitrile), finally at 95% B with a no gradient time of 2.5 minutes.

Synthesis of 1-[4-(2,4-dichloro-5-methoxy-phenyl)-2-(S)-methyl-piperazin-1-yl]-2-(4-bromo-5- Methyl-3-trifluoromethyl-pyrazol-1-yl)-ethanone:

The title compound was prepared according to coupling scheme P involving HATU using 1-(2,4-dichloro-5-methoxy-phenyl)-3-(S)-methyl-piperazine and (4- Bromo-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid as coupling component afforded the product as a solid: ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.40 (s, 1H ), 6.55(s, 1H), 4.99(d, 2H), 3.90(s, 3H), 3.54-2.73(m, 7H), 2.32(s, 3H), 1.52(d, 3H); HPLC retention time = 7.92 minutes (Agilent Zorbax SB-C18, 2.1 x 50mm, 5μ, 35°C) with an initial no-gradient time of 2.0, followed by a 5.0-minute gradient of 20-95% B, with a 1.1-minute wash at 95% B ( A = 0.1% formic acid/5% acetonitrile/94.9% water, B = 0.08% formic acid/99.9% acetonitrile), finally at 95% B with a 2.5 minute no gradient time.

Synthesis of 1-[4-(4-chloro-3-ethyl-phenyl)-piperazin-1-yl]-2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazole- 1-yl)-ethanone:

The title compound was prepared according to the coupling scheme P participated by HATU using 1-(4-chloro-3-ethyl-phenyl)-piperazine and (4-chloro-5-methyl-3-trifluoromethyl -pyrazol-1-yl)-acetic acid as a coupling component afforded the product as a solid: ¹ H NMR (DMSO-d6, 400 MHz) δ 7.26 (m, 1H), 7.03 (, 1H), 6.90 (m, 1H), 5.40(d, 2H), 3.64(m, 4H), 3.29(m, 2H), 3.20(m, 2H), 2.64(q, 2H), 2.20(s, 3H), 1.16(t, 3H ) ppm; MS(ES) M+H expected = 449.0, found = 449.0.

Synthesis of 2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(4-fluoro-2-methoxy-phenyl)-piperazine -1-yl]-ethanone:

The title compound was prepared according to coupling scheme P involving HATU using 1-(4-fluoro-3-methoxy-phenyl)-piperazine and (4-chloro-5-methyl-3-trifluoromethane yl-pyrazol-1-yl)-acetic acid as the coupling component to give the product as a solid: ¹ H NMR (DMSO-d6, 400 MHz) δ7.01 (m, 1H), 6.93 (m, 1H), 6.73 ( m, 1H), 5.38(s, 2H), 3.83(s, 3H), 3.63(m, 4H), 3.06(m, 2H), 2.97(m, 2H), 2.19(s, 3H)ppm; MS( ES) M+H expected = 435.0, found = 435.0.

Synthesis of 1-[4-(4-chloro-3-methoxy-phenyl)-2-(R)-methyl-piperazin-1-yl]-2-(4-chloro-5-methyl- 3-Trifluoromethyl-pyrazol-1-yl)-ethanone:

The title compound was prepared according to coupling scheme P involving HATU using 1-(4-chloro-3-methoxy-phenyl)-2-(R)-methyl-piperazine and (4-chloro-5 -Methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid as a coupling component afforded the product as a solid: ¹ H NMR (DMSO-d6, 400 MHz) δ 7.21 (m, 1H), 6.65(m, 1H), 6.52(m, 1H), 5.53(m, 1H), 5.27(m, 1H), 4.22(m, 1H), 3.85(s, 3H), 3.80-3.49(m, 4H) , 3.10-2.83 (m, 2H), 2.19 (s, 3H), 1.38-1.10 (m, 3H) ppm (mixture of rotamers); MS(ES) M+H expected = 465.0, found = 465.0.

Synthesis of 1-[4-(4-chloro-3-methoxy-phenyl)-2-(S)-(2-methylsulfonyl-ethyl)-piperazin-1-yl]-2-(4 -Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-ethanone:

The title compound was prepared according to coupling scheme P participated by HATU using 1-(4-chloro-3-methoxy-phenyl)-3-(S)-(2-methanesulfonyl-ethyl)-piper Oxyzine and (4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid as coupling components afforded the product as a solid: ¹ H NMR (DMSO-d6, 400 MHz) δ7 .20(m, 1H), 6.67(m, 1H), 6.52(m, 1H), 5.49(m, 1H), 5.37(m, 1H), 4.75(m, 1H), 4.21(par.obsc.m , 1H), 3.83(s, 3H), 3.81-3.65(m, 4H), 3.41(m, 1H), 3.06(m, 1H), 2.95(s, 3H), 2.81(m, 1H), 2.26( m, 1H), 2.19 (s, 3H), 2.05 (m, 1H) ppm (rotamer); MS (ES) M+H expected = 557.0, found = 557.0.

Synthesis of 1-[4-(4-chloro-3-methoxy-phenyl)-2-(R)-hydroxymethyl-piperazin-1-yl]-2-(4-chloro-5-methyl -3-Trifluoromethyl-pyrazol-1-yl)-ethanone:

The title compound was prepared according to coupling scheme P involving HATU using 1-(4-chloro-3-methoxy-phenyl)-2-(R)-hydroxymethyl-piperazine and (4-chloro- 5-Methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid as coupling component afforded the product as a solid: ¹ H NMR (DMSO-d6, 400 MHz) δ 7.21 (d, 1H) , 6.66(m, 1H), 6.52(m, 1H), 5.50(m, 1H), 5.32(m, 1H), 5.24(t, 1H), 4.22(m, 1H), 4.06(m, 1H), 3.84(s, 3H), 3.83-3.63(m, 4H), 3.04-2.62(m, 3H), 2.17(s, 3H) ppm (rotamer); MS(ES) M+H expected = 481.0 , found value = 481.0.

Synthesis of 1-[4-(4-chloro-3-dimethylaminomethyl-phenyl)-piperazin-1-yl]-2-(4-chloro-5-methyl-3-trifluoromethyl -pyrazol-1-yl)-ethanone:

The title compound was prepared according to coupling scheme P with HATU participation, in which (2-chloro-5-piperazin-1-yl-benzyl)-dimethyl-amine and (4-chloro-5-methyl-3- Trifluoromethyl-pyrazol-1-yl)-acetic acid was used as coupling component to give the product as a solid: ¹ H NMR (CDCl ₃ , 400 MHz) δ 7.32 (d, 1H), 7.25 (s, 1H ), 6.88(dd, 1H), 5.01(s, 3H), 4.88(s, 2H), 4.35(s, 2H), 3.75(t, 2H), 3.65(t, 2H), 3.25(t, 2H) , 3.20 (t, 2H), 2.86 (s, 6H) ppm; MS (ES) M+H expected = 481.0, found = 481.0.

Synthesis of (2-chloro-5-{4-[2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-piperazin-1-yl} -Benzyl)-methyl-benzyl carbamate:

The title compound was prepared according to coupling scheme P with HATU participation, in which (2-chloro-5-piperazin-1-yl-benzyl)-methyl-carbamic acid benzyl ester and (4-chloro-5-methyl -3-Trifluoromethyl-pyrazol-1-yl)-acetic acid was used as coupling component to give the product as a solid: MS (ES) M+H expected = 481.0, found = 481.0.

Synthesis of 2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-{4-[4-chloro-3-(2-morpholin-4-yl- Ethoxy)-phenyl]-piperazin-1-yl}-ethanone:

The title compound was prepared according to the coupling scheme P participated by HATU using 1-[4-chloro-3-(2-morpholin-4-yl-ethoxy)-phenyl]-piperazine and (4-chloro -5-Methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid as a coupling component to give the product as a solid: ¹ H NMR (DMSO-d6, 400 MHz) δ7.27 (d, 1H ), 6.79(m, 1H), 6.60(m, 1H), 5.41(s, 2H), 4.48(m, 2H), 4.01(m, 2H), 3.75(m, 2H), 3.62(m, 8H) , 3.30 (par obsc m, 6H), 3.20 (m, 2H), 2.20 (s, 3H) ppm; MS (ES) M+H expected = 550.0, found = 551.1.

Synthesis of 1-[4-(4-chloro-3-methoxy-phenyl)-3-(R)-methyl-piperazin-1-yl]-2-(4-chloro-5-methyl- 3-Trifluoromethyl-pyrazol-1-yl)-ethanone:

The title compound was prepared according to coupling scheme P participated by HATU using 1-(4-chloro-3-methoxy-phenyl)-3-(R)-methyl-piperazine and (4-chloro-5 -Methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid as coupling component afforded the product as a solid: ¹ H NMR (CDCl ₃ , 400 MHz) δ 7.25 (s, 1H), 6.55 (d, 1H), 6.47(d, 1H), 5.07-4.91(m, 2H), 3.88(s, 3H), 3.76-3.13(m, 5H), 2.30(s, 3H), 1.01(q, 3H ) ppm (mixture of rotamers); MS (ES) M+H expected = 465.0, found = 465.0.

Synthesis of 1-[4-(4-chloro-3-methoxy-phenyl)-3-(S)-methyl-piperazin-1-yl]-2-(4-chloro-5-methyl- 3-Trifluoromethyl-pyrazol-1-yl)-ethanone:

The title compound was prepared according to coupling scheme P involving HATU using 1-(4-chloro-3-methoxy-phenyl)-3-(S)-methyl-piperazine and (4-chloro-5 -Methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid as coupling component afforded the product as a solid: ¹ H NMR (CDCl ₃ , 400 MHz) δ 7.25 (s, 1H), 6.55 (d, 1H), 6.47(d, 1H), 5.07-4.91(m, 2H), 3.88(s, 3H), 3.76-3.13(m, 5H), 2.30(s, 3H), 1.01(q, 3H ) ppm (mixture of rotamers); MS (ES) M+H expected = 465.0, found = 465.0.

Synthesis of 1-[4-(4-chloro-3-methoxymethyl-phenyl)-piperazin-1-yl]-2-(4-chloro-5-methyl-3-trifluoromethyl- Pyrazol-1-yl)-ethanone:

The title compound was prepared according to coupling scheme P involving HATU using 1-(4-chloro-3-methoxymethyl-phenyl)-piperazine and (4-chloro-5-methyl-3-tri Fluoromethyl-pyrazol-1-yl)-acetic acid as a coupling component afforded a solid product: ¹ H NMR (CDCl ₃ , 400 MHz) δ 7.25 (s, 1H), 7.05 (d, 1H), 6.78 (dd , 1H), 4.99(s, 2H), 4.52(s, 2H), 3.75(dt, 4H), 3.48(s, 3H), 3.21(dt, 4H), 2.30(s, 3H)ppm; MS(ES ) M+H expected = 465.1, found = 465.0.

Synthesis of 2-(5-aminomethyl-4-chloro-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(2,4-dichloro-5-methoxy-phenyl )-piperazin-1-yl]-ethanone:

The title compound was prepared according to coupling scheme P involving HATU using 1-(2,4-dichloro-5-methoxy-phenyl)-piperazine and (5-azidomethyl-4-chloro- 3-Trifluoromethyl-pyrazol-1-yl)-acetic acid as coupling component. After the coupling reaction was completed, a 10-fold excess of tin(II) chloride was directly added to the reaction, and stirring was continued for another 4 hours. The reaction was purified by reverse phase HPLC to give the product: ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.38 (s, 1H), 6.73 (d, 2H), 6.56 (s, 1H), 5.32 (d, 2H), 4.41 (d, 2H) 3.89 (s, 3H), 3.80-3.73 (m, 4H), 3.37-3.02 (m, 4H); HPLC retention time = 5.83 minutes (Agilent Zorbax SB-C18, 2.1 × 50mm, 5μ, 35°C) with an initial no-gradient time of 2.0, followed by a 5.0-minute gradient of 20-95% B with a 1.1-minute wash at 95% B (A = 0.1% formic acid/5% acetonitrile/94.9% water, B = 0.08% formic acid/99.9% acetonitrile), and finally a 2.5 min no-gradient time at 95% B.

Synthesis of 2-(5-aminomethyl-4-chloro-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(4-bromo-3-methoxy-phenyl)-piper Azin-1-yl]-ethanone:

The title compound was prepared according to coupling scheme P involving HATU using 1-(4-bromo-3-methoxy-phenyl)-piperazine and (5-azidomethyl-4-chloro-3-tri Fluoromethyl-pyrazol-1-yl)-acetic acid as coupling component. After the coupling reaction was completed, a 10-fold excess of tin(II) chloride was directly added to the reaction, and stirring was continued for another 4 hours. The reaction was purified by reverse phase HPLC to give the product: ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.53(d, 1H), 6.82(s, 1H), 6.68(d, 1H), 5.35(s, 2H) , 4.41 (s, 2H), 3.93 (s, 4H), 3.90 (s, 3H), 3.52-3.39 (m, 4H); HPLC retention time = 5.44 minutes (Agilent Zorbax SB-C18, 2.1 × 50mm, 5μ, 35°C) with an initial no-gradient time of 2.0, followed by a 5.0-minute gradient of 20-95% B with a 1.1-minute wash at 95% B (A = 0.1% formic acid/5% acetonitrile/94.9% water, B = 0.08% formic acid/99.9% acetonitrile), and finally a 2.5 min no-gradient time at 95% B.

Synthesis of 2-(5-aminomethyl-4-chloro-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(4-chloro-2-fluoro-5-methoxy-benzene Base)-piperazin-1-yl]-ethanone:

The title compound was prepared following coupling scheme P with HATU participation using 1-(4-chloro-2-fluoro-5-methoxy-phenyl)-piperazine and (5-azidomethyl-4-chloro -3-Trifluoromethyl-pyrazol-1-yl)-acetic acid as coupling component. After the coupling reaction was completed, a 10-fold excess of tin(II) chloride was directly added to the reaction, and stirring was continued for another 4 hours. The reaction was purified by reverse phase HPLC to give the product: ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.10 (d, 1H), 6.48 (d, 1H), 5.33 (s, 2H), 4.39 (s, 2H), 3.85 (s, 3H), 3.78 (m, 4H), 3.05 (m, 4H) MS (ES) (M+H) expected = 484.1, found = 484.0.

Synthesis of 2-(5-aminomethyl-4-chloro-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(4-chloro-3-methoxy-phenyl)-2 -(S)-Methyl-piperazin-1-yl]-ethanone:

The title compound was prepared according to coupling scheme P involving HATU using 1-(4-chloro-3-methoxy-phenyl)-3-(S)-methyl-piperazine and (5-azidomethanol -4-Chloro-3-trifluoromethyl-pyrazol-1-yl)-acetic acid as coupling component. After the coupling reaction was completed, a 10-fold excess of tin(II) chloride was directly added to the reaction, and stirring was continued for another 4 hours. The reaction was purified by reverse phase HPLC to give the product: ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.22 (d, 1H), 6.46 (s, 1H), 6.42 (s, 1H), 5.27 (m, 2H), 4.35(s, 2H), 3.81(s, 3H), 3.76-3.42(m, 4H), 3.35-2.96(m, 4H), 1.45(d, 3H) MS(ES)(M+H) expected = 480.1, found value = 480.1.

Synthesis of 2-(5-aminomethyl-4-chloro-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(4-bromo-3-methoxy-phenyl)-2 -(S)-Methyl-piperazin-1-yl]-ethanone:

The title compound was prepared according to coupling scheme P involving HATU using 1-(4-bromo-3-methoxy-phenyl)-3-(S)-methyl-piperazine and (5-azidomethyl -4-Chloro-3-trifluoromethyl-pyrazol-1-yl)-acetic acid as coupling component. After the coupling reaction was completed, a 10-fold excess of tin(II) chloride was directly added to the reaction, and stirring was continued for another 4 hours. The reaction was purified by reverse phase HPLC to give the product: ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.51 (d, 1H), 6.98 (s, 1H), 6.59 (d, 1H), 5.35 (m, 2H), 4.45 (s, 2H), 3.90 (s, 3H), 3.83-3.60 (m, 5H), 3.32-3.19 (m, 4H), 1.45 (d, 3H); HPLC retention time = 5.72 minutes (Agilent Zorbax SB- C18, 2.1×50 mm, 5 μ, 35° C.) with an initial no-gradient time of 2.0 followed by a 5.0-minute gradient of 20-95% B with a 1.1-minute wash at 95% B (A=0.1% formic acid/5 % acetonitrile/94.9% water, B = 0.08% formic acid/99.9% acetonitrile), and finally at 95% B with a 2.5 minute no gradient time.

Scheme Q: Synthesis of 2-(5-aminomethyl-4-chloro-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(4-chlorophenyl)-piperazine-1- base]-ethanone

2.85g (6.2mmol) 2-(5-azidomethyl-4-chloro-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(4-chlorophenyl)-piper Azin-1-yl]-ethanone was dissolved in 80 mL of methanol, and 3.61 g (16.0 mmol) of SnCl ₂ hydrate was added. After 2 hours, the reaction was concentrated in vacuo to remove methanol. The residue was partitioned between 0.5M NaOH and ethyl acetate and the phases were separated. The aqueous phase was back extracted once with ethyl acetate. The combined ethyl acetate phases were extracted twice with 1M HCl. The acidic aqueous phase was basified with 1M NaOH and extracted once with ethyl acetate. The final ethyl acetate phase was washed once with brine, dried over _Na2SO4 , filtered and concentrated to an oil _. The oil was dissolved in methanol, acidified with 2M HCl in ether, precipitated and the product isolated by filtration: ¹ H NMR (DMSO-d6, 400 MHz) 8.58 (s, 3H), 7.27 (d, 2H), 7.03 (d , 2H), 5.71(s, 2H), 4.10(d, 2H), 3.64(m, 4H), 3.32(m, 2H), 3.19(m, 2H) ppm; MS(ES) M+H expected value = 436.1, found value = 436.0.

Synthesis of 2-(5-N,N-Dimethylaminomethyl-4-chloro-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(4-chlorophenyl)-piper Azin-1-yl]-ethanone:

To 50mg (0.1mmol) hydrochloride 2-(5-aminomethyl-4-chloro-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(4-chlorophenyl)-piperazine To a solution of -1-yl]-ethanone and 13 mg (0.20 mmol) of sodium cyanoborohydride in 0.7 mL of methanol was added 0.025 mL (0.3 mmol) of 37% aqueous formaldehyde. After stirring for 4 hours, the reaction was quenched with 0.1 mL of 12M HCl. After 1 hour, the solution was concentrated in vacuo. The residue was partitioned between water and ether and the phases were separated. The ether phase was back extracted once with water. The combined aqueous phases were basified with 1M NaOH and extracted once with ethyl acetate. The ethyl acetate phase was washed once with _brine , dried over _Na2SO4 , filtered, and concentrated to an oil. The oil was dissolved in methanol, acidified with 2M HCl in ether, and the product was isolated as a white solid by filtration: ¹ H NMR (DMSO-d6, 400 MHz) 11.07 (br, 1H), 7.26 (d, 2H), 7.02 (d , 2H), 5.76(s, 2H), 4.43(s, 2H), 3.62(m, 4H), 3.31(m, 2H), 3.18(m, 2H), 2.81(s, 6H)ppm; MS(ES ) M+H expected = 464.1, found = 464.0.

Synthesis of 2-(5-aminomethyl-4-chloro-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(4-chloro-3-methoxy-phenyl)-piper Azin-1-yl]-ethanone:

Following protocol Q, 224 mg (0.46 mmol) of 2-(5-azidomethyl-4-chloro-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(4-chloro-3 -Methoxy-phenyl)-piperazin-1-yl]-ethanone was dissolved in 5 mL of methanol and 256 mg (1.14 mmol) of tin(II) chloride was added. After 4 hours, the solution was concentrated in vacuo to an oil which was partitioned between ether and water and the phases separated. The aqueous phase was basified with 1M NaOH to pH>9 and extracted twice with ethyl acetate. The combined ethyl acetate phases were washed twice _with water, once with brine, dried over _Na2SO4 , filtered, and concentrated to an oil. The oil was dissolved in methanol, acidified with 2M HCl in ether and diluted with ether to give a solid product: ¹ H NMR (DMSO-d6, 400 MHz) δ 8.50 (br, 3H), 7.23 (m, 1H), 6.74 (m, 1H), 6.56(m, 1H), 5.70(s, 2H), 4.13(m, 2H), 3.84(s, 3H), 3.64(m, 4H), 3.35(m, 2H), 3.23( m, 2H) ppm; MS (ES) M+H expected = 466.0, found = 466.0.

Scheme R: Urea Derivatization of Aminomethyl Functional Groups on the Pyrazole Ring System

Synthesis of 1-(4-chloro-2-{2-[4-(4-chloro-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-5-trifluoromethyl-2H -pyrazol-3-ylmethyl)-urea:

0°C, within 5 minutes, to 12mg (0.07mmol) carbonyldiimidazole and 25mg (0.05mmol) hydrochloric acid 2-(5-aminomethyl-4-chloro-3-trifluoromethyl-pyrazol-1-yl) -1-[4-(4-Chlorophenyl)-piperazin-1-yl]-ethanone To a slurry in 1.0 mL CH ₂ Cl ₂ was added 23 mg (0.22 mmol) dissolved in 0.2 mL CH ₂ Cl ₂ triethylamine. After 1 hour, the mixture was allowed to warm to room temperature and stirred for an additional 1 hour.

0.5M ammonia in 1.0 mL (0.5 mmol) dioxane was added and the resulting solution was stirred for 12 hours. The solution was concentrated in vacuo and the resulting residue was partitioned between ethyl acetate and water. The phases were separated and the aqueous phase was back extracted once with ethyl acetate. The combined ethyl acetate phases were washed once each with _water , 1M NaOH, brine, dried over _Na2SO4 , filtered, and concentrated to a residue. The residue was triturated with ethyl acetate and the product isolated as a white solid by filtration: ¹ H NMR (DMSO-d6, 400 MHz) 7.23 (d, 2H), 6.96 (d, 2H), 6.48 (t, 1H), 5.62 (s,2H), 5.48(s,2H), 4.16(d,2H), 3.57(m,4H), 3.25(m,2H), 3.14(m,2H)ppm; MS(ES) M+H expected Value = 479.1, found value = 479.0.

Synthesis of 3-(4-chloro-2-{2-[4-(4-chloro-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-5-trifluoromethyl-2H -pyrazol-3-ylmethyl)-1,1-dimethyl-urea:

The title compound was prepared following Scheme R, using 2M dimethylamine in THF as the amine component of the second step, to give the desired component as a solid: ¹ H NMR (DMSO-d6, 400 MHz) δ 7.23 (d, 2H ), 6.96(d, 2H), 6.81(t, 1H), 5.43(s, 2H), 4.21(d, 2H), 3.56(m, 4H), 3.22(m, 2H), 3.13(m, 2H) , 2.73 (s,3H) ppm; MS(ES) M+H expected = 507.1, found = 507.1.

Synthesis of 1-(4-chloro-2-{2-[4-(4-chloro-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-5-trifluoromethyl-2H -pyrazol-3-ylmethyl)-3-methyl-urea:

The title compound was prepared following Scheme R using 2M methylamine in THF as the amine component of the second step to give the desired component as a solid: ¹ H NMR (DMSO-d6, 400 MHz) 7.23 (d, 2H), 6.96 (d, 2H), 6.45(t, 1H), 5.86(m, 1H), 5.48(s, 2H), 4.18(d, 2H), 3.58(m, 4H), 3.31(s, 3H), 3.25( m, 2H), 3.13 (m, 2H) ppm; MS (ES) M+H expected = 493.1, found = 493.0.

Synthesis of 3-(4-chloro-2-{2-[4-(4-chloro-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-5-trifluoromethyl-2H -pyrazol-3-ylmethyl)-1-methoxy-1-methyl-urea:

The title compound was prepared following Scheme R, using 1M N,O-dimethylhydroxylamine in THF as the amine component of the second step to give the desired component as a solid: ¹ H NMR (DMSO-d6, 400 MHz) 7.63 ( t, 1H), 7.23(d, 2H), 6.96(d, 2H), 5.42(s, 2H), 4.25(d, 2H), 3.57(m, 4H), 3.52(s, 3H), 3.25(m , 2H), 3.13 (m, 2H), 2.89 (s, 3H) ppm; MS (ES) M+H expected = 523.1, found 523.0.

Synthesis of 1-(4-chloro-2-{2-[4-(4-chloro-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-5-trifluoromethyl-2H -pyrazol-3-ylmethyl)-3-ethyl-urea:

The title compound was prepared following Scheme R, using 2M ethylamine in THF as the amine component of the second step, to give the desired component as a solid: ¹ H NMR (DMSO-d6, 400 MHz) 7.26 (d, 2H), 7.03 (d, 2H), 6.95(br, 1H), 6.47(br, 1H), 5.49(s, 2H), 4.17(s, 1H), 3.61(m, 4H), 3.28(m, 2H), 3.17( m, 2H), 2.95 (q, 2H), 0.93 (t, 3H) ppm; MS (ES) M+H expected = 507.1, found = 507.0.

Scheme S: Preparation of Chloroacetylarylpiperazines

Synthesis of 2-chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone

1-( ₄ -Fluorophenyl)piperazine (2.8 mmol) was dissolved in 10 mL _CH2Cl2 . Triethylamine (5.5 mmol) was added thereto, and the reactant was cooled to 0°C. Chloroacetyl chloride (4.2 mmol) was added slowly and the reaction was allowed to warm to room temperature overnight. Upon completion, the reaction was quenched with brine solution, and the reaction mixture was extracted with dichloromethane. The combined organic phases were washed with brine and water and dried over magnesium sulfate. The solvent was evaporated, and the compound was purified by column chromatography (hexane/ethyl acetate=1.5/1) to provide the title compound as a white solid. ¹ H NMR (400MHz, CDCl ₃ ) δ6.9-7.2(m, 2H), 6.82-6.92(m, 2H), 4.1(s, 2H), 6.62-3.8(m, 4H), 3.46-3.6(m , 4H). ¹³ C NMR (400 MHz, CDCl ₃ ) δ 164, 158, 156.2, 148.5, 118.2, 116.8, 52.6, 52.2, 48, 46, 42.1, 40.6.

Synthesis of 2-chloro-1-[4-(4-chloro-phenyl)-piperazin-1-yl]-ethanone

Following Protocol S using 1-(4-chloro-phenyl)piperazine, _Et3N , chloroacetyl chloride and dichloromethane. Column chromatography using a solvent mixture (hexane/ethyl acetate = 1.5/1) afforded the title compound as a white solid.

Synthesis of 2-chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone

Following Protocol S using 1-(4-chloro-3-methoxyphenyl)piperazine, _Et3N , chloroacetyl chloride and dichloromethane. Column chromatography using a solvent mixture (hexane/ethyl acetate = 1.5/1) afforded the title compound as a white solid.

Synthesis of 2-chloro-1-[4-(4-bromo-3-methoxy-phenyl)-piperazin-1-yl]-ethanone

Following Protocol S using 1-(4-bromo-3-methoxyphenyl)piperazine, _Et3N , chloroacetyl chloride and dichloromethane. Column chromatography using a solvent mixture (hexane/ethyl acetate = 1.5/1) afforded the title compound as a white solid.

Synthesis of 2-chloro-1-[4-(4-chloro-phenyl)-2-methyl-(R)-piperazin-1-yl]-ethanone

Following Protocol S using 1-(4-chloro-phenyl)-3-(R)-methyl-piperazine, _Et3N , chloroacetyl chloride and dichloromethane. Column chromatography provided the title compound.

Synthesis of 2-chloro-1-[4-(4-chloro-phenyl)-2-methyl-(S)-piperazin-1-yl]-ethanone

Following Protocol S using 1-(4-chloro-phenyl)-3-(S)-methyl-piperazine, _Et3N , chloroacetyl chloride and dichloromethane. Column chromatography provided the title compound.

_Scheme T: Coupling reaction involving _K2CO3 of chloroacetylarylpiperazine and pyrazole

Synthesis of 1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-2-pyrazol-1-yl-ethanone

Pyrazole (112.33 mg, 1.65 mmol) was dissolved in DMF (10 mL). K ₂ CO ₃ (228.05 mg, 1.65 mmol) and 2-chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone (300 mg, 1.67 mmol) were added thereto. The reaction was heated to 80°C for 14 hours. Upon completion, the reaction was cooled to room temperature, quenched with brine, and extracted with ethyl acetate. The organic layer was washed with water (2 x 25 mL) and brine (2 x 25 mL), and dried over magnesium sulfate. The solvent was removed by rotary evaporation to give a crude product which could be purified by silica gel column chromatography using a solvent mixture (hexane/ethyl acetate=1/1) to provide the title compound as a white solid. ¹ H NMR (400MHz, CDCl ₃ ) δ7.2-7.58(d, 2H), 6.94-7.2(t, 2H), 6.84-6.9(dd, 2H), 6.32-6.36(t, 1H), 5.6(s , 2H), 3.76-3.82 (m, 2H), 3.68-3.74 (m, 2H), 3.04-3.1 (m, 2H), 3.0-3.04 (m, 2H). ¹³ C NMR (400 MHz, CDCl ₃ ) δ165, 158, 146.5, 140, 130, 118.4, 118.2, 116, 115.8, 107, 54, 51, 50.845.8, 42.8.

Synthesis of 2-(4-chloro-5-phenyl-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]- Ethanone and 2-(4-chloro-3-phenyl-5-trifluoromethyl-pyrazol-1-yl)-1-[4-(4-fluoro-phenyl)-piperazin-1-yl ]-Ethanone

Following protocol T using 4 _- chloro-5-phenyl-3-trifluoromethyl-1H-pyrazole, _K2CO3 , 2-chloro-1-[4-(4-fluoro-phenyl)-piper azin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate = 1.5/1) afforded a mixture of title compounds all as white solids.

¹ H NMR (400MHz, CDCl ₃ ) δ7.44-7.54(m, 5H), 6.94-7.2(t, 2H), 6.84-6.9(dd, 2H), 4.94(s, 1H), 3.72-3.8(m , 2H), 3.5-3.6 (m, 2H), 3.0-3.1 (m, 4H). ¹³ C NMR (400 MHz, CDCl ₃ ) δ 163.8, 158, 146.5, 130, 128.6, 128.2, 118.2, 114.5, 52, 50, 44.5, 42.

1H NMR (400MHz, CDCl3) δ7.82-7.88(m, 2H), 7.38-7.48(m, 3H), 6.96-7.04(m, 2H), 6.86-6.94(m, 2H), 5.2(s, 1H ), 3.76-3.86 (m, 2H), 3.62-3.68 (m, 2H), 3.06-3.22 (m, 4H). 13C NMR (400MHz, CDCl3) δ164, 130, 128.4, 126, 118, 116.4, 52, 50, 43.8, 41.6.

Synthesis of 2-{2-[4-(4-fluoro-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-5-thiophen-2-yl-2H-pyrazole-3-yl ethyl carboxylate

Following protocol T, using ethyl 5-thiophen-2-yl-2H-pyrazole-3-carboxylate, K2CO3, 2-chloro-1-[4-(4-fluoro-phenyl)-piperazine-1- base]-ethanone and DMF. Column chromatography was performed using a solvent mixture (hexane/ethyl acetate=1.5/1) to provide the title compound. 1H NMR (400MHz, CDCl3) δ7.32-7.36(m, 1H), 7.22-7.26(m, 1H), 7.08(s, 1H), 7.02-7.08(dd, 1H), 6.96-7.2(m, 2H ), 6.86-6.92 (m, 2H), 4.3-4.4 (q, 2H), 3.52-3.58 (m, 4H), 3.05-3.25 (m, 4H), 1.3-1.42 (m, 3H). 13C NMR (400MHz, CDCl3) δ164, 130, 126.8, 126.4, 120, 118.2, 115.4, 62.3, 54, 50.5, 42, 44.5, 14.6.

Synthesis of 2-(3-amino-4-bromo-5-phenyl-pyrazol-1-yl)-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone

Following protocol T using 4-bromo-5-phenyl-1H-pyrazol-3-ylamine, _K2CO3 , ₂ -chloro-1-[4-(4-fluoro-phenyl)-piperazine- 1-yl]-ethanone and DMF. Column chromatography was performed using a solvent mixture (hexane/ethyl acetate=3/7) to provide the title compound as a yellow solid. ¹ H NMR (400MHz, CDCl ₃ ) δ7.74-7.78(m, 2H), 7.24-7.36(m, 3H), 6.86-6.92(m, 2H), 6.74-6.78(m, 2H), 4.9(s , 2H), 4.22 (s, 2H), 3.64-3.74 (m, 4H), 2.86-3.04 (m, 4H). ¹³ C NMR (400 MHz, CDCl ₃ ) δ164, 146.2, 144.8, 128, 126.8, 118, 114.8, 60, 50.2, 50, 48.8, 46, 42, 20.

Synthesis of 2-(3-amino-4-bromo-5-phenyl-pyrazol-1-yl)-1-[4-(4-chloro-phenyl)-piperazin-1-yl]-ethanone

Following protocol T using 4-bromo-5-phenyl-1H-pyrazol-3-ylamine, _K2CO3 , ₂ -chloro-1-[4-(4-chloro-phenyl)-piperazine- 1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate = 1/4) afforded the title compound as a white solid. ¹ H NMR (400MHz, CDCl ₃ ) δ7.7-7.8(m, 2H), 7.24-7.3(m, 3H), 6.8-6.92(m, 2H), 6.74-6.78(m, 2H), 4.9(s , 2H), 4.2 (s, 2H), 3.6-3.7 (m, 4H), 2.86-3.04 (m, 4H). ¹³ C NMR (400 MHz, CDCl ₃ ) δ164, 146, 145, 128, 127, 118, 114.8, 60.2, 50.4, 50, 48.8, 46, 42, 22.

Synthesis of 1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-2-(3-heptafluoropropyl-5-methyl-4-nitro-pyrazol-1-yl) - ethyl ketone

Following protocol _T , using 3-heptafluoropropyl-5-methyl-4-nitro-1H-pyrazole, _K2CO3 , 2-chloro-1-[4-(4-fluoro-phenyl)- Piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate=3/7) afforded the title compound as an oil. ¹ H NMR (400MHz, CDCl ₃ ) δ6.9-7.0 (m, 2H), 6.8-6.9 (m, 2H), 5.06-5.14 (d, 2H), 3.6-3.8 (m, 4H), 3.06-3.18 (m, 4H), 2.56-2.66 (d, 3H). ¹³ C NMR (400 MHz, CDCl ₃ ) δ160, 146.2, 144, 119.2, 118, 52.2, 50.8, 50.4, 46, 42.2, 12.

Synthesis of 1-[4-(4-chloro-phenyl)-piperazin-1-yl]-2-(4-chloro-5-phenyl-3-trifluoromethyl-pyrazol-1-yl)- ethyl ketone

Following protocol T using 4-chloro-5-phenyl-3-trifluoromethyl-1H-pyrazole _{, K2CO3} , 2-chloro-1-[4-(4-chloro-phenyl)-piper azin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate=2/3) afforded the title compound as a white solid. ¹ H NMR (400MHz, CDCl ₃ ) δ7.82-7.84(m, 2H), 7.4-7.48(m, 3H), 6.9-7.04(m, 2H), 6.88-6.94(m, 2H), 5.22(s , 1H), 3.76-3.88 (m, 2H), 3.6-3.68 (m, 2H), 3.1-3.22 (m, 4H). ¹³ C NMR (400 MHz, CDCl ₃ ) δ 164.2, 130.4, 128, 126, 118.2, 116.4, 52.2, 50, 44, 41.8.

Synthesis of 1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-2-(4-bromo-5-methyl-3-trifluoromethyl-pyrazol-1-yl)- ethyl ketone

Following protocol T using 4-bromo-5-methyl-3-trifluoromethyl-1H-pyrazole, _K2CO3 , 2-chloro-1-[4-(4-fluoro-phenyl ₎ -piper azin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate=2/3) afforded the title compound as a white solid. ¹ H NMR (400MHz, CDCl ₃ ) δ6.96-7(m, 2H), 6.84-6.9(m, 2H), 5(s, 2H), 3.6-3.8(m, 4H), 3.02-3.16(m , 4H), 2.3(s, 3H). ¹³ C NMR (400 MHz, CDCl ₃ ) δ 162.6, 146.5, 142, 118.5, 116, 52.2, 50.4, 46, 42.2, 15.

Synthesis of 1-[4-(4-chloro-phenyl)-piperazin-1-yl]-2-(4-bromo-5-methyl-3-trifluoromethyl-pyrazol-1-yl)- ethyl ketone

Following protocol T using 4-bromo-5-methyl-3-trifluoromethyl-1H-pyrazole, _K2CO3 , ₂ -chloro-1-[4-(4-chloro-phenyl)-piper azin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate=2/3) afforded the title compound as a white solid. ¹ H NMR (400MHz, CDCl ₃ ) δ6.96-7.1 (m, 2H), 6.84-6.89 (m, 2H), 5.2 (s, 2H), 3.6.2-3.8 (m, 4H), 3.0-3.16 (m, 4H), 2.32 (s, 3H). ¹³ C NMR (400 MHz, CDCl ₃ ) δ 162, 146.4, 142.2, 118.5, 116.2, 52, 50.4, 46.2, 42.2, 15.2.

Synthesis of 1-[4-(4-chloro-phenyl)-piperazin-1-yl]-2-(3-heptafluoropropyl-5-methyl-4-nitro-pyrazol-1-yl) - ethyl ketone

Following protocol T, using 3-heptafluoropropyl-5 _- methyl-4-nitro-1H-pyrazole, _K2CO3 , 2-chloro-1-[4-(4-chloro-phenyl)- Piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate = 1/4, _Rf = 0.81) afforded the title compound as a colorless oil. ¹ H NMR (400MHz, CDCl ₃ ) δ6.92-7.02 (m, 2H), 6.82-6.9 (m, 2H), 5.04-5.14 (m, 2H), 3.64-3.82 (m, 4H), 3.06-3.18 (m, 4H), 2.6-2.66 (d, 3H). ¹³ C NMR (400 MHz, CDCl ₃ ) δ 160.4, 146, 144.2, 119.2, 118.2, 52, 50.8, 50.6, 46, 42, 12.2.

Synthesis of 1-[4-(4-chloro-3-methoxyphenyl)-piperazin-1-yl]-2-(4-chloro-5-phenyl-3-trifluoromethyl-pyrazole- 1-yl)-ethanone

Following protocol T using 4-chloro-5-phenyl-3-trifluoromethyl-1H-pyrazole, _K2CO3 , ₂ -chloro-1-[4-(4-chloro-3methoxy- phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography was performed using a solvent mixture (hexane/ethyl acetate=2/3) to provide the title compound as a white solid. ¹ H NMR (400MHz, CDCl ₃ ) δ7.4-7.52(m, 5H), 7.18-7.22(d, 1H), 6.44-6.48(d, 1H), 6.36-6.42(dd, 1H), 4.72(s , 2H), 3.86(s, 3H), 3.5-3.78(m, 4H), 3.1(s, 4H). ¹³ C NMR (400 MHz, CDCl ₃ ) 164, 156.2, 150.4, 130.5, 130, 128.5, 110, 102.2, 56, 52, 50, 44.8, 42.

Synthesis of 1-[4-(4-bromo-3-methoxyphenyl)-piperazin-1-yl]-2-(4-chloro-3-phenyl-5-trifluoromethyl-pyrazole- 1-yl)-ethanone

Following protocol T using 4-chloro-5-phenyl-3-trifluoromethyl-1H-pyrazole, _K2CO3 , ₂ -chloro-1-[4-(4-bromo-3-methoxy -phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography was performed using a solvent mixture (hexane/ethyl acetate=2/3) to provide the title compound as a white solid. ¹ H NMR (400MHz, CDCl ₃ ) δ7.42-7.52(m, 4H), 7.36-7.38(d, 1H), 6.42-6.46(d, 1H), 6.34-6.38(dd, 1H), 4.72(s , 2H), 3.88 (s, 3H), 3.74-3.78 (m, 2H), 3.54-3.58 (m, 2H), 3.12-3.18 (m, 4H). ¹³ C NMR (400 MHz, CDCl ₃ ) δ164, 156.2, 152, 132.6, 130.2, 130, 128.8, 110, 102.2, 56, 52, 50, 44.8, 42.

Synthesis of 1-[4-(4-chloro-3-methoxy-piperazin-1-yl]-2-(4-bromo-5-methyl-3-trifluoromethyl-pyrazol-1-yl )-Ethanone

Following protocol T using 4-bromo-5-methyl-3-trifluoromethyl-1H-pyrazole, _K2CO3 , ₂ -chloro-1-[4-(4-chloro-3-methoxy -phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate = 1/4) afforded the title compound as a white solid. ¹ H NMR (400MHz, CDCl ₃ ) δ7.18-7.22(d, 1H), 6.44-6.48(d, 1H), 6.36-6.42(dd, 1H), 5.0(s, 2H), 3.6.2-3.8 (m, 4H), 3.1-3.2 (m, 4H), 2.3 (s, 3H). ¹³ C NMR (400 MHz, CDCl ₃ ) δ 162, 146.6, 142.2, 118.8, 116, 52.2, 50.4, 46.2, 42.2, 15.2.

Synthesis of 2-(3-amino-4-bromo-5-phenyl-pyrazol-1-yl)-1-[4-(4-chloro-3-methoxyphenyl)-piperazin-1-yl ]-Ethanone

Following protocol T using 4-bromo-5-phenyl-1H-pyrazol-3-ylamine, _K2CO3 , ₂ -chloro-1-[4-(4-chloro-3-methoxy-benzene base)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate = 1/4) afforded the title compound as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ7.78-7.84 (d, 2H), 7.32-7.42 (m, 3H), 7.18-7.22 (d, 1H), 6.44-6.48 (d, 1H), 6.36- 6.42 (dd, 1H), 4.94 (s, 2H), 4.28 (s, 2H), 3.88 (s, 3H), 3.76-3.86 (m, 4H), 3.12-3.18 (m, 4H). ¹³ CNMR (400 MHz, CDCl ₃ ) δ164.6, 154.8, 150.2, 144.6, 130, 128.2, 128, 126.4, 109.2, 102, 56, 51, 50, 49.6, 45.6, 42.

Synthesis of 2-(3-amino-4-chloro-5-methyl-pyrazol-1-yl)-1-[4-(4-chloro-3-methoxyphenyl)-piperazin-1-yl ]-Ethanone

Following protocol T using 4-chloro-5-methyl-1H-pyrazol-3-ylamine, _K2CO3 , ₂ -chloro-1-[4-(4-chloro-3-methoxy-benzene base)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate = 1/4) afforded the title compound as a colorless oil. ¹ H NMR (400MHz, CDCl ₃ ) δ7.18-7.22(d, 1H), 6.44-6.48(d, 1H), 6.36-6.42(dd, 1H), 5.0(s, 2H), 4.24(s, 2H ), 2.4(s, 3H), 3.76-3.86(m, 4H), 3.12-3.18(m, 4H). ¹³ C NMR (400 MHz, CDCl ₃ ) δ 164.6, 154.8, 144.6, 130.2, 130, 128.8, 109.2, 102, 56, 51, 49.6, 45.6, 42.

Synthesis of 1-[4-(4-bromo-3-methoxy-piperazin-1-yl]-2-(4-bromo-5-methyl-3-trifluoromethyl-pyrazol-1-yl )-Ethanone

Following protocol T using 4-bromo-5-methyl-3-trifluoromethyl-1H-pyrazole, _K2CO3 , ₂ -chloro-1-[4-(4-bromo-3-methoxy -phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate = 1/4) afforded the title compound as a white solid. ¹ H NMR (400MHz, CDCl ₃ ) δ7.38-7.4(d, 1H), 6.44-6.46(d, 1H), 6.26-6.4(dd, 2H), 5.0(s, 2H), 3.88(s, 3H ), 3.68-3.8 (m, 4H), 3.14-3.22 (m, 4H), 2.3 (s, 3H). ¹³ C NMR (400 MHz, CDCl ₃ ) δ 164.4, 158, 152.2, 144, 134, 110, 102.2, 56.6, 54.2, 50, 48.8, 46, 42.2, 12.

Synthesis of 1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-2-(3-thiophen-2-yl-pyrazol-1-yl)-ethanone

Following protocol T using 3-(2-thienyl)pyrazole, K ₂ CO ₃ , 2-chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography was performed using a solvent mixture (hexane/ethyl acetate=1/1) to provide the title compound as a white solid. ¹ H NMR (400MHz, CDCl ₃ ) δ7.48-7.52(d, 1H), 7.24-7.28(dd, 1H), 7.14-7.2(dd, 1H), 6.98-7.2(m, 1H), 6.88-6.96 (m, 2H), 6.78-6.84 (m, 2H), 6.46-6.52 (d, 1H), 5.0 (s, 2H), 3.64-3.8 (m, 4H), 2.94-3.1 (m, 4H). ¹³ C NMR (400 MHz, CDCl ₃ ) δ 164.4, 158, 152.2, 144, 134, 132, 126, 124, 123.8, 118, 116, 115.8, 102.2, 54, 51.2, 50.8, 45.8, 42.2.

Synthesis of 2-(4-chloro-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone

Following protocol T using 4-chloro-3-trifluoromethyl-1H-pyrazole _{, K2CO3} , 2-chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl ]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate = 1/1) afforded the title compound as a colorless oil. ¹ H NMR (400MHz, CDCl ₃ ) δ7.64-7.68(d, 1H), 6.98-7.4(m, 2H), 6.86-6.92(m, 2H), 6.98-7.2(m, 1H), 5.4(s , 2H), 3.78-3.84 (m, 2H), 3.68-3.92 (m, 2H), 3-3.1 (m, 4H). ¹³ C NMR (400 MHz, CDCl ₃ ) δ 164.4, 158, 152.2, 144, 132, 118.2, 116, 54, 50.2, 50.0, 46.0, 42.2.

Synthesis of 1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-2-(3,4,5-tribromo-pyrazol-1-yl)-ethanone

Following protocol T using 3,4,5-tribromo-1H-pyrazole, _K2CO3 , 2-chloro-1-[4-(4-fluoro- _phenyl )-piperazin-1-yl]- Ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate = 1/4) afforded the title compound as a white solid. ¹ H NMR (400MHz, CDCl ₃ ) δ6.96-7.2(m, 2H), 6.84-6.9(m, 2H), 5.4(s, 2H), 3.74-3.8(m, 2H), 3.6-3.68(m , 2H), 3.04-3.14 (m, 4H). ¹³ C NMR (400 MHz, CDCl ₃ ) δ 164.4, 158, 156, 144.2, 128, 118.4, 118.2, 116, 100, 52.8, 50.2, 50.0, 46.0, 42.2.

Synthesis of 2-(3-tert-butyl-4-chloro-5-trifluoromethyl-pyrazol-1-yl)-1-[4-(4-fluoro-phenyl)-piperazin-1-yl] - ethyl ketone

Following protocol T, using 5-tert- _butyl -4-chloro-3-trifluoromethyl-1H-pyrazole, _K2CO3 , 2-chloro-1-[4-(4-fluoro-phenyl)- Piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate = 1/1) afforded the title compound as a white solid. ¹ H NMR (400MHz, CDCl ₃ ) δ6.94-7.22(m, 2H), 6.84-6.92(m, 2H), 5.3(s, 2H), 3.68-3.8(m, 2H), 3.6-3.68(m , 2H), 3.04-3.2 (m, 4H), 1.4 (s, 9H). ¹³ C NMR (400 MHz, CDCl ₃ ) δ 164.8, 119, 118.4, 118.2, 116.2, 116, 54, 51, 50.8, 45.4, 42.2, 30, 29, 27.

Synthesis of 2-[3-(4-fluoro-phenyl)-5-methylthio-pyrazol-1-yl]-1-[4-(4-fluoro-phenyl)-piperazin-1-yl] - ethyl ketone

Following protocol T, using 3-(4-fluoro-phenyl)-5-methylthio-1H-pyrazole, K ₂ CO ₃ , 2-chloro-1-[4-(4-fluoro-phenyl)- Piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate=2/3) afforded the title compound as a white solid. ¹ H NMR (400MHz, CDCl ₃ ) δ7.7-7.76(m, 2H), 6.96-7.1(m, 4H), 6.88-6.92(m, 2H), 6.64(s, 1H), 5.3(s, 2H ), 3.7-3.84 (m, 4H), 3.04-3.2 (m, 4H), 2.5 (s, 3H). ¹³ C NMR (400 MHz, CDCl ₃ ) δ 164.8, 152, 140, 127.4, 119, 118.4, 118.2, 116.2, 116, 108, 52.8, 52, 51.8, 45.4, 42.2, 20.

Synthesis of 2-[4-chloro-5-(4-fluoro-phenyl)-3-methylthio-pyrazol-1-yl]-1-[4-(4-fluoro-phenyl)-piperazine- 1-yl]-ethanone

Following protocol T, using 4-chloro-3-(4-fluoro-phenyl)-5-methylthio-1H-pyrazole, K ₂ CO ₃ , 2-chloro-1-[4-(4-fluoro- phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate=2/3) afforded the title compound as a white solid. ¹ H NMR (400MHz, CDCl ₃ ) δ7.82-7.88(m, 2H), 7.06-7.12(m, 2H), 6.96-7.1(m, 2H), 6.88-6.92(m, 2H), 5.2(s , 2H), 3.68-3.84 (m, 4H), 3.06-3.18 (m, 4H), 2.4 (s, 3H). ¹³ C NMR (400 MHz, CDCl ₃ ) δ 164.8, 158, 147, 135, 127.4, 127, 119, 112.4, 112.2, 110, 108.8, 52.8, 52, 51.8, 45.4, 42.2, 18.6.

Synthesis of 2-[4-chloro-3-(4-fluoro-phenyl)-5-methylthio-pyrazol-1-yl]-1-[4-(4-fluoro-phenyl)-piperazine- 1-yl]-ethanone

Following protocol T, using 4-chloro-3-(4-fluoro-phenyl)-5-methylthio-1H-pyrazole, K ₂ CO ₃ , 2-chloro-1-[4-(4-fluoro- phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate=2/3) afforded the title compound as a white solid. ¹ H NMR (400MHz, CDCl ₃ ) δ7.46-7.5(m, 2H), 7.12-7.18(m, 2H), 6.96-7.1(m, 2H), 6.88-6.92(m, 2H), 4.86(s , 2H), 3.72-3.78 (m, 2H), 3.56-3.62 (m, 2H), 3.06-3.18 (m, 4H), 2.54 (s, 3H).

Synthesis of 2-{2-[4-(4-fluoro-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-4-chloro-3-thiophen-2-yl-2H-pyridine Ethyl azole-5-carboxylate

Following protocol T using ethyl 4-chloro-3-thiophen-2-yl-2H-pyrazole-5-carboxylate, K ₂ CO ₃ , 2-chloro-1-[4-(4-fluoro-phenyl )-piperazin-1-yl]-ethanone and DMF. Column chromatography was performed using a solvent mixture (hexane/ethyl acetate = 1.5/1: _Rf = 0.62) to provide the title compound. ¹ H NMR (400MHz, CDCl ₃ ) δ7.06-7.36(m, 1H), 6.96-7.2(m, 3H), 6.84-6.92(m, 3H), 54.46(s, 2H), 4.3-4.4(q , 2H), 3.6-3.82 (m, 4H), 3.05-3.25 (m, 4H), 1.3-1.42 (m, 3H).

Synthesis of 2-(4-amino-3-heptafluoropropyl-5-methyl-pyrazol-1-yl)-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]- ethyl ketone

Following protocol T using ₄ -amino-3-heptafluoropropyl-5-methyl-1H-pyrazole, _K2CO3 , 2-chloro-1-[4-(4-fluoro-phenyl)-piper azin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate = 1/4) afforded the title compound as a colorless oil. ¹ H NMR (400MHz, CDCl ₃ ) δ6.92-7.02(m, 4H), 5.14(s, 2H), 3.64-3.82(m, 4H), 3.6(s, 2H), 3.1-3.22(m, 4H) ), 2.16(s, 3H). ¹³ C NMR (400 MHz, CD ₆ CO) δ 160.4, 158, 146, 144.2, 119.8, 118.2, 52, 50.8, 50.6, 46, 42, 12.2.

Synthesis of 2-(5-butyl-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(4-chloro-phenyl)-piperazin-1-yl]-ethanone

Following protocol T using 5-n-butyl-3-trifluoromethyl-1H-pyrazole, _K2CO3 , ₂ -chloro-1-[4-(4-fluoro-phenyl)-piperazine-1 -yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate = 1/4) afforded the title compound as a colorless oil. ¹ H NMR (400MHz, CDCl ₃ ) δ7.18-7.24(m, 2H), 6.78-6.84(m, 2H), 6.32(s, 1H), 5.0(s, 2H), 3.66-3.78(m, 4H) ), 3.08-3.18 (m, 4H), 2.58-2.64 (t, 2H), 1.6-1.7 (m, 2H), 1.38-1.48 (m, 2H), 0.6-1.0 (t, 3H). ¹³ C NMR (400 MHz, CDCl ₃ ) δ 160.4, 150, 148, 142, 130, 126, 119.8, 103.2, 52, 50.8, 50.6, 46, 42, 30, 26, 22, 14.

Synthesis of 2-(4-chloro-5-butyl-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(4-chloro-phenyl)-piperazin-1-yl]- ethyl ketone

Following protocol T, using 4-chloro-5 _- n-butyl-3-trifluoromethyl-1H-pyrazole, _K2CO3 , 2-chloro-1-[4-(4-fluoro-phenyl)- Piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate = 1/4) afforded the title compound as a colorless oil. ¹ H NMR (400MHz, CDCl ₃ ) δ7.18-7.24(m, 2H), 6.78-6.84(m, 2H), 5.0(s, 2H), 3.66-3.78(m, 4H), 3.08-3.2(m , 4H), 2.58-2.64(t, 2H), 1.5-1.54(m, 2H), 1.38-1.48(m, 2H), 0.6-1.0(t, 3H). ¹³ C NMR (400 MHz, CDCl ₃ ) δ 160.4, 148, 142, 130, 128, 119.8, 52, 50.8, 50.6, 46, 42, 30.4, 26, 23, 14.

Synthesis of 2-(3-amino-4-bromo-5-phenyl-pyrazol-1-yl)-1-[4-(4-bromo-3-methoxyphenyl)-piperazin-1-yl ]-Ethanone

Following protocol T using 4-bromo-5-phenyl-1H-pyrazol-3-ylamine, _K2CO3 , ₂ -chloro-1-[4-(4-bromo-3-methoxy-benzene base)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate = 1/1.5) afforded the title compound as a white solid. ¹ H NMR (400MHz, CDCl ₃ ) δ7.78-7.84(d, 2H), 7.32-7.42(m, 3H), 7.18-7.22(d, 1H), 6.44-6.52(d, 1H), 6.36-6.42 (dd, 1H), 4.94(s, 2H), 4.28(s, 2H), 3.84(s, 3H), 3.76-3.82(m, 4H), 3.12-3.18(m, 4H). ¹³ CNMR (400MHz, CDCl ₃ ) δ164.6, 154.8, 150.2, 144.6, 130, 128.8, 128.6, 126.4, 109.2, 102, 56, 51, 50, 49.6, 45.6, 42.

Synthesis of 2-(4-bromopyrazolyl)-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone

Following protocol T using 4-bromo-1H-pyrazole, _K2CO3 , 2-chloro- _1- [4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography was performed using a solvent mixture (hexane/ethyl acetate=1/1) to provide the title compound as a white solid. ¹ H NMR (400MHz, CDCl ₃ ) δ7.52-7.58(d, 1H), 7.48-7.52(d, 1H), 6.95-7.0(m, 2H), 6.82-6.92(dd, 2H), 5.00(s , 2H), 3.72-3.80 (t, 2H), 3.64-3.72 (t, 2H), 3.02-3.12 (m, 4H). ¹³ C NMR (400MHz, CDCl ₃ ) δ164.6, 158.2, 156.2, 146.6, 141.6, 140.2, 130.5, 129.6, 118.2, 118.0, 115.2, 116.4, 94.2, 53.8, 50.8, 50.2, 45.4, 42.

Synthesis of 2-(4-iodopyrazolyl)-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone

Following protocol T using 4-iodo-1H-pyrazole, _K2CO3 , 2-chloro- _1- [4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography was performed using a solvent mixture (hexane/ethyl acetate=1/1) to provide the title compound as a white solid. ¹ H NMR (400MHz, CDCl ₃ ) δ7.58-7.62(d, 1H), 7.52(s, 1H), 6.95-7.1(m, 2H), 6.84-6.92(dd, 2H), 5.00(s, 2H) ), 3.72-3.80 (t, 2H), 3.64-3.72 (t, 2H), 3.02-3.12 (m, 4H). ¹³ C NMR (400 MHz, CDCl ₃ ) δ 164.6, 158.2, 156.2, 146.8, 140.8, 140.2, 130.5, 129.6, 118.2, 118.0, 115.4, 116.8, 96.0, 53.4, 51.2, 50.2, 45.2, 42.

Synthesis of 2-(3,5-diisopropyl-pyrazol-1-yl)-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone

Following protocol T using 3,5-diisopropyl-1H-pyrazole, _K2CO3 , ₂ -chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]- Ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate = 1/1) afforded the title compound as a white solid. ¹ H NMR (400MHz, CDCl ₃ ) δ6.92-7.0(m, 2H), 6.80-6.88(dd, 2H), 5.88(s, 1H), 4.92(s, 2H), 3.70-3.80(t, 4H ), 2.90-3.10 (m, 4H), 1.40-1.60 (m, 12H). ¹³ C NMR (400 MHz, CDCl ₃ ) δ 160.6, 158.2, 150.2, 119.2, 118.0, 100.0, 50.8, 50.5, 50.2, 45.2, 42, 28.2, 26.0, 22.4.

Synthesis of 1-{2-[4-(4-fluoro-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-3-trifluoromethyl-1H-pyrazole-4-carboxy ethyl acetate

Following protocol T using ethyl 3-trifluoromethyl-1H-pyrazole-4-carboxylate, _K2CO3 , ₂ -chloro-1-[4-(4-fluoro-phenyl)-piperazine- 1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate = 1/1) afforded the title compound as a colorless oil. ¹ H NMR (400MHz, CDCl ₃ ) δ8.15(s, 1H), 6.98-7.04(m, 2H), 6.86-6.92(m, 2H), 5.1(s, 2H), 4.28-4.38(q, 2H ), 3.78-3.84 (m, 2H), 3.62-3.74 (m, 2H), 3.04-3.2 (m, 4H), 1.3-1.4 (t, 3H). ¹³ C NMR (400 MHz, CDCl ₃ ) δ 163.4, 160.5, 159.2, 156.2, 147, 137.2, 119, 118.8, 116, 115.8, 61, 54, 50.8, 50.0, 45.0, 42.2, 14.2.

Synthesis of 1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-2-(4-iodo-3,5-dimethyl-pyrazol-1-yl)-ethanone

Following protocol T using 4-iodo-3,5-dimethyl-pyrazole, _K2CO3 , ₂ -chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl] - ethyl ketone and DMF. Column chromatography was performed using a solvent mixture (hexane/ethyl acetate=1/1) to provide the title compound as a white solid. ¹ H NMR (400MHz, CDCl ₃ ) δ6.95-7.1(m, 2H), 6.84-6.92(dd, 2H), 5.00(s, 2H), 3.62-3.82(m, 4H), 3.02-3.12(m , 4H), 2.22-2.32(d, 6H). ¹³ C NMR (400 MHz, CDCl ₃ ) δ165, 158.2, 156.2, 150.2, 146.8, 141.8, 118.8, 115.4, 115.2, 52.8, 51.6, 50.2, 45.2, 42, 14.8, 12.6.

Synthesis of 2-(3-chloro-indol-1-yl)-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone

Following protocol T using 3-chloro-1H-indole, _K2CO3 , ₂ -chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography was performed using a solvent mixture (hexane/ethyl acetate=1/4) to provide the title compound as a white solid. ¹ H NMR (400MHz, CDCl ₃ ) δ7.64-7.70(m, 1H), 7.38-7.48(m, 2H), 7.18-7.26(m, 2H), 6.94-7.0(m, 2H), 6.82-6.88 (dd, 2H), 5.2 (s, 2H), 3.72-3.82 (m, 4H), 3.02-3.08 (m, 4H). ¹³ C NMR (400 MHz, CDCl ₃ ) δ165, 158.2, 142.8, 134.8, 128.8, 128.4, 122, 121.6, 118.8, 118.6, 115.4, 115.2, 110.6, 110.0, 51.8, 50.6, 50.2, 45.2, 42.

Synthesis of ethyl 2-{2-[4-(4-fluoro-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-5-propyl-2H-pyrazole-3-carboxylate ester

Following protocol T using ethyl 5-propyl-2H-pyrazole-3-carboxylate, K ₂ CO ₃ , 2-chloro-1-[4-(4-fluoro-phenyl)-piperazine-1- base]-ethanone and DMF. Column chromatography was performed using a solvent mixture (hexane/ethyl acetate=1/1) to provide the title compound as a white solid. ¹ H NMR (400MHz, CDCl ₃ ) δ6.94-7.0(m, 2H), 6.82-6.90(dd, 2H), 6.7(s, 1H), 5.5(s, 2H), 4.26-4.32(q, 2H ), 3.62-3.82(m, 4H), 3.04-3.18(m, 4H), 2.58-2.64(t, 2H), 1.64-1.74(m, 2H), 1.34-1.38(t, 3H), 0.96-1.0 (t, 3H). ¹³ C NMR (400MHz, CDCl ₃ ) δ165, 160, 156.2, 152.4, 146.8, 132.8, 118.2, 118.1, 115.8, 115.4, 110.2, 61, 53, 50.6, 50.2, 45, 42, 30, 22.8, 14.2, 14 .

Synthesis of ethyl 2-{2-[4-(4-fluoro-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-3-propyl-2H-pyrazole-5-carboxylate ester

Following protocol T using ethyl 5-propyl-2H-pyrazole-3-carboxylate, _K2CO3 , ₂ -chloro-1-[4-(4-fluoro-phenyl)-piperazine-1- base]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate = 1/1) afforded the title compound as a white solid. ¹ H NMR (400MHz, CDCl ₃ ) δ6.94-7.0(m, 2H), 6.82-6.90(dd, 2H), 6.2(s, 1H), 5.06(s, 2H), 4.34-4.40(q, 2H ), 3.62-3.8(m, 4H), 3.02-3.12(m, 4H), 2.54-2.60(t, 2H), 1.64-1.78(m, 2H), 1.34-1.38(t, 3H), 0.98-1.4 (t, 3H). ¹³ C NMR (400MHz, CDCl ₃ ) δ165, 160, 156.4, 152.2, 146.6, 132.8, 118.4, 118.2, 115.8, 115.4, 113.2, 61, 53, 50.6, 50.2, 45.2, 42, 28, 21.8, 14.2, 14 .

Synthesis of 2-(3,5-di-trifluoromethyl-pyrazol-1-yl)-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone

Following protocol T using 3,5-di-trifluoromethyl-1H-pyrazole, _K2CO3 , 2-chloro-1-[ _4- (4-fluoro-phenyl)-piperazin-1-yl ]-ethanone and DMF. Column chromatography was performed using a solvent mixture (hexane/ethyl acetate=1/1) to provide the title compound as a white solid. ¹ H NMR (400MHz, CDCl ₃ ) δ6.94-7.0(m, 2H), 6.92(s, 1H), 6.82-7.90(dd, 2H), 5.2(s, 2H), 3.72-3.8(t, 2H ), 3.58-3.66(t, 2H), 3.12-3.18(t, 2H), 3.02-3.12(t, 2H). ¹³ C NMR (400 MHz, CDCl ₃ ) δ 162.2, 158.2, 156.4, 146.5, 118.4, 116.2, 115.8, 113.2, 60.4, 53.2, 50.6, 50.2, 45.2, 42.2, 21.2, 14.2.

Synthesis of 1-{2-[4-(4-fluoro-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-1H-pyrazole-3,5-dicarboxylic acid diethyl ester

Following protocol T using diethyl 1H-pyrazole-3,5-dicarboxylate, _K2CO3 , ₂ -chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl ]-ethanone and DMF. Column chromatography was performed using a solvent mixture (hexane/ethyl acetate=1/1) to provide the title compound as a white solid. ¹ H NMR (400MHz, CDCl ₃ ) δ7.38(s, 1H), 6.94-7.0(m, 2H), 6.82-7.90(dd, 2H), 5.54(s, 2H), 4.36-4.42(q, 2H ), 4.26-4.32 (q, 2H), 3.60-3.80 (m, 4H), 3.02-3.20 (m, 4H), 1.22-1.42 (m, 6H). ¹³ C NMR (400MHz, CDCl ₃ ) δ164.2, 162.2, 158.2, 157.4, 156.2, 148.5, 144.4, 134.2, 118.4, 116.2, 115.8, 114.2, 62, 61.8, 54.2, 50.6, 50.2, 45.2, 42.2, 14. , 14.2.

Synthesis of 2-(3-amino-4-t-butyl-pyrazol-1-yl)-1-[4-(4-fluorophenyl)-piperazin-1-yl]-ethanone

Following protocol T using 5-tert-butyl-1H-pyrazol-3-ylamine, _K2CO3 , 2-chloro-1-[ _4- (4-fluoro-phenyl)-piperazin-1-yl ]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate = 3/7: _Rf = 0.49) afforded the title compound as a colorless oil. ¹ H NMR (400MHz, CDCl ₃ ) δ6.92-7.98(t, 2H), 6.82-6.88(dd, 2H), 4.84(s, 2H), 3.95(s, 2H), 3.70-3.90(m, 4H ), 2.95-3.10 (m, 4H), 1.25 (s, 9H).

Synthesis of 2-{2-[4-(4-fluoro-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-4-chloro-5-propyl-2H-pyrazole-3 - ethyl carboxylate

Following Protocol T using ethyl 4-chloro-5-propyl-2H-pyrazole-3-carboxylate, K ₂ CO ₃ , 2-chloro-1-[4-(4-fluoro-phenyl)-piper azin-1-yl]-ethanone and DMF. Column chromatography was performed using a solvent mixture (hexane/ethyl acetate=3/7) to provide the title compound as a white solid. ¹ H NMR (400MHz, CDCl ₃ ) δ6.94-7.0(m, 2H), 6.82-6.90(dd, 2H), 5.0(s, 2H), 4.36-4.40(q, 2H), 3.62-3.82(m , 4H), 3.04-3.18(m, 4H), 2.58-2.66(t, 2H), 1.64-1.76(m, 2H), 1.34-1.38(t, 3H), 0.94-1.0(t, 3H). ¹³ C NMR (400MHz, CDCl ₃ ) δ165, 160.2, 156.2, 152.4, 147, 133, 118.4, 118.2, 115.8, 115.4, 112.2, 61, 53, 50.6, 50.2, 45, 42, 30, 22.8, 14.4, 14.2 .

Synthesis of 2-(3-tert-butyl-5-trifluoromethyl-pyrazol-1-yl)-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone

Following protocol T using 5-tert-butyl-3-trifluoromethyl-1H-pyrazole, _K2CO3 , 2-chloro-1-[ _4- (4-fluoro-phenyl)-piperazine-1 -yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate = 1/1) afforded the title compound as a colorless oil. ¹ H NMR (400MHz, CDCl ₃ ) δ6.92-7.08(t, 2H), 6.82-6.88(dd, 2H), 6.52(s, 1H), 5.08(s, 2H), 3.70-3.80(m, 2H ), 3.58-3.68 (m, 2H), 3.05-3.15 (m, 4H), 1.3 (s, 9H). ¹³ C NMR (400 MHz, CDCl ₃ ) δ164, 161.2, 158.2, 156.4, 147.2, 118.4, 118.2, 115.8, 115.4, 108.2, 54, 50.6, 50.2, 45, 44, 30.

Synthesis of 2-(5-amino-3-furan-2-yl-pyrazol-1-yl)-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone

Following Protocol T using 3-furan-2-yl-2H-pyrazolyl-5-ylamine, K ₂ CO ₃ , 2-chloro-1-[4-(4-fluoro-phenyl)-piperazine- 1-yl]-ethanone and DMF. Column chromatography using 100% ethyl acetate provided the title compound as a white solid. ¹ H NMR (400MHz, CD ₆ CO) δ7.48-7.52 (m, 1H), 6.98-7.06 (m, 2H), 6.52-6.56 (m, 2H), 6.44-6.48 (m, 2H), 5.74 ( s, 1H), 4.98 (s, 2H), 3.68-3.88 (m, 4H), 3.12-3.24 (m, 4H). MS (ES)M+H) expected = 369.4, found 370.1.

Synthesis of 1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-2-(4-bromo-3,5-dimethyl-pyrazol-1-yl)-ethanone

Following protocol T using 4-bromo-3,5-dimethyl-pyrazole, _K2CO3 , ₂ -chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl] - ethyl ketone and DMF. Column chromatography was performed using a solvent mixture (hexane/ethyl acetate=1/1) to provide the title compound as a white solid. ¹ H NMR (400MHz, CDCl ₃ ) δ6.95-7.1(m, 2H), 6.84-6.92(dd, 2H), 4.90(s, 2H), 3.62-3.82(m, 4H), 3.02-3.12(m , 4H), 2.24-2.34(d, 6H). ¹³ C NMR (400 MHz, CDCl ₃ ) δ165, 158.4, 156.6, 150.6, 146.8, 141.4, 119, 115.6, 115.2, 52.6, 51.6, 50.4, 45.2, 42.2, 14.8, 12.6.

Synthesis of 2-[4-chloro-3-(5-chloro-thiophen-2-yl)-pyrazol-1-yl]-1-[4-(4-fluoro-phenyl)-piperazin-1-yl ]-Ethanone

Following protocol T using 4-chloro-3- ₍ 5-chloro-thiophen-2-yl)-1H-pyrazole, _K2CO3 , 2-chloro-1-[4-(4-fluoro-phenyl) -piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate=2/3) afforded the title compound as a yellow solid. ¹ H NMR (400MHz, CDCl ₃ ) 67.58(s, 1H), 7.38-7.42(d, 1H), 6.94-7.1(m, 2H), 6.84-6.88(dd, 2H), 4.96(s, 2H), 3.62-3.81 (m, 4H), 3.02-3.14 (m, 4H). ¹³ C NMR (400 MHz, CDCl ₃ ) δ165, 158.8, 156.8, 142.4, 131, 126.8, 124.8, 119, 116, 115.6, 54, 52, 51.6, 46, 42.6.

Synthesis of 4-chloro-2-{2-[4-(4-fluoro-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-5-methyl-2H-pyrazole-3 - ethyl carboxylate

Following protocol T using ethyl 4-chloro-5-methyl-2H-pyrazole-3-carboxylate, K ₂ CO ₃ , 2-chloro-1-[4-(4-fluoro-phenyl)-piper azin-1-yl]-ethanone and DMF. Column chromatography was performed using a solvent mixture (hexane/ethyl acetate=2/3) to provide the title compound as a white solid. ¹ H NMR (400MHz, CDCl ₃ ) δ6.94-7.1(m, 2H), 6.846.88(dd, 2H), 5.04(s, 2H), 4.38-4.44(q, 2H), 3.62-3.80(m , 4H), 3.02-3.14 (m, 4H), 2.3 (s, 3H), 1.36-1.42 (t, 3H). ¹³ C NMR (400 MHz, CDCl ₃ ) δ182, 165, 119, 116.2, 116, 61.4, 52.3, 51, 50.8, 45.8, 42.6, 14.4, 10.

Synthesis of 4-chloro-5-(5-chloro-thiophen-2-yl)-2-{2-[4-(4-fluoro-phenyl)-piperazin-1-yl]-2-oxo-ethyl Ethyl}-2H-pyrazole-3-carboxylate

Following protocol T using ethyl 4-chloro-5-(5-chloro-thiophen-2-yl)-2H-pyrazole-3-carboxylate, K ₂ CO ₃ , 2-chloro-1-[4-( 4-Fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate=2/3) afforded the title compound as a yellow solid. ¹ H NMR (400MHz, CDCl ₃ ) δ7.46-7.48(m, 1H), 6.94-7.1(m, 2H), 6.84-6.92(m, 3H), 5.4(s, 2H), 4.34-4.4(q , 2H), 3.62-3.81 (m, 4H), 3.04-3.24 (m, 4H), 1.36-1.44 (m, 3H). MS(ES) M+H expected = 511.41, 511 found.

Synthesis of 2-(3-amino-4-chloro-5-methyl-pyrazol-1-yl)-1-[4-(4-chlorophenyl)-piperazin-1-yl]-ethanone

Following protocol T using 4-chloro-5-methyl-1H-pyrazol-3-ylamine, _K2CO3 , ₂ -chloro-1-[4-(4-chloro-phenyl)-piperazine- 1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate = 1/4) afforded the title compound as a colorless oil. ¹ H NMR (400MHz, CDCl ₃ ) δ7.18-7.22(d, 1H), 6.78-6.84(d, 2H), 4.8(s, 2H), 4.4(s, 2H), 3.72-3.82(m, 4H ), 3.08-3.18 (m, 4H), 2.14 (s, 3H).

Synthesis of 1-[4-(4-bromo-3-methoxyphenyl)-piperazin-1-yl]-2-(4-chloro-5-phenyl-3-trifluoromethyl-pyrazole- 1-yl)-ethanone

Following protocol T using 4-chloro-5-phenyl-3-trifluoromethyl-1H-pyrazole, _K2CO3 , ₂ -chloro-1-[4-(4-bromo-3-methoxy -phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate = 2/3: _Rf = 0.58) provided the title compound as a white solid. ¹ H NMR (400MHz, CDCl ₃ ) δ7.81-7.86(m, 1H), 7.36-7.44(m, 4H), 6.42-6.48(d, 1H), 6.34-6.38(dd, 2H), 5.2(s , 2H), 3.88 (s, 3H), 3.62-3.82 (m, 4H), 3.12-3.22 (m, 4H).

Synthesis of 1-[4-(4-fluorophenyl)-piperazin-1-yl]-2-(3-trifluoromethyl-pyrazolyl)-ethanone

Following protocol T using 3-trifluoromethyl-1H-pyrazole, _K2CO3 , 2-chloro-1-[4-(4-fluoro-phenyl)-piperazin-1 _- yl]-ethanone and DMF. Column chromatography was performed using a solvent mixture (hexane/ethyl acetate=1/1) to provide the title compound as a white solid. ¹ H NMR (400MHz, CDCl ₃ ) δ7.54-7.60(m, 1H), 6.94-7.0(m, 2H), 6.80-6.88(m, 2H), 6.52-6.58(d, 1H), 5.2(s , 2H), 3.72-3.80 (t, 2H), 3.62-3.72 (t, 2H), 3.02-3.12 (m, 4H). MS(ES) M+H expected 356.33, found 357.1.

Synthesis of 1-[4-(4-fluorophenyl)-piperazin-1-yl]-2-(3-methyl-pyrazolyl)-ethanone

Following protocol T using 3-methyl-1H-pyrazole, _K2CO3 , 2-chloro-1- _[ 4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF . Column chromatography was performed using a solvent mixture (hexane/ethyl acetate=1/1) to provide the title compound as a white solid. ¹ H NMR (400MHz, CDCl ₃ ) δ7.38-7.41(m, 1H), 6.94-7.0(m, 2H), 6.80-6.88(m, 2H), 6.08-6.10(d, 1H), 4.95(s , 2H), 3.74-3.82(t, 2H), 3.62-3.72(t, 2H), 3.0-3.1(m, 4H), 2.28(s, 3H). MS(ES) M+H expected 302.05, found 303.1.

Synthesis of ethyl 1-{2-[4-(4-fluoro-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-1H-pyrazole-4-carboxylate

Following protocol T using ethyl 1H-pyrazole-4-carboxylate, _K2CO3 , ₂ -chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography was performed using a solvent mixture (hexane/ethyl acetate=1/1) to provide the title compound as a white solid. ¹ H NMR (400MHz, CDCl ₃ ) δ8.2(s, 1H), 7.92(s, 1H), 6.94-7.0(m, 2H), 6.82-6.88(m, 2H), 5.0(s, 2H), 4.1-4.2(q, 2H), 3.74-3.82(t, 2H), 3.62-3.72(t, 2H), 3.0-3.12(m, 4H), 1.28-1.42(t, 3H). MS(ES) M+H expected 360.39, found 361.1.

Synthesis of 1-[4-(4-fluorophenyl)-piperazin-1-yl]-2-(4-methyl-pyrazolyl)-ethanone

Following protocol T using 4-methyl-1H-pyrazole, _K2CO3 , 2-chloro-1- _[ 4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF . Column chromatography was performed using a solvent mixture (hexane/ethyl acetate=1/1) to provide the title compound as a white solid. ¹ H NMR (400MHz, CDCl ₃ ) δ7.26-7.32(m, 1H), 6.94-7.0(m, 2H), 6.80-6.88(m, 2H), 5.0(s, 2H), 3.62-3.82(m , 4H), 3.0-3.1 (m, 4H), 2.1 (s, 3H). MS(ES) M+H expected 302.35, found 303.1.

Synthesis of 1-[4-(4-fluorophenyl)-piperazin-1-yl]-2-(3-amino-4-bromopyrazole)-ethanone

Following protocol T using 4-bromo-3-aminopyrazole, _K2CO3 , ₂ -chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF . Column chromatography using a solvent mixture (hexane/ethyl acetate=3/7) afforded the title compound as a white solid. ¹ H NMR (400MHz, CDCl ₃ ) δ7.23(s, 1H), 6.94-7.0(m, 2H), 6.80-6.88(m, 2H), 4.9(s, 2H), 4.2(s, 2H), 3.72-3.82 (m, 4H), 3.0-3.14 (m, 4H). MS(ES) M+H expected 382.24, found 382.

Synthesis of 1-[4-(4-fluorophenyl)-piperazin-1-yl]-2-(3-amino-4-cyanopyrazole)-ethanone

Following protocol T using 3-amino-4-cyano-pyrazole, _K2CO3 , ₂ -chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography was performed using a solvent mixture (hexane/ethyl acetate=3/7) to provide the title compound as a solid. ¹ H NMR (400MHz, CDCl ₃ ) δ7.48(s, 1H), 6.96-7.2(m, 2H), 6.86-6.92(m, 2H), 4.96(s, 2H), 4.88(s, 2H), 3.78-3.86 (m, 4H), 3.08-3.16 (m, 4H). MS(ES) M+H expected 328.25, found 329.1.

Synthesis of 3-amino-5-cyanomethyl-1-{2-[4-(4-fluoro-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-1H-pyrazole -4-carbonitrile

Following protocol T using 5 _- amino-3-cyanomethyl-1H-pyrazole-4-carbonitrile, _K2CO3 , 2-chloro-1-[4-(4-fluoro-phenyl)-piper azin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate=3/2) afforded the title compound as a white solid. ¹ H NMR (400MHz, CDCl ₃ ) δ6.96-7.2(m, 2H), 6.86-6.92(m, 2H), 5.2(s, 2H), 4.86(s, 2H), 3.78-3.86(m, 4H) ), 3.7(s, 2H), 3.08-3.16(m, 4H). MS(ES) M+H expected 367.39, found 368.1.

Synthesis of 1-[4-(4-fluorophenyl)-piperazin-1-yl]-2-(4-chloro-pyrazolyl)-ethanone

Following protocol T _using 4-chloro-1H-pyrazole, _K2CO3 , 2-chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate=3/2) afforded the title compound as a white solid. ¹ H NMR (400MHz, CDCl ₃ ) δ7.54-7.56(d, 2H), 7.46(s, 1H), 6.94-7.2(m, 2H), 6.84-6.88(m, 2H), 4.98(s, 2H) ), 3.62-3.82 (m, 4H), 3.0-3.1 (m, 4H). MS(ES) M+H expected 322.77, found 323.1.

Synthesis of 2-(3-amino-5-methyl-pyrazol-1-yl)-1-[4-(4-fluorophenyl)-piperazin-1-yl]-ethanone

Following protocol T using 5-methyl-1H-pyrazol-3-ylamine, _K2CO3 , 2-chloro-1-[ _4- (4-fluoro-phenyl)-piperazin-1-yl] - ethyl ketone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate = 1/4) afforded the title compound as a colorless oil. ¹ H NMR (400MHz, CDCl ₃ ) δ7.12-7.18(m, 3H), 7.0-7.08(t, 2H), 4.8(s, 2H), 5.1(s, 2H), 3.78-3.88(m, 4H ), 3.18-3.38 (m, 4H), 2.28 (s, 3H). MS(ES) M+H expected 317.37, found 318.1.

Synthesis of 3-amino-1-{2-[4-(4-fluoro-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-5-methyl-1H-pyrazole-4 - ethyl carboxylate

Following protocol T using ethyl 3-amino-5-methyl-1H-pyrazole-4-carboxylate _{, K2CO3} , 2-chloro-1-[4-(4-fluoro-phenyl)-piper azin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate = 1/4) afforded the title compound as a colorless oil. ¹ H NMR (400MHz, CDCl ₃ ) δ6.94-7.1(m, 2H), 6.84-6.88(m, 2H), 5.52(s, 2H), 4.78(s, 2H), 4.24-4.32(q, 2H ), 3.74-3.82 (m, 4H), 3.0-3.1 (m, 4H), 2.3 (s, 3H), 1.31-1.38 (t, 3H). MS(ES) M+H expected 389.43, found 390.1.

Synthesis of 2-(3-amino-4-chloro-5-methyl-pyrazol-1-yl)-1-[4-(4-fluorophenyl)-piperazin-1-yl]-ethanone

Following protocol T using 4-chloro-5-methyl-1H-pyrazol-3-ylamine, _K2CO3 , ₂ -chloro-1-[4-(4-fluoro-phenyl)-piperazine- 1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate = 1/4) afforded the title compound as a colorless oil. ¹ H NMR (400MHz, CDCl ₃ ) δ7.02-7.08(m, 2H), 6.94-7.0(t, 2H), 4.85(s, 2H), 4.2(s, 2H), 3.80-3.88(m, 4H ), 3.14-3.34 (m, 4H), 2.34 (s, 3H). MS(ES) M+H expected 317.37, found 318.1. MS(ES) M+H expected 351.81, found 352.1.

Synthesis of 2-(3-amino-4-bromo-5-methyl-pyrazol-1-yl)-1-[4-(4-fluorophenyl)-piperazin-1-yl]-ethanone

Following protocol T using 4-bromo-5-methyl-1H-pyrazol-3-ylamine, _K2CO3 , ₂ -chloro-1-[4-(4-fluoro-phenyl)-piperazine- 1-yl]-ethanone and DMF. Column chromatography using ethyl acetate provided the title compound as a colorless oil. ¹ H NMR (400MHz, CDCl ₃ ) δ6.94-7.02(m, 2H), 6.82-6.88(t, 2H), 4.84(s, 2H), 4.1(s, 2H), 3.72-3.78(m, 4H ), 3.04-3.08 (m, 4H), 2.16 (s, 3H). MS(ES) M+H expected 317.37, found 318.1. MS(ES) M+H expected 396.27, found 396.

Synthesis of 2-(5-tert-butyl-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone

Following protocol T using 5-tert-butyl-3-trifluoromethyl-1H-pyrazole _{, K2CO3} , 2-chloro-1-[4-(4-fluoro-phenyl)-piperazine-1 -yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate = 1/1) afforded the title compound as a colorless oil. ¹ H NMR (400MHz, CDCl ₃ ) δ6.94-7.08(t, 2H), 6.82-6.88(dd, 2H), 6.32(s, 1H), 5.14(s, 2H), 3.62-3.80(m, 4H ), 3.05-3.18 (m, 4H), 1.35 (s, 9H). MS(ES) M+H expected 412.43, found 413.1.

Synthesis of ethyl 2-{2-[4-(4-fluoro-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-5-methyl-2H-pyrazole-3-carboxylate ester

Following protocol T using _ethyl 5-methyl-2H-pyrazole-3-carboxylate, _K2CO3 , 2-chloro-1-[4-(4-fluoro-phenyl)-piperazine-1- base]-ethanone and DMF. Column chromatography was performed using a solvent mixture (hexane/ethyl acetate=1/1) to provide the title compound as a white solid. ¹ H NMR (400MHz, CDCl ₃ ) δ6.94-7.0(m, 2H), 6.84-6.88(dd, 2H), 6.58(s, 1H), 5.04(s, 2H), 4.3-4.38(q, 2H ), 3.62-3.80 (m, 4H), 3.02-3.14 (m, 4H), 2.3 (s, 3H), 1.32-1.38 (t, 3H). ¹³ C NMR (400 MHz, CDCl ₃ ) δ 180, 165, 119, 116.2, 116, 109, 61.8, 52, 51.5, 50.8, 45.8, 42.6, 14.4, 10.2.

Synthesis of 2-(3,5-diisopropyl-4-chloro-pyrazol-1-yl)-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone

Following protocol T using 3,5 _- diisopropyl-4-chloro-1H-pyrazole, _K2CO3 , 2-chloro-1-[4-(4-fluoro-phenyl)-piperazine-1 -yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate = 1/1, _Rf = 0.76) afforded the title compound as a white solid. MS (ES)M+H) expected = 406.9, found 407.1.

Synthesis of 2-{2-[4-(4-chloro-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-5-thiophen-2-yl-2H-pyrazole-3- ethyl carboxylate

Following protocol T using ethyl 5-thiophen-2-yl-2H-pyrazole-3-carboxylate, _K2CO3 , 2-chloro-1-[4-(4- _chloro -phenyl)-piperazine -1-yl]-ethanone and DMF. Column chromatography was performed using a solvent mixture (hexane/ethyl acetate=1.5/1) to provide the title compound. ¹ H NMR (400MHz, CDCl ₃ ) δ7.34-7.38(m, 1H), 7.24-7.26(m, 1H), 7.12(s, 1H), 7.04-7.08(dd, 1H), 6.96-7.2(m , 2H), 6.88-6.94 (m, 2H), 4.32-4.42 (q, 2H), 3.52-3.58 (m, 4H), 3.05-3.35 (m, 4H), 1.32-1.42 (m, 3H). ¹³ C NMR (400 MHz, CDCl ₃ ) δ 164.2, 128, 126.8, 126.6, 120.2, 118.4, 115.2, 62.5, 54.2, 50.5, 42.6, 44, 14.6.

Synthesis of 2-(4-amino-3-heptafluoropropyl-5-methyl-pyrazol-1-yl)-1-[4-(4-chloro-phenyl)-piperazin-1-yl]- ethyl ketone

Following protocol T using ₄ -amino-3-heptafluoropropyl-5-methyl-1H-pyrazole, _K2CO3 , 2-chloro-1-[4-(4-chloro-phenyl)-piper azin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate = 1/4, _Rf = 0.42) afforded the title compound as a colorless oil. ¹ H NMR (400MHz, CDCl ₃ ) δ6.88-6.94(d, 2H), 7.22-7.26(d, 2H), 4.98(s, 2H), 3.64-3.82(m, 4H), 3.1-3.22(m , 4H), 2.98(s, 2H), 2.18(s, 3H). MS (ES)M+H) expected = 501.82, found 502.1.

Synthesis of 1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-(4-chloro-5-ethyl-3-trifluoromethyl-pyrazole -1-yl)-ethanone:

Following protocol T using 4-chloro-5-ethyl-3-trifluoromethyl-1-H-pyrazole, K ₂ CO ₃ , 1-[4-(4-chloro-3-methoxyphenyl )-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate = 2/3, _Rf = 0.53) afforded the title compound as a white solid. ¹ H NMR (400MHz, CDCl ₃ ) δ7.18-7.22(d, 2H), 6.38-6.48(m, 2H), 4.98(s, 2H), 3.86(s, 3H), 3.66-3.76(m, 4H) ), 3.1-3.2 (m, 4H), 2.66-2.74 (q, 2H), 1.18-1.28 (m, 3H). MS (ES)M+H) expected = 464.82, found 465.

Synthesis of 2-(4-chloro-5-isopropyl-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(4-chloro-3-methoxy-phenyl)-piper Azin-1-yl]-ethanone:

Following protocol T using 4-chloro-5-isopropyl-3-trifluoromethyl-1-H-pyrazole, K ₂ CO ₃ , 1-[4-(4-chloro-3-methoxybenzene base)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate = 5.5/4.5, _Rf = 0.52) afforded the title compound as a white solid. ¹ H NMR (400MHz, CDCl ₃ ) δ7.19-7.22(d, 2H), 6.42-6.48(m, 2H), 5.18(s, 2H), 3.88(s, 3H), 3.56-3.78(m, 4H) ), 3.22-3.44 (m, 4H), 3.04-3.14 (m, 1H), 1.44-1.48 (d, 6H). ¹³ C NMR (400MHz, CDCl3) δ 164.2, 154.8, 151, 130, 109.8, 102, 56.2, 54, 50.5, 50, 45.2, 42.6, 26.2, 22.1.

Synthesis of 2-(4-chloro-3-isopropyl-5-trifluoromethyl-pyrazol-1-yl)-1-[4-(4-chloro-3-methoxy-phenyl)-piper Azin-1-yl]-ethanone:

Following protocol T, using 4-chloro-3-isopropyl-5-trifluoromethyl-1-H-pyrazole, K ₂ CO ₃ , 1-[4-(4-chloro-3-methoxybenzene base)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate = 2/3, _Rf = 0.45) afforded the title compound as a white solid. ¹ H NMR (400MHz, CDCl ₃ ) δ7.19-7.22(d, 2H), 6.38-6.48(m, 2H), 5(s, 2H), 3.86(s, 3H), 3.62-3.78(m, 4H) ), 3.08-3.18 (m, 4H), 2.98-3.04 (m, 1H), 1.35-1.41 (d, 6H). ¹³ C NMR (400MHz, CDCl3) δ 163.8, 154.8, 150.5, 130, 109.8, 102, 56.4, 52.8, 50, 49.8, 45.2, 42.6, 26.8, 20.

Synthesis of 2-(4-chloro-3-n-propyl-5-trifluoromethyl-pyrazol-1-yl)-1-[4-(4-chloro-3-methoxy-phenyl)- Piperazin-1-yl]-ethanone:

Following protocol T, using 4-chloro-3-n-propyl-5-trifluoromethyl-1-H-pyrazolyl, K ₂ CO ₃ , 1-[4-(4-chloro-3-methoxy phenyl)-piperazine-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate = 3/7, _Rf = 0.78) afforded the title compound as a white solid. ¹ H NMR (400MHz, CDCl ₃ ) δ7.22-7.24(d, 2H), 6.42-6.48(m, 2H), 5.7(s, 2H), 3.8(s, 3H), 3.72-3.78(m, 4H) ), 3.22-3.42 (m, 4H), 2.66-2.72 (t, 2H), 1.58-1.68 (m, 2H), 0.98-1.02 (t, 3H). ¹³ CNMR (400MHz, CDCl ₃ ) δ164, 154.8, 150.5, 130, 109.8, 102.2, 56.4, 52.8, 50, 49.8, 45.2, 42.6, 26, 21.8, 14.

Synthesis of 1-[4-(4-chloro-3-methoxyphenyl)-piperazin-1-yl]-2-(4-bromo-3-phenyl-5-trifluoromethyl-pyrazole- 1-yl)-ethanone

Following protocol T using 4-bromo-3-phenyl-5-trifluoromethyl-1H-pyrazole, _K2CO3 , ₂ -chloro-1-[4-(4-chloro-3-methoxy -phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate = 1/1, _Rf = 0.51) afforded the title compound as a white solid. ¹ H NMR (400MHz, CDCl ₃ ) δ7.42-7.52(m, 5H), 7.18-7.22(d, 1H), 6.38-6.42(dd, 1H), 6.46-6.48(d, 1H), 4.94(s , 2H), 3.88(s, 3H), 3.5-3.78(m, 4H), 3.18(s, 4H).

Synthesis of 1-[4-(4-chloro-3-methoxyphenyl)-piperazin-1-yl]-2-(4-chloro-5-phenyl-3-trifluoromethyl-pyrazole- 1-yl)-ethanone

Following protocol T using 4-chloro-5-phenyl-3-trifluoromethyl-1H-pyrazole, _K2CO3 , ₂ -chloro-1-[4-(4-chloro-3-methoxy -phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate = 2/3, _Rf = 0.92) afforded the title compound as a white solid. ¹ H NMR (400MHz, CDCl ₃ ) δ7.78-7.84(m, 2H), 7.36-7.52(m, 4H), 6.38-6.48(m, 2H), 5.2(s, 2H), 3.88(s, 3H ), 3.62-3.78 (m, 4H), 3.18-3.26 (s, 4H). ¹³ C NMR (400 MHz, CDCl ₃ ) 164.4, 156, 150.4, 130.4, 130, 128.6, 110.2, 102.4, 56.4, 52, 50.4, 44.6, 42.

Synthesis of 1-[4-(4-chloro-3-methoxyphenyl)-piperazin-1-yl]-2-(4-chloro-3-[3-fluoro-phenyl]-5-trifluoro Methyl-pyrazol-1-yl)-ethanone

Following protocol T, using 4-chloro-3-[3-fluorophenyl]-5-trifluoromethyl-1H-pyrazole, K ₂ CO ₃ , 2-chloro-1-[4-(4-chloro- 3-methoxy-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate = 2/3, _Rf = 0.51) afforded the title compound as a white solid. ¹ H NMR (400MHz, CDCl ₃ ) δ7.44-7.52(m, 1H), 7.18-7.28(m, 4H), 6.38-6.48(m, 2H), 4.94(s, 2H), 3.84(s, 3H ), 3.52-3.78 (m, 4H), 3.12 (s, 4H).

Synthesis of 1-[4-(4-chloro-3-methoxyphenyl)-piperazin-1-yl]-2-(4-chloro-5-[3-fluoro-phenyl]-3-trifluoro Methyl-pyrazol-1-yl)-ethanone

Following protocol T, using 4-chloro-5-[3-fluorophenyl]-3-trifluoromethyl-1H-pyrazole, K ₂ CO ₃ , 2-chloro-1-[4-(4-chloro- 3-methoxy-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate = 2/3, _Rf = 0.59) afforded the title compound as a white solid. ¹ H NMR (400MHz, CDCl ₃ ) δ7.64-7.68(d, 1H), 7.56-7.62(d, 1H), 7.36-7.42(m, 1H), 7.22-7.24(m, 2H), 7.08-7.12 (m, 1H), 6.42-6.52 (m, 2H), 5.2 (s, 2H), 3.9 (s, 3H), 3.62-3.82 (m, 4H), 3.12-3.22 (m, 4H).

1-[4-(4-chloro-3-methoxyphenyl)-piperazin-1-yl]-2-(4-chloro-3,5-di-trifluoromethyl-pyrazole-1- base)-ethanone:

Following general protocol T using 4-chloro-3,5-di-trifluoromethyl-pyrazole, K ₂ CO ₃ , 2-chloro-1-[4-(4-chloro-3-methoxy-benzene base)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate = 1/1) afforded the title compound as a white solid. ¹ H NMR (400MHz, CDCl ₃ ) δ7.22-7.24(m, 2H), 6.42-6.52(m, 2H), 5.2(s, 2H), 3.88(s, 3H), 3.58-3.82(m, 4H) ), 3.14-3.24 (m, 4H). MS (ES) (M+H) expected = 505.24, 506 found.

1-[4-(4-chloro-3-methoxyphenyl)-piperazin-1-yl]-2-(3-methyl-4,5-dibromopyrazol-1-yl)-ethyl ketone:

Following general protocol T using 3-methyl-4,5-dibromo-pyrazole, _K2CO3 , 2chloro-1- _[ 4(4-chloro-3-methoxy-phenyl)-piperazine -1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate = 1/1) afforded the title compound as a white solid. ¹ H NMR (400MHz, CDCl ₃ ) δ7.22-7.23(m, 1H), 6.42-6.50(m, 2H), 4.95(s, 2H), 3.90(s, 3H), 3.68-3.78(m, 4H) ), 3.14-3.24 (m, 4H). MS (ES) (M+H) expected = 506.6, found 506.9.

2-(3-Amino-4-chloro-5-phenyl-pyrazol-1-yl)-1-[4-(4-chloro-3-methoxyphenyl)-piperazin-1-yl] - ethyl ketone:

Following general protocol T using 4-chloro-5-phenyl-1H-pyrazol-3-ylamine, _K2CO3 , ₂ -chloro-1-[4-(4-chloro-3-methoxy- phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate = 1/4, _Rf = 0.68) afforded the title compound as a white solid. ¹ H NMR (400MHz, CDCl ₃ ) δ7.79-7.81(d, 2H), 7.32-7.42(m, 3H), 7.18-7.22(d, 1H), 6.44-6.48(d, 1H), 6.36-6.42 (dd, 1H), 4.94(s, 2H), 4.28(s, 2H), 3.88(s, 3H), 3.76-3.86(m, 4H), 3.12-3.18(m, 4H). MS (ES) (M+H) expected = 460.36, 460 found.

1-[4-(4-chloro-3-methoxyphenyl)-piperazin-1-yl]-2-(4-chloro-3,5-dimethyl-pyrazol-1-yl)- Ethyl ketone:

Following general protocol T using 4-chloro-3,5-dimethyl-pyrazole, K ₂ CO ₃ , 2-chloro-1-[4-(4-chloro-3-methoxy-phenyl)- Piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate = 1/1, _Rf = 0.28) afforded the title compound as a white solid. ¹ H NMR (400MHz, CDCl ₃ ) δ7.19-7.22(m, 2H), 6.39-6.49(m, 2H), 4.86(s, 2H), 3.84(s, 3H), 3.64-3.78(m, 4H) ), 3.1-3.18 (m, 4H), 2.12-2.42 (d, 6H). MS (ES) (M+H) expected = 397.3, found 397.

1-[4(4-chloro-3-methoxyphenyl)-2-methyl-piperazin-1-yl]2-(4-chloro-3-phenyl-5-trifluoromethyl-pyrazole-1 -yl)-ethanone:

Following general protocol T using 4- _chloro -5-phenyl-3-trifluoromethyl-1H-pyrazole, _K2CO3 , 2-chloro-1-[4-(4-chloro-3-methoxy [0010]-phenyl)-2-(S)-methyl-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate = 2/3, _Rf = 0.6) afforded the title compound as a white solid. ¹ H NMR (400MHz, CDCl ₃ ) δ7.4-7.52(m, 5H), 7.19-7.22(d, 1H), 6.38-6.48(d, 2H), 4.78-5.22(m, 3H), 4.4-4.42 (m, 2H), 4.0(s, 1H), 3.88(s, 3H), 3.42-3.58(m, 2H), 3.32-3.38(d, 1H), 3.15(s, 1H), 2.72-2.96(m , 3H) 1.28-1.38 (m, 4H). MS (ES) (M+H) expected = 527.4, found 527.

1-[4-(4-chloro-3-methoxyphenyl)-piperazin-1-yl]-2-(3-methyl-4-chloro-5-bromopyrazol-1-yl)- Ethyl ketone:

Following general protocol T using 3-methyl-4-chloro-5-bromo-pyrazole, _K2CO3 , ₂ -chloro-1-[4-(4-chloro-3-methoxy-phenyl) -piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate = 1/1) afforded the title compound as a white solid. ¹ H NMR (400MHz, CDCl ₃ ) δ7.22-7.23(m, 1H), 6.42-6.50(m, 2H), 4.92(s, 2H), 3.90(s, 3H), 3.70-3.80(m, 4H) ), 3.12-3.22 (m, 4H). MS (ES) (M+H) expected = 462.17, found 462.9.

1-[4-(4-chloro-3-methoxy-phenyl)-2-(S)-methyl-piperazin-1-yl]-2-(3-methyl-4-chloro-5 -Bromopyrazol-1-yl)-ethanone:

Following general protocol T using 3-methyl-4-chloro-5-bromo-pyrazole, _K2CO3 , ₂ -chloro-1-[4-(4-chloro-3-methoxy-phenyl) -2-(S)-Methyl-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate = 1/1) afforded the title compound as a white solid. ¹ H NMR (400MHz, CDCl ₃ ) δ7.18-7.22(m, 1H), 6.38-6.46(m, 2H), 4.78-5.22(m, 3H), 4.38-4.42(m, 1H), 4.2(s , 1H), 3.85(s, 3H), 3.8(s, 1H), 3.42-3.58(m, 2H), 3.32-3.38(d, 1H), 3.15(s, 1H), 2.72-2.96(m, 3H ), 1.26-1.38 (m, 4H). MS (ES) (M+H) expected = 476.19, found 476.9.

1-[4-(4-chloro-3-methoxyphenyl)-piperazin-1-yl]-2-(4-chloro-5-[2-fluoro-phenyl]-3-trifluoromethane Base-pyrazol-1-yl)-ethanone:

Following general protocol T, using 4-chloro-5-[2-fluorophenyl]-3-trifluoromethyl-1H-pyrazole, K ₂ CO ₃ , 2-chloro-1-[4-(4-chloro -3-methoxy-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate = 2/3, _Rf = 0.6) afforded the title compound as a white solid. ¹ H NMR (400MHz, CDCl ₃ ) δ7.44-7.56(m, 2H), 7.26-7.32(t, 1H), 7.18-7.26(m, 2H), 6.44-6.46(d, 1H), 6.36-6.42 (dd, 1H), 4.95(s, 2H), 3.86(s, 3H), 3.5-3.68(m, 4H), 3.02-3.14(s, 4H). MS (ES) (M+H) expected = 531.3, found 531.

1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-(4-chloro-5-methyl-3-phenyl-pyrazole-1- base)-ethanone:

Following general protocol T using 4-chloro-5-methyl-3-phenyl-pyrazole, K ₂ CO ₃ , 2-chloro-1-[4-(4-chloro-3-methoxy-phenyl )-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate = 1/3, _Rf = 0.7) afforded the title compound as a white solid. ¹ H NMR (400MHz, CDCl ₃ ) δ7.82-7.88(m, 2H), 7.38-7.42(t, 2H), 7.32-7.36(m, 1H), 7.18-7.22(d, 1H), 6.38-6.48 (m, 2H), 4.99 (s, 2H), 3.88 (s, 3H), 3.72 (m, 4H), 3.083.18 (m, 4H), 2.34 (s, 3H). MS (ES) (M+H) expected = 459.38, found 459.

1-[4-(4-chloro-3-methoxyphenyl)-piperazin-1-yl]-2-(4-chloro-3-[2-fluoro-phenyl]-5-trifluoromethane Base-pyrazol-1-yl)-ethanone:

Following general protocol T, using 4-chloro-5-[2-fluorophenyl]-3-trifluoromethyl-1H-pyrazole, K ₂ CO ₃ , 2-chloro-1-[4-(4-chloro -3-methoxy-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate = 2/3, _Rf = 0.6) afforded the title compound as a white solid. ¹ H NMR (400MHz, CDCl ₃ ) δ7.52-7.58(m, 1H), 7.38-7.46(m, 1H), 7.14-7.26(m, 3H), 6.44-6.51(m, 2H), 5.22(s , 2H), 3.84 (s, 3H), 3.62-3.82 (m, 4H), 3.12-3.24 (m, 4H). MS (ES) (M+H) expected = 531.0, 531 found.

1-[4-(4-chloro-3-methoxyphenyl)-piperazin-1-yl]-2-(4-chloro-3-[4-trifluoromethyl-phenyl]-5- Trifluoromethyl-pyrazol-1-yl)-ethanone:

Following general protocol T, using 4-chloro-5-[4-trifluoromethylphenyl]-3-trifluoromethyl-1H-pyrazole, K ₂ CO ₃ , 2-chloro-1-[4-( 4-Chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate = 1/3, _Rf = 0.91) afforded the title compound as a colorless oil. ¹ HNMR (400MHz, CDCl ₃ ) δ7.99-8.12(d, 1H), 7.66-7.71(d, 1H), 7.22-7.24(m, 1H), 6.44-6.52(m, 2H), 5.22(s, 2H), 3.85 (s, 3H), 3.62-3.82 (m, 4H), 3.16-3.24 (m, 4H). MS (ES) (M+H) expected = 581.35, found 581.

1-[4-(4-chloro-3-methoxyphenyl)-piperazin-1-yl]-2-(4-chloro-5-[4-trifluoromethyl-phenyl]-3- Trifluoromethyl-pyrazol-1-yl)-ethanone:

Following general protocol T, using 4-chloro-3-[4-trifluoromethylphenyl]-5-trifluoromethyl-1H-pyrazole, K ₂ CO ₃ , 2-chloro-1-[4-( 4-Chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate = 1/3, _Rf = 0.85) afforded the title compound as a white solid. ¹ H NMR (400MHz, CDCl ₃ ) δ7.78-7.8(d, 1H), 7.62-7.66(d, 1H), 7.20-7.22(m, 1H), 6.40-6.48(m, 2H), 4.92(s , 2H), 3.88 (s, 3H), 3.60-3.78 (m, 4H), 3.16-3.20 (m, 4H). MS (ES) (M+H) expected = 581.35, found 581.

1-[4-(4-chloro-3-methoxyphenyl)-piperazin-1-yl]-2-(4-chloro-3-[4-methoxyphenyl]-5-trifluoro Methyl-pyrazol-1-yl)-ethanone:

Following general protocol T, using 4-chloro-5-[4-methoxyphenyl]-3-trifluoromethyl-1H-pyrazole, K ₂ CO ₃ , 2-chloro-1-[4-(4 -Chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate = 3/7, _Rf = 0.45) afforded the title compound as a colorless oil. ¹ H NMR (400MHz, CDCl ₃ ) δ7.76-7.78(d, 1H), 7.22-7.24(d, 1H), 6.94-6.96(d, 1H), 6.42-6.52(m, 2H), 4.98(s , 2H), 3.88(s, 3H), 3.82(s, 3H), 3.62-3.82(m, 4H), 3.16-3.24(m, 4H). MS (ES) (M+H) expected = 543.38, found 543.

1-[4-(4-chloro-3-methoxyphenyl)-piperazin-1-yl]-2-(4-chloro-5-[4-methoxyphenyl]-3-trifluoro Methyl-pyrazol-1-yl)-ethanone:

Following general protocol T, using 4-chloro-5-[4-methoxyphenyl]-3-trifluoromethyl-1H-pyrazole, K ₂ CO ₃ , 2-chloro-1-[4-(4 -Chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate = 3/7, _Rf = 0.36) afforded the title compound as a colorless oil. ¹ H NMR (400MHz, CDCl ₃ ) δ7.36-7.39(d, 1H), 7.20-7.22(d, 1H), 6.88-7.22(d, 2H), 6.38-6.48(m, 2H), 4.92(s , 2H), 3.88 (s, 3H), 3.84 (s, 3H), 3.56-3.78 (m, 4H), 3.14-3.18 (m, 4H). MS (ES) (M+H) expected = 543.38, found 542.9.

2-[4-chloro-5-(4-fluoro-phenyl)-3-methylthio-pyrazol-1-yl]-1-[4-(4-chloro-3-methoxy-phenyl )-piperazin-1-yl]-ethanone:

Following general protocol T using 4-chloro-5-(4-fluoro-phenyl)-3-methylthio-pyrazol-]-yl, K ₂ CO ₃ , 2-chloro-1-[4-(4 -Chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate = 1/4, _Rf = 0.77) afforded the title compound as a colorless oil. ¹ H NMR (400MHz, CDCl ₃ ) δ7.82-7.88(m, 2H), 7.21-7.25(m, 1H), 7.04-7.14(t, 2H), 6.42-6.51(m, 2H), 5.4(s , 2H), 3.9(s, 3H), 3.7-3.8(m, 4H), 3.25-3.52(m, 4H), 2.4(s, 3H). ¹³ C NMR (400 MHz, CDCl ₃ ) δ 164.8, 158, 152, 147, 135, 131, 130, 119, 115.4, 115, 110, 104, 56.5, 52.8, 50.8, 50, 45.4, 42.2, 18.6.

1-[4-(4-chloro-3-methoxyphenyl)-piperazin-1-yl]-2-(4-chloro-5-[4-fluorophenyl]-3-trifluoromethyl -pyrazol-1-yl)-ethanone:

Following general protocol T, using 4-chloro-3-[4-fluorophenyl]-5-trifluoromethyl-1H-pyrazole, K ₂ CO ₃ , 2-chloro-1-[4-(4-chloro -3-methoxy-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate = 3.5/6.5, _Rf = 0.83) afforded the title compound as a white solid. ¹ H NMR (400MHz, CDCl ₃ ) δ7.44-7.49(m, 2H), 7.14-7.22(m, 3H), 6.38-6.48(m, 2H), 4.9(s, 2H), 3.89(s, 3H ), 3.54-3.78 (m, 4H), 3.14 (s, 4H). ¹³ C NMR (400 MHz, CDCl ₃ ) δ 164.8, 162, 155, 152, 143, 132, 131, 122, 115.4, 115, 110, 100, 56.2, 52.2, 50.8, 50, 45.4, 42.2.

2-[4-chloro-3-(5-chloro-thiophen-2-yl)-5-methyl-pyrazol-1-yl]-1-[4-(4-chloro-3-methoxy- Phenyl)-piperazin-1-yl]-ethanone:

Following general protocol T, using 4-chloro-3-(5-chloro-thiophen-2-yl)-5-methyl-pyrazol-1-yl, K ₂ CO ₃ , 2-chloro-1-[4- (4-Chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate = 1/4, _Rf = 0.8) afforded the title compound. ¹ H NMR (400MHz, CDCl ₃ ) δ7.39-7.41(d, 1H), 7.21-7.24(m, 1H), 6.86-6.88(d, 1H), 6.42-648(dd, 1H), 6.48-6.51 (m, 1H) 4.95 (s, 2H), 3.88 (s, 3H), 3.72-3.82 (m, 4H), 3.11-3.21 (m, 4H), 2.3 (s, 3H).

2-[4-Chloro-3-(2-thiophene)-5-methyl-pyrazol-1-yl]-1-[4-(4-chloro-3-methoxyphenyl)-piperazine- 1-yl]-ethanone:

Following general protocol T, using 4-chloro-3-(5-chloro-thiophen-2-yl)-5-methyl-pyrazol-1-yl, K ₂ CO ₃ , 2-chloro-1-[4- (4-Chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate = 1/4, _Rf = 0.8) afforded the title compound. ¹ H NMR (400MHz, CDCl ₃ ) δ7.62-7.66(m, 1H), 7.24-7.26(m, 1H), 7.18-7.22(d, 1H), 7.45-7.8(m, 1H), 6.39-6.48 (m, 2H), 4.95 (s, 2H), 3.86 (s, 3H), 3.70-3.78 (m, 4H), 3.09-3.18 (m, 4H), 2.3 (s, 3H).

2-(4-Chloro-5-hydroxymethyl-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(4-chloro-3-methoxy-phenyl)-piperazine -1-yl]-ethanone:

Following general protocol T, using 4-chloro-5-hydroxymethyl-3-trifluoromethyl-pyrazol-1-yl, K ₂ CO ₃ , 2-chloro-1-[4-(4-chloro-3 -methoxy-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate = 1/8, _Rf = 0.5) provided the title compound. ¹ H NMR (400MHz, CDCl ₃ ) δ7.21-7.28(m, 1H), 6.41-6.51(m, 2H), 5.18(s, 2H), 4.66(s, 2H), 3.86(s, 3H), 3.70-3.78 (m, 4H), 3.11-3.24 (m, 4H).

2-(4-chloro-5-methoxymethyl-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(4-chloro-3-methoxy-phenyl)- Piperazin-1-yl]-ethanone:

Following general protocol T, using 4-chloro-5-methoxymethyl-3-trifluoromethyl-pyrazol-1-yl, K ₂ CO ₃ , 2-chloro-1-[4-(4-chloro -3-methoxy-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography was performed using a solvent mixture (hexane/ethyl acetate = 1/4, _Rf = 0.65) to provide the title compound. ¹ H NMR (400MHz, CDCl ₃ ) δ7.15-7.18(d, 1H), 6.65-6.68(d, 1H), 6.51-6.58(dd, 1H), 5.32(s, 2H), 4.58(s, 3H ), 4.52 (s, 2H), 3.86 (s, 3H), 3.70-3.75 (m, 4H), 3.18-3.28 (m, 4H). MS (ES) (M+H) expected = 481.31, found 481.2.

4-chloro-1-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-5-methyl-1H - Ethyl pyrazole-3-carboxylate:

Following general protocol T using ethyl 4-chloro-5-methyl-1H-pyrazole-3-carboxylate, _K2CO3 , 2-chloro-1-[ _4- (4-chloro-3-methoxy yl-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography was performed using a solvent mixture (hexane/ethyl acetate = 1/4, _Rf = 0.81) to provide the title compound. ¹ H NMR (400MHz, CDCl ₃ ) δ7.18-7.21(d, 1H), 6.66-6.68(d, 1H), 6.52-6.55(dd, 1H), 5.42(s, 2H), 4.30-4.36(q , 2H), 3.85(s, 3H), 3.70-3.77(m, 4H), 3.18-3.28(m, 4H), 2.22(s, 3H), 1.32-1.38(t, 3H). MS (ES) (M+H) expected = 455.34, found 455.2.

4-chloro-1-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-3-methyl-1H - Ethyl pyrazole-5-carboxylate:

Following general protocol T using ethyl 4- _chloro -3-methyl-1H-pyrazole-5-carboxylate, _K2CO3 , 2-chloro-1-[4-(4-chloro-3-methoxy yl-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography was performed using a solvent mixture (hexane/ethyl acetate = 1/4, _Rf = 0.75) to provide the title compound. ¹ H NMR (400MHz, CDCl ₃ ) δ7.19-7.22(d, 1H), 6.64-6.66(d, 1H), 6.54-6.58(dd, 1H), 5.44(s, 2H), 4.30-4.35(q , 2H), 3.85(s, 3H), 3.70-3.77(m, 4H), 3.20-3.28(m, 4H), 2.24(s, 3H), 1.34-1.38(t, 3H). MS (ES) (M+H) expected = 455.34, found 455.2.

2-(4-Chloro-5-cyclopropyl-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(4-chloro-3-methoxy-phenyl)-piperazine -1-yl]-ethanone:

Following general protocol T, using 4-chloro-5-cyclopropyl-3-trifluoromethyl-pyrazol-1-yl, K ₂ CO ₃ , 2-chloro-1-[4-(4-chloro-3 -methoxy-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate = 1/5, _Rf = 0.88) provided the title compound. ¹ H NMR (400MHz, CDCl ₃ ) δ7.20-7.24(d, 1H), 6.48-6.50(d, 1H), 6.42-6.46(dd, 1H), 5.03(s, 2H), 3.85(s, 3H ), 3.58-3.78 (m, 4H), 3.14-3.24 (m, 4H), 1.86-1.94 (m, 1H), 0.51-0.59 (m, 4H). MS (ES) (M+H) expected = 477.32, found 477.2.

4-chloro-1-{2-[4-(4-chloro-3-methoxy-phenyl)-2-methylpiperazin-1-yl]-2-oxo-ethyl}-5- Ethyl methyl-1H-pyrazole-3-carboxylate:

Following general protocol T using ethyl 4-chloro-5-methyl-1H-pyrazole-3-carboxylate, _K2CO3 , 2-chloro-1-[ _4- (4-chloro-3-methoxy [0010]-phenyl)-2-(S)-methyl-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate = 1/4, _Rf = 0.81) afforded the title compound: HPLC retention time = 4.51 min (Agilent Zorbax SB-C18, 2.1 x 50 mm, 5 μ, 35 °C) with a 4.5 minute gradient of 20-95% B with a 1.1 minute wash at 95% B (A = 0.1% formic acid/5% acetonitrile/94.9% water, B = 0.08% formic acid/99.9% acetonitrile).

2-(4-chloro-3-(3-methoxyphenyl)-5-trifluoromethyl-pyrazol-1-yl)-1-[4-(4-chloro-3-methoxy- Phenyl)-2-methyl-piperazin-1-yl]-ethanone:

Following general protocol T, using 4-chloro-3-(3-methoxyphenyl)-5-trifluoromethyl-pyrazol-1-yl, K ₂ CO ₃ , 2-chloro-1-[4- (4-Chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate = 1/5, _Rf = 0.82) provided the title compound. ¹ H NMR (400MHz, CDCl ₃ ) δ7.42-7.48(m, 2H), 7.28-7.34(m, 1H), 7.19-7.22(d, 1H), 6.86-6.91(dd, 1H), 6.39-6.47 (m, 2H), 4.99 (s, 2H), 3.88 (s, 3H), 3.84 (s, 3H), 3.72-3.8 (m, 4H), 3.12-3.18 (m, 4H), 2.3 (3H). MS (ES) (M+H) expected = 491.34, found 491.2. ¹³ CNMR (400MHz, CDCl ₃ ) δ164.8, 160, 156, 152, 145, 140, 132, 131, 120, 115.4, 115, 110, 108, 100, 56.2, 52.2, 50.8, 50, 45.4, 42.2, 20.

4-chloro-1-{2-[4-(4-chloro-3-methoxy-phenyl)-2-methylpiperazin-1-yl]-2-oxo-ethyl}-3- Methyl-1H-pyrazole-5-carboxylic acid ethyl ester:

Following general protocol T using ethyl 4- _chloro -3-methyl-1H-pyrazole-5-carboxylate, _K2CO3 , 2-chloro-1-[4-(4-chloro-3-methoxy [0010]-phenyl)-2-(S)-methyl-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate = 1/4, _Rf = 0.75) afforded the title compound: HPLC retention time = 4.74 min (Agilent Zorbax SB-C18, 2.1 x 50 mm, 5 μ, 35 °C) with a 4.5 minute gradient of 20-95% B with a 1.1 minute wash at 95% B (A = 0.1% formic acid/5% acetonitrile/94.9% water, B = 0.08% formic acid/99.9% acetonitrile).

2-(4-Chloro-3-cyclopropyl-5-trifluoromethyl-pyrazol-1-yl)-1-[4-(4-chloro-3-methoxy-phenyl)-piperazine -1-yl]-ethanone:

Following general protocol T, using 4-chloro-3-cyclopropyl-5-trifluoromethyl-pyrazol-1-yl, K ₂ CO ₃ , 2-chloro-1-[4-(4-chloro-3 -methoxy-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography was performed using a solvent mixture (hexane/ethyl acetate = 1/5, _Rf = 0.83) to provide the title compound. ¹ H NMR (400MHz, CDCl ₃ ) δ7.20-7.24(d, 1H), 6.46-6.49(d, 1H), 6.42-6.46(dd, 1H), 5.1(s, 2H), 3.88(s, 3H ), 3.65-3.78 (m, 4H), 3.14-3.24 (m, 4H), 1.65-1.72 (m, 1H), 1.01-1.12 (m2H), 0.51-0.59 (m, 2H). MS (ES) (M+H) expected = 477.32, found 477.22.

2-(4-chloro-5-cyclopropyl-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(4-chloro-3-methoxy-phenyl)-2- Methyl-piperazin-1-yl]-ethanone:

Following general protocol T, using 4-chloro-5-cyclopropyl-3-trifluoromethyl-pyrazol-1-yl, K ₂ CO ₃ , 2-chloro-1-[4-(4-chloro-3 -methoxy-phenyl)-2-(S)-methyl-piperazin-1-yl]-ethanone and DMF. Column chromatography was performed using a solvent mixture (hexane/ethyl acetate = 1/5, _Rf = 0.68) to provide the title compound. ¹ H NMR (400MHz, CDCl ₃ ) δ7.19-7.22(d, 1H), 6.41-6.49(m, 2H), 4.94-5.26(m, 2H), 4.8(s, 1H), 4.41-4.44(d , 1H), 4.0(s, 1H), 3.91(s, 3H), 3.52-3.58(d, 2H), 3.36-3.42(m, 1H), 3.2(s, 1H), 2.8(s, 1H), 1.84-1.94 (m, 1H), 1.3-1.5 (m, 3H), 0.51-0.59 (m, 4H). MS (ES) (M+H) expected = 491.34, found 491.2.

2-(4-chloro-3-cyclopropyl-5-trifluoromethyl-pyrazol-1-yl)-1-[4-(4-chloro-3-methoxy-phenyl)-2- Methyl-piperazin-1-yl]-ethanone:

Following general protocol T, using 4-chloro-3-cyclopropyl-5-trifluoromethyl-pyrazol-1-yl, K ₂ CO ₃ , 2-chloro-1-[4-(4-chloro-3 -methoxy-phenyl)-2-(S)-methyl-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate = 1/5, _Rf = 0.62) provided the title compound. ¹ H NMR (400MHz, CDCl ₃ ) δ7.19-7.22(d, 1H), 6.39-6.48(m, 2H), 5.01-5.21(m, 2H), 4.75(s, 1H), 4.38-4.42(d , 1H), 4.18(s, 1H), 3.92(s, 3H), 3.53-3.59(d, 2H), 3.42-3.48(m, 1H), 3.25(s, 1H), 2.8(s, 1H), 1.84-1.94 (m, 1H), 1.3-1.5 (m, 3H), 0.98-1.41 (d, 2H), 0.51-0.59 (m, 2H). MS (ES) (M+H) expected = 491.34, found 491.2.

Scheme U: Coupling reaction of aminoacetyl-substituted arylpiperazines with a novel heteroaromatic ring system involving K ₂ CO ₃

Synthesis of 1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-2-[5-nitro-indazol-1-yl]-ethanone

2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone (0.834g, 3.3mmol) was dissolved in anhydrous DMF (15mL), and anhydrous Potassium carbonate water (1.6 g, 11.6 mmol) and the reaction mixture was stirred at room temperature under nitrogen for 1 hour. 5-Nitro-lH-indazole (0.5 g, 2.9 mmol) in DMF (2 mL) was then added via syringe. The reaction was heated at 70°C for 14 hours, cooled, then quenched with water and extracted with ethyl acetate. The organic layer was dried over _Na2SO4 , then concentrated and purified by column on neutral alumina (petroleum ether _/ ethyl acetate) to give the title compound as a light yellow solid.

Synthesis of 1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-2-[7-nitro-indazol-1-yl]-ethanone

2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone (0.834 g, 3.3 mmol) was dissolved in anhydrous DMF (15 mL), to which was added Anhydrous potassium carbonate (1.6 g, 11.6 mmol), the reaction mixture was stirred at room temperature under nitrogen for 1 hour. To this mixture was then added 7-nitro-lH-indazole (0.5 g, 2.9 mmol) in DMF (2 mL) via syringe. The reaction was heated at 70°C for 14 hours, cooled, then quenched with water and extracted with ethyl acetate. The organic layer was dried over _Na2SO4 , then concentrated _to provide material by purification on neutral alumina column (petroleum ether/ethyl acetate). The solid was recrystallized from DCM/petroleum ether to obtain the pure product as a pale yellow solid.

Synthesis of 2-benzimidazol-1-yl-1-[4-(4-chloro-phenyl)-piperazin-1-yl]-ethanone

Benzimidazole (0.785 g, 0.7 mmol) was dissolved in anhydrous DMF (15 mL), anhydrous potassium carbonate (340 mg) and KI (20 mg) were added thereto, and the reaction mixture was stirred at room temperature under nitrogen for 1 hour. To this mixture was then added 2-chloro-1-[4-(4-chloro-phenyl)-piperazin-1-yl]-ethanone (200 mg, 1.1 mmol) in DMF (5 mL) via syringe. The reaction was heated at 140°C for 14 hours, cooled then quenched with water and extracted with ethyl acetate. The organic layer was dried over Na ₂ SO ₄ and concentrated to provide a material which was purified by flash chromatography (CHCl ₃ /MeOH) to provide the pure product: ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.10-7.65 ( m, 4H), 7.26 (d, 2H), 6.83 (d, 2H), 4.99 (s, 2H), 3.79-3.66 (m, 4H), 3.14 (br, 4H).

Synthesis of 1-[4-(4-chloro-phenyl)-piperazin-1-yl]-2-(2,4-dimethyl-imidazol-1-yl)-ethanone

2,4-Dimethylimidazole (0.633g, 0.7mmol) was dissolved in anhydrous DMF (15mL), anhydrous potassium carbonate (340mg) and KI (20mg) were added thereto, and the reaction mixture was stirred at room temperature under nitrogen. Hour. To this mixture was then added 2-chloro-1-[4-(4-chloro-phenyl)-piperazin-1-yl]-ethanone (200 mg, 1.1 mmol) in DMF (5 mL) via syringe. The reaction was heated at 140°C for 14 hours, cooled then quenched with water and extracted with ethyl acetate. The organic layer was dried _{over Na2SO4} and concentrated to provide a material which was purified by silica gel column ( _CHCl3 /MeOH). δ ¹ H NMR (300MHz, CDCl ₃ ) δ 7.25(d, 2H), 6.80(d, 2H), 6.53(s, 1H), 4.62(s, 2H), 3.78(br, 2H), 3.59(br , 2H), 3.21 (br, 4H), 2.31 (s, 3H), 2.17 (s, 1H).

Synthesis of 2-(5-amino-3-methylthio-[1,2,4]triazol-1-yl)-1-[4-(4-chloro-phenyl)-piperazin-1-yl] - ethyl ketone

5-Methylthio-2H-[1,2,4]triazol-3-ylamine (0.216g, 1.7mmol) was dissolved in anhydrous DMF (15mL), and anhydrous potassium carbonate (800mg) was added thereto and KI (20 mg), the reaction mixture was stirred at room temperature under nitrogen for 1 hour. To this mixture was then added 2-chloro-1-[4-(4-chloro-phenyl)-piperazin-1-yl]-ethanone (500 mg, 1.8 mmol) in DMF (5 mL) via syringe. The reaction was heated at 140°C for 14 hours, cooled then quenched with water and extracted with ethyl acetate. The organic layer was dried over _Na2SO4 and concentrated to provide _crude product which was purified by column chromatography ( _CHCl3 /MeOH). δ ¹ H NMR (300MHz, DMSO-d6) δ 7.24 (d, 2H), 6.98 (d, 2H), 6.24 (s, 2H), 4.84 (s, 2H), 3.57 (m, 4H), 3.21 ( m, 2H), 3.13 (m, 2H), 2.37 (s, 3H).

Synthesis of 2-[5-(2-bromo-phenyl)-tetrazol-1-yl]-1-[4-(4-chloro-phenyl)-piperazin-1-yl]-ethanone

5-Phenyl-1H-tetrazole (0.1216g, 0.832mmol) was dissolved in anhydrous DMF (15mL), anhydrous potassium carbonate (400mg) and KI (20mg) were added thereto, and the reaction mixture was stirred at room temperature under nitrogen. Hour. To this mixture was then added 2-chloro-1-[4-(4-chloro-phenyl)-piperazin-1-yl]-ethanone (250 mg, 0.92 mmol) in DMF (5 mL) via syringe. The reaction was heated at 140°C for 14 hours, cooled then quenched with water and extracted with ethyl acetate. The organic layer was dried over _Na2SO4 and concentrated to provide a material _which was purified by flash column chromatography (ethyl acetate/petroleum ether). ¹ H NMR (300MHz, CDCl ₃ ) δ8.17(br, 2H), 7.49(br, 3H), 7.24(br, 2H), 6.85(br, 2H), 5.60(s, 2H), 3.82(m, 2H), 3.71 (m, 2H), 3.19 (m, 4H).

Synthesis of 2-[5-(2-bromo-phenyl)-tetrazol-1-yl]-1-[4-(4-chloro-phenyl)-piperazin-1-yl]-ethanone

5-(2-Bromo-phenyl)-1H-tetrazole (0.374g, 1.66mmol) was dissolved in anhydrous DMF (15mL), and anhydrous potassium carbonate (800mg) and KI (20mg) were added thereto, in Stir at room temperature under nitrogen for 1 hour. To this mixture was then added 2-chloro-1-[4-(4-chloro-phenyl)-piperazin-1-yl]-ethanone (500 mg, 1.8 mmol) in DMF (5 mL) via syringe. The reaction was heated at 140°C for 14 hours, cooled then quenched with water and extracted with ethyl acetate. The organic layer was dried over _Na2SO4 and concentrated to provide a material _which was further purified by flash column chromatography (ethyl acetate/petroleum ether). ¹ H NMR (300MHz, CDCl ₃ ) δ7.90(d, 1H), 7.74(d, 1H), 7.45(t, 1H), 7.35(t, 1H), 7.25(d, 2H), 6.87(d, 2H), 5.65 (s, 2H), 3.84 (m, 2H), 3.73 (m, 2H), 3.20 (m, 4H).

Synthesis of 2-(5-methyl-3-trifluoromethyl-1,2,4-triazol-1-yl)-1-[4-(4-chloro-3-methoxy-phenyl)- Piperazin-1-yl]-ethanone:

0.04g (0.00026mol) 5-methyl-3-trifluoromethyl-1,2,4-triazole, 0.078g (0.00026mol) 1-(chloroacetyl)-4-(4-chloro-3 -Methoxyphenyl)-piperazine and 0.04 g (0.0004 mol) of potassium carbonate were heated in 3 mL of anhydrous DMF at 80° C. for 14 hours. The reaction mixture was quenched with water and extracted with ethyl acetate. The ethyl acetate phase was washed once each with water and brine, dried over _Na2SO4 , filtered, and _concentrated to give 2-(5-methyl-3-trifluoromethyl-1,2,4-triazole-1- yl)-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone: ¹ HNMR (CDCl ₃ , 300MHz) δ7.22 (m, 1H) , 6.48(s, 1H), 6.443(m, 1H), 5.07(s, 2H), 3.87(s, 3H), 3.71(m, 4H), 3.18(m, 4H), 2.50(s, 3H)ppm ; MS(ES) M+H expected = 418.0, found = 418.2.

Scheme V: Preparation of Compounds by Acid or Base Involved Deprotection

Synthesis of 1-[4-(4-chloro-3-methoxy-phenyl)-3-(R)-hydroxymethyl-piperazin-1-yl]-2-(4-chloro-5-methyl -3-Trifluoromethyl-pyrazol-1-yl)-ethanone and acetic acid 1-(4-chloro-3-methoxy-phenyl)-4-[2-(4-chloro-5-methyl Base-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-piperazin-2-(R)-ylmethyl ester:

0°C, to 620mg (1.79mmol) 2-(R)-benzyloxymethyl-1-(4-chloro-3-methoxy-phenyl in 6mL of N,N-dimethylformamide )-piperazine, 500mg (2.05mmol) (4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid and 280mg (2.05mmol) 1-hydroxybenzotriazole 430 mg (2.24 mmol) of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride were added. After 2 hours, the reaction was allowed to warm to ambient temperature and stirred for an additional 12 hours. The solution was partitioned between water and ethyl acetate and the phases were separated. The ethyl acetate phase was washed once each with 1M _NaHSO4 , water, 1M NaOH, water and brine, dried over _Na2SO4 , filtered and concentrated to an oil _.

A solution of the oil obtained above in 6 mL of 48% HBr in acetic acid was heated at 70° C. for 1 h with an additional 5 mL of acetic acid and then cooled to ambient temperature. The mixture was partitioned between ethyl acetate and water and the phases were separated. The ethyl acetate phase was washed once each with 1M NaOH and brine, dried over _Na2SO4 , filtered, and concentrated _. The residue was chromatographed to give 1-[4-(4-chloro-3-methoxy-phenyl)-3-(R)-hydroxymethyl-piperazin-1-yl]- 2-(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-ethanone: ¹ H NMR (DMSO-d6, 400MHz) δ7.18 (m, 1H), 6.59 (m, 1H), 6.51(m, 1H), 5.43(m, 1H), 5.24(m, 1H), 5.14(m, 1H), 4.34-3.90(m, 2H), 3.18(s, 3H), 3.17(par.obsc.m, 1H), 3.49-3.30(m, 4H), 3.27-3.07(m, 3H), 2.18(m, 3H) ppm (rotamer); MS(ES) M+H Expected = 481.0, Found = 481.0.

In addition, 1-(4-chloro-3-methoxy-phenyl)-4-[2-(4-chloro-5-methyl-3-trifluoromethyl)acetate was isolated as a colorless glass -pyrazol-1-yl)-acetyl]-piperazin-2-ylmethyl ester: ¹ H NMR (DMSO-d6, 400MHz) δ7.19 (m, 1H), 6.68 (s, 1H), 6.46 ( m, 1H), 5.50(m, 1H), 5.37(m, 1H), 4.28-3.87(m, 5H), 3.82(s, 3H), 3.59-3.10(m, 4H), 2.18(s, 3H) , 1.84 (m,3H) ppm (rotamer); MS (ES) M+H expected = 523.0, found = 523.0.

Synthesis of 1-[4-(4-chloro-3-methylaminomethyl-phenyl)-piperazin-1-yl]-2-(4-chloro-5-methyl-3-trifluoromethyl- Pyrazol-1-yl)-ethanone:

Room temperature, 90mg (0.15mmol) (2-chloro-5-{4-[2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-piper Treatment of benzyl-azin-1-yl}-benzyl)-methyl-carbamate with excess HBr/AcOH for several hours followed by purification by preparative HPLC afforded 1-[4-(4-chloro-3-methylaminomethyl yl-phenyl)-piperazin-1-yl]-2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-ethanone: ¹ H NMR (CDCl ₃ , 400MHz) δ7.30(d, 1H), 7.10(s, 1H), 6.87(d, 1H), 5.08(s, 2H), 4.24(s, 2H), 3.71(d, 4H), 3.21(d , 4H), 2.71 (s, 3H), 2.28 (s, 3H) ppm MS (ES) M+H expected = 464.1, found = 464.0.

Synthesis of 1-[4-(3-amino-4-chloro-phenyl)-piperazin-1-yl]-2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazole-1 -yl)-ethanone:

284mg (0.5mmol) 1-[4-(3-tert-butoxycarbonylamino-4-chloro-phenyl)-piperazin-1-yl]-2-(4-chloro-5-methyl-3- Trifluoromethyl-pyrazol-1-yl)-ethanone was dissolved in 1 mL each of acetonitrile, methanol, and 1 mL of 5M HCl in isopropanol. After several hours, the title compound was isolated as a solid by filtration: ¹ H NMR (DMSO-d6, 400 MHz) δ 7.24 (m, 1H), 7.15 (br, 4H), 6.88 (s, 1H), 6.67 (m, 1H ), 5.41 (s, 2H), 3.70 (m, 4H), 3.31 (m, 2H), 3.22 (m, 2H), 2.20 (s, 3H) ppm; MS(ES) M+H expected value = 436.0, Found value = 436.0.

Synthesis of 4-(4-chloro-3-methoxy-phenyl)-1-[2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl ]-piperazine-2-carboxylic acid:

The title compound was prepared according to coupling scheme P involving HATU using (-)-ol 4-(4-chloro-3-methoxy-phenyl)-piperazine-2-carboxylate and (4- Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid as coupling component affords a solid product. The product was also treated with a 10-fold excess of 1/1 THF/LiOH in water for 24 hours, and the reactant was purified by reverse-phase HPLC to obtain the product as an oil: ¹ H NMR (400 MHz, CDCl ₃ ) δ7.27 (s, 1H), 6.79(d, 1H), 6.59(d, 1H), 5.22(m, 2H), 3.91(s, 3H), 3.05-2.99(m, 3H), 3.32-3.19(m, 4H), 2.29 (m,3H), 2.06 (m,1H) MS (ES) (M+H) expected = 495.1, found = 495.1.

Scheme W: Preparation of compounds by borohydride-involved reductive alkylation

Synthesis of 1-[4-(4-chloro-3-methylamino-phenyl)-piperazin-1-yl]-2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazole -1-yl)-ethanone:

To 60 mg (0.13 mmol) of 1-[4-(3-amino-4-chloro-phenyl)-piperazin-1-yl]-2-(4-chloro-5-methyl-3 in 1 mL of methanol -Trifluoromethyl-pyrazol-1-yl)-ethanone was added 13 mg (0.19 mmol) sodium cyanoborohydride and 14 μL (0.16 mmol) 12.3 M aqueous formaldehyde. After 3 hours, the reaction was quenched by adding 50 μL of concentrated HCl. After 30 minutes, the solution was partitioned between ether and water and the phases were separated. The aqueous phase was basified with 1M NaOH and extracted twice with ethyl acetate. The combined ethyl acetate phases were washed once with brine, dried over _Na2SO4 , filtered and concentrated to an oil _. The oil was dissolved in methanol, acidified with 2M HCl in ether, and diluted with ether to give a solid product: MS(ES) M+H expected = 450.0, found = 450.0; HPLC retention time = 4.89 minutes (Agilent Zorbax SB-C18, 2.1 x 50 mm, 5 μ, 35°C), using a 4.5-minute gradient of 20-95% B, with a 1.1-minute wash at 95% B (A = 0.1% formic acid/5% acetonitrile/94.9% water, B = 0.08% formic acid/99.9% acetonitrile).

Synthesis of 2-(4-chloro-3-dimethylamino-5-methyl-pyrazol-1-yl)-1-[4-(4-chloro-3-methoxy-phenyl)-piperazine -1-yl]-ethanone:

120mg (0.30mmol) 2-(4-chloro-3-amino-5-methyl-pyrazol-1-yl)-1-[4-(4-chloro-3-methoxy-phenyl)- Piperazin-1-yl]-ethanone was dissolved in 5 mL of tetrahydrofuran, and 0.10 mL of 0.1M H ₂ SO ₄ was added. To this mixture was added 0.75 mL (9 mmol) of 37% aqueous formaldehyde followed by 113 mg (3 mmol) of sodium borohydride. After 4 hours, the solution was quenched with 50 μL concentrated HCl. The mixture was then partitioned between 1/1 ether/hexane and water and the phases were separated. The aqueous phase was basified to pH>10 with 1M NaOH and extracted twice with ethyl acetate. The combined ethyl acetate phases were washed twice _with water, once with brine, dried over _Na2SO4 , filtered, and concentrated to an oil. The oil was purified by chromatography to give the solid product: ¹ H NMR (CDCl ₃ , 300 MHz) δ 7.20 (d, 1H), 6.48 (s, 1H), 6.42 (d, 1H), 4.84 (s, 2H) , 3.86(s, 3H), 3.74(m, 2H), 3.63(m, 2H), 3.17(m, 4H), 2.79(s, 6H), 2.16(s, 3H) ppm; MS(ES) M+ H expected = 426.0, found = 426.0.

Synthesis of 1-[4-(4-chloro-3-dimethylamino-phenyl)-piperazin-1-yl]-2-(4-chloro-5-methyl-3-trifluoromethyl-pyridine Azol-1-yl)-ethanone:

To 80 mg (0.17 mmol) of 1-[4-(3-amino-4-chloro-phenyl)-piperazin-1-yl]-2-(4-chloro-5-methyl-3 in 1 mL of methanol -Trifluoromethyl-pyrazol-1-yl)-ethanone was added with 30 mg (0.39 mmol) of sodium cyanoborohydride and 32 μL (0.39 mmol) of 12.3 M aqueous formaldehyde. After 3 hours, the reaction was quenched by the addition of 50 μL concentrated HCl. After 30 minutes, the solution was partitioned between ether and water and the phases were separated. The aqueous phase was basified with 1M NaOH and extracted twice with ethyl acetate. The combined ethyl acetate phases were washed once with brine, dried over _Na2SO4 , filtered and concentrated to an oil _. The oil was dissolved in methanol, acidified with 2M HCl in ether, and diluted with ether to give a solid product: ¹ H NMR (DMSO-d6, 400 MHz) δ 7.35 (m, 1H), 7.14 (s, 1H), 6.89(m, 1H), 5.41(s, 2H), 3.68(m, 4H), 3.35(m, 2H), 3.25(m, 2H), 2.91(br s, 6H), 2.20(s, 3H)ppm ; MS(ES) M+H expected = 464.0, found = 464.0.

Scheme X: Preparation of compounds by acylation or sulfonylation

Synthesis of N-(2-chloro-5-{4-[2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-piperazine-1- Base}-phenyl)-methanesulfonamide:

To 50 mg (0.1 mmol) of 1-[4-(4-chloro-3-dimethylamino-phenyl)piperazin-1-yl]-2-(4-chloro-5- Methyl-3-trifluoromethyl-pyrazol-1-yl)-ethanone 39 mg (0.5 mmol) pyridine and 21 mg (0.12 mmol) methanesulfonic anhydride were added. After 20 hours, the solution was partitioned between ethyl acetate and water and the phases were separated. The ethyl acetate phase was washed once with _brine , dried over _Na2SO4 , filtered, and concentrated to an oil. The oil was triturated with ether to give the title compound as a solid: ¹ H NMR (DMSO-d6, 400 MHz) δ 9.33 (s, 1H), 7.34 (m, 1H), 6.97 (m, 1H), 6.90 ( m, 1H), 5.39(s, 2H), 3.63(m, 4H), 3.26(m, 2H), 3.17(m, 2H), 3.03(s, 3H), 2.20(s, 3H)ppm; MS( ES) M+H expected = 514.0, found = 514.0.

Synthesis of N-(2-chloro-5-{4-[2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-piperazine-1- Base}-phenyl)-acetamide:

To 50 mg (0.1 mmol) 1-[4-(4-chloro-3-dimethylamino-phenyl)-piperazin-1-yl]-2-(4-chloro- 5-Methyl-3-trifluoromethyl-pyrazol-1-yl)-ethanone 39 mg (0.5 mmol) pyridine and 11 mg (0.12 mmol) acetic anhydride were added. After 20 hours, the solution was partitioned between ethyl acetate and water and the phases were separated. The ethyl acetate phase was washed once with _brine , dried over _Na2SO4 , filtered, and concentrated to an oil. The oil was triturated with ether to give the title product as a solid: ¹ H NMR (DMSO-d6, 400 MHz) δ 9.38 (s, 1H), 7.33 (s, 1H), 7.29 (m, 1H), 6.81 ( m, 1H), 5.39(s, 2H), 3.61(m, 4H), 3.22(m, 2H), 3.13(m, 2H), 2.19(s, 3H), 2.07(s, 3H)ppm; MS( ES) M+H expected = 478.0, found = 478.0.

Synthesis of N-(2-chloro-5-{4-[2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-piperazine-1- Base}-phenyl)-formamide:

To 50 mg (0.1 mmol) 1-[4-(4-chloro-3-dimethylamino-phenyl)-piperazin-1-yl]-2 in 1.5 mL N,N-dimethylformamide -(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-ethanone was added with 22 mg (0.2 mmol) triethylamine and 30 μL (0.25 mmol) cyanomethyl formate, and the mixture Heat at 90°C for 18 hours. The solution was partitioned between ethyl acetate and water and the phases were separated. The ethyl acetate phase was washed once with _brine , dried over _Na2SO4 , filtered, and concentrated to an oil. The oil was triturated with ether to give the title product as a solid: ¹ H NMR (DMSO-d6, 400 MHz) δ 9.76 (s, 1H), 8.34 (s, 1H), 7.79 (m, 1H), 7.32 ( m, 1H), 6.79(m, 1H), 5.40(s, 2H), 3.61(m, 4H), 3.23(m, 2H), 3.14(m, 2H), 2.20(s, 3H)ppm; MS( ES) M+H expected = 464.0, found = 464.0.

Scheme Y: Preparation of Compounds by Alkylation

Synthesis of 1-[4-(4-chloro-3-methoxy-phenyl)-3-(R)-methoxymethyl-piperazin-1-yl]-2-(4-chloro-5- Methyl-3-trifluoromethyl-pyrazol-1-yl)-ethanone:

To 53 mg (0.11 mmol) 1-[4-(4-chloro-3-methoxy-phenyl)-3-(R)-hydroxymethyl- Add 9 mg ( 0.22 mmol) 60% sodium hydride in oil. After 1 hour, the reaction was quenched with water and extracted with ethyl acetate. The ethyl acetate phase was washed with _brine , dried over _Na2SO4 , filtered, and concentrated to give the title product as a foam: MS (ES) M+H expected = 495.0, found = 495.0; HPLC retention time = 5.08 min (Agilent Zorbax SB-C18, 2.1×50mm, 5μ, 35°C), using a 4.5 min gradient from 20-95% B, with a 1.1 min wash at 95% B (A = 0.1% formic acid/5% acetonitrile/ 94.9% water, B = 0.08% formic acid/99.9% acetonitrile).

Synthesis of 1-[4-(4-chloro-3-methoxy-phenyl)-2-(R)-methoxymethyl-piperazin-1-yl]-2-(4-chloro-5- Methyl-3-trifluoromethyl-pyrazol-1-yl)-ethanone:

The title compound was prepared according to coupling scheme P participated by HATU using 1-(4-chloro-3-methoxy-phenyl)-3-(R)-methoxymethyl-piperazine and (4- Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid was used as a coupling component to obtain a solid product: ¹ H NMR (DMSO-d6, 400MHz) δ7.20 (m, 1H) , 6.63(m, 1H), 6.49(m, 1H), 5.50(m, 1H), 5.25(m, 1H), 4.21(m, 1H), 3.82(s, 3H), 3.81-3.40(m, 5H ), 3.25(s, 3H), 3.08-2.82(m, 2H), 2.63(m, 1H), 2.16(m, 3H) ppm (rotamer); MS(ES) M+H expected = 495.0 , found value = 495.0.

Scheme Z: Preparation of compounds by peracid-involved N-oxidation

Synthesis of 1-[4-(4-chloro-3-methoxy-phenyl)-4-oxo-piperazin-1-yl]-2-(4-chloro-5-methyl-3-trifluoro Methyl-pyrazol-1-yl)-ethanone:

0°C, to 103mg (0.23mmol) 1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-(4-chloro -5-Methyl-3-trifluoromethyl-pyrazol-1-yl)-ethanone 60 mg (0.34 mmol) m-chloroperbenzoic acid were added. After 30 minutes, the reaction was partitioned between 1/1 ether/ethyl acetate and water and the phases were separated. The organic phase was washed once each with 1M NaOH, water, and brine, dried with Na ₂ SO ₄ , filtered, and a solid product was precipitated: ¹ H NMR (DMSO-d6, 400 MHz) δ8.09 (s, 1H), 7.70 (m, 1H ), 7.52(m, 1H), 5.40(m, 2H), 4.28(m, 1H), 4.10(m, 2H), 3.98(m, 1H), 3.90(s, 3H), 3.85(par.obs. m, 1H), 3.66 (m, 1H), 2.90 (m, 2H), 2.20 (s, 3H) ppm; MS (ES) M+H expected = 467.0, found = 467.0.

Scheme AA: Synthesis of trisubstituted pyrazoles by SUZUKI coupling

4-Chloro-3-methyl-5-phenyl-pyrazole:

4-Chloro-3-methyl-5-bromopyrazole (1.27 mmole) was dissolved in anhydrous DMF (20 mL), to which Pd(PPH ₃ ) ₄ (0.44 mmole) was added, followed by Na ₂ CO ₃ ( 344.1 mg) and phenylboronic acid (1.41 mmole) in 1 mL of water. Then, the mixture was refluxed at 150°C for 22 hours, cooled to room temperature, and then filtered to remove inorganic salts. To this was added 20 mL of dichloromethane, washed with water to remove all DMF. The organic layer was dried over _Na2SO4 and removed to give the crude product which was then chromatographed _to obtain the pure compound.

Other pyrazoles prepared by Scheme AA:

Scheme BB: Cyclocondensation of hydrazides and thioamides to give triazoles

5-Methyl-3-trifluoromethyl-1,2,4-triazole

2.3g (0.03125mol) thioacetamide and 4g (0.03125mol) trifluoroacetic acid hydrazide (trifluoroacetic acid hydrazide) were heated at 150°C for 2 days. The obtained white solid was washed with ether and dried in vacuo to give 5-methyl-3-trifluoromethyl-1,2,4-triazole.

Preparation of Compounds with Modified Linker Regions

α-Substituted Acetyl Bonding Group

Synthesis of 2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]- propan-1-one

1-(4-Fluorophenyl)-piperazine (1 g, 5.5 mmol) dissolved in anhydrous CH ₂ Cl ₂ (20 mL) was cooled to 0° C., and triethylamine (1.66 g, 16.5 mmol) was added thereto. 2-Bromopropionyl chloride (1.14 g, 6.6 mol) was added slowly, and the reaction mixture was further stirred at the same temperature for 1 hour. The mixture was washed _with sodium bicarbonate and brine, dried over _Na2SO4 . Evaporation of the solvent provided the intermediate alkyl bromide (0.68 g, 3.7 mmol), which was dissolved in anhydrous DMF (20 mL). Potassium carbonate (2.1 g) was added. After stirring at room temperature under nitrogen for 1 hour, to this mixture was added 3-methyl-4-chloro-5-trifluoromethyl-(1H)-pyrazole (1.3 g, 4.1 mmol). The reaction was then heated at 70°C for 14 hours, cooled and quenched with water, extracted with ethyl acetate. The organic layer was dried over _Na2SO4 , then concentrated to provide material _which was purified on neutral alumina column (chloroform/methanol).

Synthesis of 2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(4-chloro-phenyl)-piperazin-1-yl]- 2-Phenyl-ethanone

To 4-chloro-5-methyl-3-( _{trifluoromethyl} )-1H-pyrazol-1- _yl ]phenylacetic acid (0.1 g, 0.00036 mol) and 1 -(4-Chlorophenyl)piperazine (0.060 g, 0.00031 mol) was added with 0.2 mL of triethylamine, and the reaction mixture was stirred at room temperature for 30 minutes. Then TBTU (0.1 g, 0.00031 mol) was added and the reaction mixture was stirred at room temperature for 17 hours. The reaction mixture was diluted with 60 mL of _CH2Cl2 , washed with saturated aqueous _NaHCO3 (2 x 50 mL), brine _, and dried over sodium sulfate. The crude product obtained after concentration was purified by column chromatography to give the product as a beige solid: ¹ H NMR (CDCl ₃ , 300 MHz) 7.40-6.61 (m, 10H), 3.99 (m, 1H), 3.80 (m, 1H) , 3.50-2.81 (m, 6H), 1.90 (s, 3H) ppm; MS (ES) M+H expected = 497.1, found 497.2.

Synthesis of 2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(4-chloro-phenyl)-piperazin-1-yl]- 2-(3-Methoxy-phenyl)-ethanone

AIBN (10 mg) was added to a solution of (3-methoxy-phenyl)-acetic acid methyl ester (2 g, 11 mmol) in _CCl4 (30 mL). Then, the solution was heated to reflux and NBS (2.3 g, 13 mmol) was added in portions. After the addition was complete, the reaction mixture was refluxed for 4 hours. After cooling, the solid residue was filtered off, and the filtrate was concentrated to yield the bromo-(3-methoxy-phenyl)-acetic acid methyl ester product, which was washed repeatedly with petroleum ether.

4-Chloro-3-methyl-5-trifluoromethyl-1H-pyrazole (610 mg, 3.3 mmol) was dissolved in anhydrous CH ₃ CN (15 mL), to which was added anhydrous potassium carbonate (1.15 g) , and the resulting mixture was stirred at room temperature under nitrogen for 1 h. To this mixture was then added bromo-(3-methoxy-phenyl)-acetic acid methyl ester (900 mg, 2.8 mmol) in _CH3CN (5 mL) via syringe. The reaction was then heated at reflux for 10 hours, cooled and filtered through a celite filter. The filtrate was concentrated to obtain (4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-(3-methoxy-phenyl)-ethyl acetate, which was passed through a silica gel column Purify by analysis (petroleum ether/ethyl acetate).

Then, (4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-(3-methoxy-phenyl)-acetic acid methyl ester was dissolved in THF (20 mL) and added LiOH (0.39 g) in water (5 mL). The mixture was stirred at room temperature for 4 hours. After this period, THF was completely evaporated from the reaction mixture under vacuum. The residual aqueous layer was extracted with ethyl acetate (3 x 5 mL), and the organic layer was discarded. The aqueous layer was cooled in ice and neutralized with concentrated HCl. The neutralized aqueous layer was extracted with ethyl acetate (3×10 mL), the organic layer was dried over Na ₂ SO ₄ , concentrated and purified by flash chromatography (CHCl ₃ /MeOH) to give (4-chloro-5-methyl -3-Trifluoromethyl-pyrazol-1-yl)-(3-methoxy-phenyl)-acetic acid.

_This compound (90 mg, 0.275 mmol) was dissolved in anhydrous _CH2Cl2 (10 mL), cooled to 0 °C. To this cold mixture was added first 4chlorophenyl-piperazine (0.059 g, 0.31 mmol) followed by T3P (0.35 g, 0.55 mmol, 50% in EtOAc). The reaction was left overnight at room temperature. The mixture was diluted with _CH2Cl2 , then washed sequentially with saturated _NaHCO3 solution, brine, dried over _Na2SO4 , and concentrated to afford _the crude product _. Purification by column chromatography on neutral alumina gave 2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(4-chloro -phenyl)-piperazin-1-yl]-2-(3-methoxy-phenyl)-ethanone: ¹ H NMR (300MHz, CDCl ₃ ) δ7.37-7.21 (m, 3H), 6.96 -6.79(m, 4H), 6.60(s, 1H), 5.31(s, 1H), 3.99(m, 1H), 3.80(s, 3H), 3.79(m, 1H), 3.46(m, 2H), 3.24 (m, 1H), 3.13 (m, 2H), 2.91 (m, 1H), 1.95 (s, 3H).

Example 2

The protocol mentioned in the following examples is that described in Example 2.

Scheme A: Metal-catalyzed arylation of secondary amines

Synthesis of tert-butyl 1-[4-(4-chloro-3-methoxy-phenyl)-[1,4]diazepane-1-carboxylate:

5-Bromo-2-chloroanisole (1.10g, 5mmol, 1.0equiv), N-Boc-homopiperazine (1.0g, 1equiv), NaOtBu (0.72g, 1.5eq), rac-BINAP (58mg , 0.015 equiv) and Pd2Dba3 (28 mg, 0.005 eq) was heated in 3 mL of toluene at 90 °C overnight. After cooling to room temperature, the residue was dissolved in EtOAc and washed with water and brine. The organic layer was dried over _Na2SO4 , filtered, evaporated, and subjected to flash column chromatography (1:4 EtOAc _/ hexanes) to give 1-[4-(4-chloro-3-methoxy-phenyl)- [1,4]tert-butyl diazepane-1-carboxylate. ¹ H NMR (400MHz, CDCl ₃ ) δ7.13(d, 1H), 6.22(d, 1H), 6.20(dd, 1H), 3.86(s, 3H), 3.45(m, 6H), 3.32(m, 2H), 3.20(m, 2H), 1.95(m, 2H), 1.20(s, 9H). LCMS observed for (M+H-Boc)+: 241.

1-(4-Chloro-3-propoxy-phenyl)-piperazine dihydrochloride

Following Scheme A, 4-bromo-1-chloro-2-propoxybenzene and N-Boc-piperazine were coupled to give the Boc-protected intermediate.

Treatment of the Boc-protected intermediate with 4M HCl in p-dioxane afforded the title compound.

1-(4-Chloro-3-(2,2,2-trifluoro)ethoxy-phenyl)-piperazine dihydrochloride

Following Scheme A, 4-bromo-1-chloro-2-(2,2,2-trifluoro)ethoxybenzene and N-Boc-piperazine were coupled to afford the corresponding Boc-protected intermediate.

Treatment of the Boc-protected intermediate with 4M HCl in p-dioxane afforded the title compound.

1-(4-Chloro-3-(2-fluoro)ethoxy-phenyl)-piperazine dihydrochloride

Following Scheme A, 4-bromo-1-chloro-2-(2-fluoro)ethoxybenzene was coupled with N-Boc-piperazine to afford the corresponding Boc-protected intermediate.

Treatment of the Boc-protected intermediate with 4M HCl in p-dioxane afforded the title compound.

1-(4-Chloro-3-methoxy-phenyl)-3-trifluoromethyl-piperazine

Following Scheme A, 2-trifluoromethylpiperazine was coupled with 5-bromo-2-chloro-anisole to afford the title compound.

(S)-1-(3-methoxy-phenyl)-3-methyl-piperazine

Into a 25mL flask was added 467mg 3-bromoanisole (2.5mmol, 1.0eq), 300mg (S)-2-methylpiperazine (2.99mmol, 1.2eq), 27mg Pd ₂ dba ₃ (0.03mmol, 0.01eq ), 50mg BINAP (0.08mmol, 0.03eq), 336mg NaOtBu (3.5mmol, 1.4eq) and 5mL toluene. The mixture was stirred overnight in an 85 °C oil bath under _N2 , then the solvent was removed in vacuo and the crude material was treated with aqueous HCl to give the dihydrochloride salt.

1-(4-Chloro-3-methoxy-phenyl)-2,3-(cis)-dimethyl-piperazine

Step 1: 26 gm ethylenediamine (0.43 mole) and 37.2 gm 2,3-butanedione (0.433 mole) were dissolved in 1.21 anhydrous diethyl ether, and the reaction mixture was stirred overnight. The solvent was removed and the oily residue was distilled off, yielding 22 gm (45%) of the intermediate diimine.

Step 2: To a solution of LAH (1.86 gm, 0.049 mole) in anhydrous THF (10 ml) was added the intermediate diimine (5 gm, 0.047 mole) dissolved in THF (5 ml) at 0°C. Then, the reaction mixture was refluxed overnight at 70°C. The reaction was cooled to room temperature, quenched with 5 mL of 15% NaOH, and filtered through celite. The filtrate was concentrated to obtain the intermediate cis-2,3-dimethylpiperazine.

Step 3: Following Scheme A, 2,3-dimethylpiperazine was coupled with 5-bromo-2-chloro-anisole to afford the title compound.

Synthesis of 1-(7-chloro-benzofuran-4-yl)-piperazine:

Step 1: Following Scheme A, mono-BOC-piperazine is coupled with 4-bromo-7-chloro-benzofuran to afford the Boc-protected intermediate.

Step 2: 0.139 g (0.41 mmol) of the above Boc-protected intermediate was dissolved in anhydrous ether, and 2 mL of 1M HCl in ether was added. After 9 hours, the solid was isolated by filtration and washed with anhydrous ether to give the title compound.

1-(4-Chloro-3-methoxy-phenyl)-cis-2,5-dimethyl-piperazine

Following Scheme A, cis-2,5-dimethylpiperazine was coupled with 5-bromo-2-chloro-anisole to afford the title compound.

Synthesis of 1-(4-chloro-3-methoxy-phenyl)-trans-2,5-dimethyl-piperazine:

Step 1: Following Scheme A, trans-2,4-dimethylpiperazine was coupled with 5-bromo-2-chloroanisole to afford the crude title compound. Purification was not possible, so this mixture was taken for step 2:

Step 2: 0.159g (0.624mmol) of the impurity-containing title compound, 0.204g (0.936mmol) of BOC-anhydride and 0.26mL (1.87mmol) of triethylamine were dissolved in anhydrous dichloromethane (10ml), and the solution was stirred for 4 hours. Then, the solution was washed twice with 10% citric acid, once with 10% _NaHCO3 , dried over _Na2SO4 , and concentrated _. The residue was purified by column chromatography.

Step 3: To 150 mg (0.42 mmol) of the above BOC-intermediate in methanol was added 5 m HCl in ether under _N2 atmosphere, and the mixture was stirred for 7 hours. The solid formed was isolated by filtration to give the title compound (0.110 g, 85%) as the hydrochloride salt.

Scheme B: Formation of the piperazine ring by cyclization

Synthesis of 1-(4-fluoro-3-methoxy-phenyl)-piperazine:

Step 1: Concentrated HCl (54.26 g, 1.486 mol) was added to 2-methoxy-4-nitroaniline (50 g, 0.29 mol) in a 3 L three necked round bottom flask. The reaction mixture was heated at 80°C for 0.5 hours. Then cooled to -10°C. Aqueous sodium nitrate solution (24.62 g, 0.356 mol) was added thereto. Hexafluorophosphoric acid (86.82 g, 0.594 mol) was then added, while maintaining the temperature in the range of -2°C to 0°C, and stirred for 0.5 hours. Solid separated. The solid was filtered off and washed with cold water followed by 50% methanol in ether. The solid was then dried overnight at room temperature under high vacuum.

The solid was added to mineral oil (170°C) and stirred at 170°C for 0.5 hour, then cooled to room temperature and left to stand. Sodium carbonate solution (300 mL) was added, followed by steam distillation to obtain 4-fluoro-3-methoxynitrobenzene (3.5 g, 6.8%).

Step 2: Raney nickel (0.6g) was added to a solution of 4-fluoro-3-methoxynitrobenzene (3.5g, 0.02046mol) in anhydrous methanol, the solution was shaken in a par-shaker in 10PSI hydrogen 12 hours. The Raney nickel was then filtered off and the filtrate was concentrated to obtain the crude compound. The compound was purified by column chromatography using petroleum ether:ethyl acetate (100:3) as eluent to give 4-fluoro-3-methoxyaniline (1.4 g, 48%) as a reddish liquid.

Step 3: Dissolve 4-fluoro-3-methoxyaniline (0.5g, 0.00354mol) in n-butanol (10mL), add bis(2-chloroethyl)amine hydrochloride (0.632g , 0.00354mol) in n-butanol solution. Then, the reaction mixture was refluxed for 2 days, cooled to room temperature, and anhydrous sodium carbonate (1.12 g, 0.01062 mol) was added. The mixture was refluxed for another 2 days, after which time the solvent was evaporated. The residue was _dissolved in ethyl acetate, washed with water, brine solution, dried over _Na2SO4 , and concentrated. The crude residue was purified by column chromatography using chloroform: methanol as eluent (100:5) to afford the title compound (58 mg, 7%) as a beige solid.

Scheme D: Synthesis of piperazines and addition to aryl and heteroaryl halides via aryl-halogen displacement

2-Chloro-5-piperazin-1-yl-benzoic acid ethyl ester:

Step 1: To 5-chloro-2-nitrobenzoic acid (15 g, 0.07 mol) in ethanol (200 ml) was added thionyl chloride (27 ml, 0.37 mol) dropwise at 0°C. The reaction mixture was refluxed overnight at 85°C. The reaction was cooled to room temperature, methanol was removed in vacuo, and the residue was added to ice water. The resulting mixture was basified with solid NaHCO3 and extracted with ethyl acetate. The ethyl acetate layer was washed with water, _brine , dried over _Na2SO4 , and concentrated to give the corresponding ethyl ester.

Step 2: Ethyl 5-chloro-2-nitrobenzoate (15g, 0.0655mol), benzylpiperazine (28.8g, 0.16mol), anhydrous _K2CO3 ( _9g , 0.16mol), tetraiodide Butylammonium (1.5 g) was heated in anhydrous DMSO (150 ml) at 120°C overnight. The mixture was cooled to ambient temperature, quenched with water and extracted with ethyl acetate. The ethyl acetate layer was extracted with 1.5N HCl and discarded. The acidic layer was washed with ether, basified with NaHCO ₃ and extracted with fresh ethyl acetate. The ethyl acetate layer was washed with water and _brine , dried over _Na2SO4 , and concentrated to give ethyl 2-nitro-5-piperazin-1-yl-benzoate.

Step 3: To ethyl 2-nitro-5-piperazin-1-yl-benzoate (22 g, 0.059 mol) in methanol (150 ml) was added palladium on carbon (2.2 g, 10%) under nitrogen. The reaction mixture was stirred under H ₂ for 2 h. The mixture was filtered and concentrated to afford the corresponding aniline.

Step 4: To copper chloride (3.0 g, 0.017 mol) in acetonitrile (50 ml) was slowly added tert-butyl nitrite (1.7 ml, 0.015 mol) and the mixture was heated to 60°C for 15 minutes. The above aniline (5.0 g, 0.015 mol) in acetonitrile (10 ml) was added slowly, and the mixture was stirred at 60°C for 30 minutes. The reaction was cooled to room temperature, quenched with water, and extracted with ethyl acetate. The ethyl acetate phase was washed with water and _brine , dried over _Na2SO4 , and concentrated. The crude product was purified by column chromatography to give 2-chloro-5-piperazin-1-yl-benzoic acid ethyl ester.

Step 5: Add 1-chloroethyl chloroformate (0.3 ml, 0.0026mol), and the mixture was heated at 85°C for 3.0 hours. The solvent was removed in vacuo, the residue was dissolved in methanol (10ml), and the solution was refluxed at 85°C for 1 hour. The solution was cooled to ambient temperature, the methanol was removed in vacuo, and the residue was dissolved in water. The solution was washed with ether and chloroform. The aqueous layer was basified with NaHCO ₃ , extracted with dichloromethane, dried over Na ₂ SO ₄ , and concentrated. The residue was purified by chromatography to afford the title compound.

1-(2-Bromo-4-chloro-5-methoxy-phenyl)-piperazine

Step 1: 2,5-dichlorophenol (25g, 0.15mol), methyl iodide (108g, 0.76mol) and anhydrous K ₂ CO ₃ (105g, 0.76mol) were mixed in anhydrous acetone (250ml), The mixture was stirred for 12 hours. The reaction mixture was concentrated. The residue was slurried in ethyl acetate, washed _with water and brine, dried over _Na2SO4 , and concentrated to give 2,5-dichloroanisole.

Step 2: To 2,5-dichloroanisole (17.5g, 0.099mol) in acetic acid (50ml) at 0°C was added a mixture of concentrated nitric acid (9ml) and concentrated sulfuric acid (13ml). The reaction mixture was stirred for 2 hours. The solid was isolated by filtration, washed with water, and dried. The mixture was washed with petroleum ether to remove the ortho isomer and the remaining solid was pure 2,5-dichloro-4-nitroanisole.

Step 3: Mix 2,5-dichloro-4-nitroanisole (6.0 g, 0.027 mol), benzylpiperazine (9.5 g, 0.05 mol and anhydrous K ₂ CO ₃ (9.36 g, 0.067 mol) Mixed in anhydrous DMSO (150ml). Tetrabutylammonium iodide (0.6g) was added and the mixture was heated at 120°C for 12 hours. The reaction was cooled to room temperature, quenched with water and extracted with ethyl acetate. The ethyl acetate phase was washed with Na Drying over ₂ SO ₄ and concentration gave the N-benzylpiperazine intermediate.

Step 4: Add iron powder (7.38g, 0.13mol) to the anhydrous methanol solution of the intermediate (11g, 0.033mol) obtained in step 3, followed by dropwise addition of ammonium chloride (12.7g, 0.23mol) aqueous solution (100ml) , and the mixture was heated at 75°C for 14 hours. The reaction mixture was cooled to ambient temperature, filtered, and concentrated. The residue was dissolved in ethyl acetate, washed with water and brine, dried over _Na2SO4 , and concentrated to give 2-(4-benzylpiperazin- ₁ -yl)-5-chloro-4-methoxy-aniline .

Step 5: Treatment of 2-(4-benzyl-piperazin-1-yl)-5-chloro-4-methoxy-aniline with copper bromide and tert-butyl nitrite according to Protocol G affords 1-benzyl yl-4-(2-bromo-4-chloro-5-methoxy-phenyl)-piperazine.

Step 6: To 1-benzyl-4-(2-bromo-4-chloro-5-methoxy-phenyl)-piperazine (1.0 g, 0.0025mol) was added 1-chloroethyl chloroformate (0.3ml, 0.0026mol) and the reaction was heated at 85°C for 3.0 hours. The solvent was removed in vacuo, methanol (10ml) was added and the solution was refluxed for 1 hour. Methanol was removed in vacuo, the residue was dissolved in water, and the aqueous layer was washed with ether. The aqueous layer was basified with NaHCO3 and extracted with dichloromethane. The dichloromethane phase was dried over Na2SO4 and concentrated. The crude product was purified by chromatography to afford the title compound.

Scheme E: Selected examples of halogenation of aromatic systems following attachment of piperazine ring systems

1-(2,4-Dichloro-5-methoxy-phenyl)-3-(S)-methyl-piperazine

500 mg of 1-(3-methoxy-phenyl)-3-(S)-methyl-piperazine (1.79 mmol, 1.00 eq) in 5 mL of 1:1 DCM:AcOH was added to a 25 mL flask. The mixture was cooled to 0°C in an ice-water bath, then 550mg NCS (3.58mmol, 2.00eq) was added to the stirred solution at once. The ice bath was removed and the mixture was stirred at room temperature for about 1 hour. LC/MS showed: a mixture of chlorinated products which could be separated by preparative HPLC.

(S)-1-(4-bromo-3-methoxy-phenyl)-3-methyl-piperazine

500 mg of (S)-1-(3-methoxy-phenyl)-3-methyl-piperazine (1.79 mmol, 1.00 eq) in 5 mL of 1:1 DCM:AcOH was added to a 25 mL flask. The mixture was cooled to 0°C in an ice-water bath, then 91 μL of Br ₂ (1.79 mmol, 1.00 eq) was immediately added to the stirred solution. The ice bath was removed and the mixture was stirred at room temperature for about 1 hour. LC/MS showed a mixture of brominated products which could be separated by preparative HPLC.

Scheme F: Demethylation/etherification of aromatic precursors for attachment of piperazine ring systems to give selected examples of key arylpiperazine moieties

Synthesis of 4-bromo-7-chloro-benzofuran:

Step 1: Mix 1.46g (6.99mmol) 3-bromo-6-chlorophenol, 1.93g (13.98mmol) anhydrous K ₂ CO ₃ and 2.07g (10.48mmol) bromoacetaldehyde diethyl acetate and Heat at 140°C for 3 hours. The reaction was then cooled to ambient temperature, partitioned between ethyl acetate and water, and the phases were separated. The ethyl acetate layer _was washed once each with water and brine, dried over _Na2SO4 , and concentrated to give the crude acetal (2.3 g, 99%).

Step 2: 2.29 g of the above crude acetal and 4 g of polyphosphoric acid were mixed in 20 mL of toluene, and the mixture was heated at 90° C. for 3 hours. The reaction was then cooled to ambient temperature, partitioned between ethyl acetate and water, and the phases were separated. The ethyl acetate layer was washed once each with water, 10% NaHCO ₃ and brine, dried over Na ₂ SO ₄ , and concentrated. The residue was purified by column chromatography to obtain the title compound (0.550 g, 31%).

4-Bromo-1-chloro-2-(2,2,2-trifluoro)ethoxybenzene

Mix 14.7 g of 5-bromo-2-chlorophenol (71 mmol, 1.0 eq), 18.6 g of triphenylphosphine (71 mmol, 1.0 eq) and 200 mL of anhydrous THF in a 500 mL round bottom flask equipped with a _N inlet . The mixture was cooled in an ice-water bath, and then 12.4 g of diethyl azodicarboxylate (71 mmol, 1.0 eq) was added. After stirring for 1 hour, 5.7 mL of 2,2,2-trifluoroethanol (78 mmol, 1.1 eq) was added, the flask was taken out from the ice bath, and stirred overnight at room temperature. The reaction was quenched with a small amount of water and the solvent was removed in vacuo. The residue was dissolved in 150 mL DCM and diluted with hexanes until cloudy. The solution was placed in the refrigerator for several hours, the crystallized triphenylphosphine oxide by-product was discarded, the mother liquor was concentrated in vacuo and purified by column chromatography (EtOAc/Hexane).

4-Bromo-1-chloro-2-(2-fluoro)ethoxybenzene

Mix 14.7 g of 5-bromo-2-chlorophenol (71 mmol, 1.0 eq), 18.6 g of triphenylphosphine (71 mmol, 1.0 eq) and 200 mL of anhydrous THF in a 500 mL round bottom flask equipped with a N _inlet . The mixture was cooled in an ice-water bath, and then 12.4 g of diethyl azodicarboxylate (71 mmol, 1.0 eq) was added. After stirring for 1 hour, 4.6 mL of 2-fluoroethanol was added, the flask was taken out from the ice bath, and stirred overnight at room temperature. The reaction was quenched with a small amount of water and the solvent was removed in vacuo. The residue was dissolved in 150 mL DCM and diluted with hexanes until cloudy. The solution was placed in the refrigerator for several hours, the crystallized triphenylphosphine oxide by-product was discarded, the mother liquor was concentrated in vacuo and purified by column chromatography (EtOAc/Hexane).

4-Bromo-1-chloro-2-propoxybenzene

In a 50 mL round bottom flask equipped with a reflux condenser and N _inlet tube, mix 1.2 g of 5-bromo-2-chlorophenol (5.9 mmol, 1.0 eq), 1.6 _{g of K} CO (11.8 mmol, 2.0 eq), 1.0 g iodopropane (5.9 mmol, 1.0 eq) and 16 mL acetone. The mixture was refluxed overnight under _N2 . LC/MS showed the reaction was complete. 5 mL of _H2O was added to the flask and the mixture was extracted with 2 x 20 mL of 1:1 EtOAc/Hexane. The aqueous phase was discarded and the combined organics were dried in vacuo to give 1.8 g of pure product.

Scheme H: Synthesis of pyrazoles by addition of hydrazine to α,β-ynones:

Synthesis of 2-(5-methyl-1H-pyrazol-3-yl)-6-trifluoromethylpyridine

Step 1: To 2-chloro-6-trifluoromethylpyridine (91 mg), 2-butynol (0.043 mL), Pd ₂ (PPh ₃ ) ₂ Cl ₂ (17.5 mg) and To a solution of CuI (4.8 mg) was added Et ₃ N (0.3 mL). The reaction mixture was stirred at 25°C for 12 hours and the residue was purified on preparative HPLC to provide the coupled alcohol.

Step 2: The alcohol was dissolved in _CH2Cl2 (2 _mL ) and Dess-Martin periodate (320 mg) was added. The reaction mixture was stirred at 25°C for 2 hours and evaporated in vacuo. The residue was purified by preparative HPLC to provide the ketone.

Step 3: The ketone was dissolved in EtOH (10 mL) and hydrazine was added. The reaction mixture was heated to reflux for 1 hour, cooled to room temperature and evaporated in vacuo. The residue was purified by preparative HPLC to provide the title compound.

5-(5-Methyl-1H-pyrazol-3-yl)-pyridine-2-carbonitrile

Step 1: To a solution of 2,5-dibromopyridine (10 gm, 0.0422 mol) in DMF (100 ml) was added Cu(I)CN (2.5 g, 3.4 mole) under _N2 . The reaction mixture was heated to 115°C overnight. The reaction mixture was cooled to ambient temperature, poured into water and extracted four times with EtOAc. The combined ethyl acetate phases were concentrated and the residue was purified by chromatography to yield 5-bromo-2-cyanopyridine.

Steps 2 and 3: To 5-bromo-2-cyanopyridine (1.8 g, 9.84 mmol) in anhydrous THF (50 ml) was added _Et3N (2.75 ml, 19.7 mmol), 3-butyne-2- Alcohol (1.03 gm, 14.75 mmol) and PdCl ₂ (PPh ₃ ) ₂ (200 mg), the reaction mixture was refluxed at 80° C. overnight. The reaction mixture was cooled to ambient temperature and the THF was removed in vacuo. The residue was slurried with water and extracted with chloroform. The chloroform layer was separated and washed once each with water, _NaHCO3 , 1M citric acid and brine. _The chloroform layer was dried over _Na2SO4 , and concentrated. The crude residue was dissolved in acetone (25ml), cooled to 0°C and Jones reagent (4ml) was added. After 12 hours, the acetone was removed and the residue was washed with water and brine, dried over _Na2SO4 , and concentrated to give the corresponding acetylenone _.

Step 4: Dissolve the acetylenone intermediate (1.83g, 10.75mmol) in anhydrous THF (30ml), add hydrazine hydrate (0.582g, 11.83mmol), and stir the solution for 3 hours. The reaction mixture was then concentrated and the residue was partitioned between water and _CHCl3 . _The chloroform layer was washed with water and brine, dried over _Na2SO4 , and concentrated. The residue was purified by chromatography to afford the title compound.

6-(5-Methyl-1H-pyrazol-3-yl)-pyridine-2-carboxylic acid methylamide

Step 1: Following Scheme X, 6-bromopicolinic acid is coupled with methylamine to give the corresponding amide.

Steps 2 and 3: Following the same two-step procedure as in previous examples, 6-bromo-N-methylpicolinamide was converted to the corresponding conjugated ketone.

Step 4: Following the same method as in previous examples, the conjugated ketone was reacted with hydrazine to obtain the title compound.

6-(5-Methyl-1H-pyrazol-3-yl)-pyridine-2-carboxylic acid ethyl ester

Steps 1 and 2: To ethyl 6-bromopicolinate (5.37 g, 0.23 mole) in anhydrous THF (60 ml) was added Et ₃ N (3 ml, 0.0215 mole), 3-butyn-2-ol (1.5 ml, 0.0214 mole) and PdCl ₂ (PPh ₃ ) ₂ (200 mg), the reaction mixture was refluxed at 80°C overnight. The reaction mixture was cooled to ambient temperature, the solvent was removed and the residue was partitioned between water and chloroform. The chloroform layer was washed once _each with water, _NaHCO3 , 1M citric acid and brine, dried over _Na2SO4 , and concentrated. The residue was dissolved in acetone (25ml), cooled to 0°C, and Jones reagent (25ml) was added. After stirring overnight, the acetone was removed in vacuo and the residue was partitioned between water and _CHCl3 . The chloroform layer was washed with water and _brine , dried over _Na2SO4 , and concentrated to give the corresponding ketone.

Step 3: Following Scheme H, the intermediate ketone is treated with hydrazine to afford the title compound.

2-Methyl-4-(5-methyl-1H-pyrazol-3-yl)-pyridine

Step 1: 2-picoline (25 g, 0.268 mole) was dissolved in 150 mL of glacial acetic acid, and 20 mL of 50% H ₂ O ₂ was added thereto. The reaction mixture was heated to 85°C overnight. When TLC showed complete consumption of starting material, the reaction mixture _was cooled to ambient temperature and treated with Pd/C to destroy excess _H2O2 . The Pd/C was then filtered off, and the excess AcOH was spun off. Retreatment with toluene followed by azeotropic removal of excess toluene yielded 27 g of N-oxide 1 in 95% yield.

Step 2: The N-oxide 1 (27 g, 0.247 mole) was dissolved in 62 mL concentrated H ₂ SO ₄ and cooled to 0°C. A mixture of 90 mL _H2SO4 and 115 mL _HNO3 was then added slowly and the resulting mixture was heated at 95 °C _for 12 hours. The solution was cooled to ambient temperature, basified to pH 3 with aqueous NH ₃ , and extracted three times with CHCl ₃ . The combined _CHCl3 layers were washed once each with water and _brine , dried over _Na2SO4 , and concentrated to give product 2 (37 g, 96%) as a yellow solid.

Step 3: 2-Methyl-4-nitropyridine-N-oxide 2 (10 g, 0.0649 mole) was cooled, then CH ₃ COBr (30 ml) was added dropwise thereto. After the addition was complete, the reaction mixture was heated at 50°C for 5 hours. The reaction mixture was cooled to ambient temperature, basified with 10% NaHCO ₃ and extracted with CHCl ₃ . _The chloroform phase was washed with water and brine, dried over _Na2SO4 , and concentrated. The residue was purified by chromatography to afford 3.

Step 4: 3 (7 g, 0.0372 mole) was dissolved in CHCl ₃ (45 ml), and the solution was cooled to 0°C. Then _PCl3 (14ml) was added via dropping funnel and the reaction mixture was kept for 12 hours. The reaction was quenched with 10% NaHCO ₃ and extracted with CHCl ₃ . The CHCl ₃ layer was washed with water and _brine , dried over _Na2SO4 , and concentrated to afford pyridine 4 (5.9 g, 91%).

Steps 5 and 6: Pyridine 4 (5.8 g, 0.0337 mole) was dissolved in anhydrous THF (30 ml). Et ₃ N (9.5 ml, 0.0674 mole), 3-butyn-2-ol (3.6 ml, 0.505 mole) and PdCl ₂ (PPh ₃ ) ₂ (400 mg) were added, and the reaction mixture was refluxed at 75° C. overnight. The reaction mixture was cooled to ambient temperature and the THF was removed in vacuo. The residue was partitioned between water and chloroform and the layers were separated. The chloroform layer was washed once _each with water, _NaHCO3 , 1M citric acid and brine, dried over _Na2SO4 , and concentrated.

The above residue was dissolved in acetone (25ml), cooled to 0°C, and Jones reagent (10ml) was added. After stirring for 12 hours, the acetone was removed in vacuo and the residue was partitioned between water and _CHCl3 . The chloroform layer was washed with water and _brine , then dried over _Na2SO4 , and concentrated to give product 5 in 20% yield.

Step 7: Intermediate 5 (0.6 g, 0.0038 mole) was dissolved in ethanol (15 ml), hydrazine hydrate (3.5 ml) was added, and the solution was stirred for 12 hours. The reaction mixture was concentrated and the residue was partitioned between water and _CHCl3 . _The chloroform layer was washed with water and brine, dried over _Na2SO4 , and concentrated. The residue was purified by chromatography to afford the title compound.

Scheme I: General method for the synthesis of pyrazoles by condensing hydrazines and β-diketones:

Synthesis of 3-(2-pyridyl)-5-methylpyrazole:

Step 1: Under stirring at room temperature, NaH (9.6g, 400mmol) was added in one portion to dibenzo-18-crown-6 (1.24g, 3.4mmol) and 2-acetylpyridine (22.4mL, 200mmol) in THF (80mL ) solution. The mixture was stirred at room temperature for 30 minutes, and EtOAc (25 mL) was added. The mixture was then heated to reflux for 2 hours and cooled to room temperature. Additional EtOAc (300 mL) was added and the reaction mixture was quenched with saturated aqueous NaHCO ₃ (150 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (3 x 100 mL). _The combined organic solvents were dried ( _Na2SO4 ), filtered and evaporated in vacuo. The crude mixture was used without treatment.

Step 2: A solution of the crude mixture from the previous step in denatured EtOH (500 mL) was stirred at room temperature and hydrazine hydrate (15 mL) was added. The solution was then heated to reflux for 1 hour, cooled to room temperature and evaporated in vacuo. The residue was dissolved in EtOAc (300 mL), washed with saturated aqueous NaCl (3 x 50 mL). The organic layer was dried ( _Na2SO4 ), filtered and evaporated _in vacuo. The crude mixture was used without treatment.

Synthesis of 3-(3-pyridyl)-4-chloro-5-methylpyrazole:

Following the same procedure as in the above example, the 3-acetylpyridine was first converted to the corresponding diketone, followed by treatment with hydrazine in methanol to give the pyrazole. Treatment of this intermediate with N-chlorosuccinimide affords the title compound.

Synthesis of 2-(5-trifluoromethyl-2H-pyrazol-3-yl)-pyridine:

The above pyrazole was prepared following the first two steps in the previous example to give the title compound: LCMS (M+1) = 214.1.

4-(4-Chloro-5-methyl-1H-pyrazol-3-yl)pyridine

Following the same procedure as for the preparation of 3-(3-pyridyl)-4-chloro-5-methylpyrazole, starting from 4-acetylpyridine, the title compound was prepared.

Synthesis of 2-methyl-6-(5-methyl-1H-pyrazol-3-yl)-pyridine:

Step 1: Ethyl 6-picolinate (10 g, 0.061 mol) and acetone (8.91 ml, 0.12 mol) in THF were added to NaOMe in anhydrous THF (10 ml) at ambient temperature under nitrogen ( 4.19 g, 0.091 mol). The reaction mixture was refluxed overnight at 65°C. The reaction was then cooled to -10°C, diluted with water (150ml) and the THF was removed in vacuo. The pH was adjusted to 3.5 with acetic acid, and the mixture was extracted with chloroform. The chloroform layer was washed once _each with water and brine, dried over _Na2SO4 , and concentrated to afford the corresponding diketone.

Step 2: Following Scheme I, the diketone of Step 1 is treated with hydrazine to afford the title compound.

Synthesis of ethyl pyrimidine-4-carboxylate:

Step 1: To 4-methylpyrimidine (5 g, 0.05 mol) in pyridine (50 ml) was added selenium dioxide in portions with stirring over 10 minutes. The reaction mixture was heated at 60°C for 2 hours, then cooled to ambient temperature and stirred for a further 12 hours. The solution was concentrated and the obtained brown solid was washed with water and dried in vacuo to give 8 gm of 4-pyrimidinecarboxylic acid.

Step 2: To 4-pyrimidinecarboxylic acid (8g, 0.06mol) in absolute ethanol (150ml) was added sulfuric acid (3.16ml) and the mixture was refluxed for 12 hours. The reaction mixture was concentrated, partitioned between 10% sodium bicarbonate and ethyl acetate, and the phases were separated. The ethyl acetate layer was washed with water and brine, dried over sodium sulfate, and concentrated to give 7.7 gm of the title compound.

Synthesis of 4-(5-methyl-1H-pyrazol-3-yl)-pyrimidine:

Step 1: To sodium methoxide (0.02 mol) in dry THF (15 ml) was added dry acetone (0.07 mol) under a nitrogen atmosphere, and the solution was stirred for 30 minutes. Ethyl pyrimidine-4-carboxylate (3.0 g, 0.02 mol) in dry THF (20 ml) was added dropwise. The reaction mixture was stirred for 30 minutes, then heated at reflux for 1 hour. The reaction mixture was cooled to room temperature, neutralized with acetic acid, and extracted with ethyl acetate. The ethyl acetate layer was washed once each with water and brine, dried over sodium sulfate, and concentrated to give the corresponding diketone.

Step 2: Following Scheme I, the diketone of Step 1 was treated with hydrazine to afford the title compound.

5-(5-Methyl-1H-pyrazol-3-yl)-pyridine-2-carboxylic acid ethyl ester

Step 1: According to the method adopted in the previous examples, 2-cyano-nicotinic acid methyl ester was reacted with acetone to obtain the corresponding diketone intermediate.

Step 2: To the diketone intermediate (1.85 gm) in 50 mL ethanol was added 2.5 mL concentrated HCl. The reaction mixture was heated at 100°C for 12 hours. The solvent was spun off and 10% _NaHCO3 was added until the pH of the reaction was >8. The mixture was extracted with _CHCl3 . _The chloroform layer was washed with water, dried over _Na2SO4 , and concentrated to give the corresponding ethyl ester.

Step 3: Following Scheme I, the intermediate from Step 2 was reacted with hydrazine to afford the title compound.

Methyl pyrimidine-2-carboxylate:

2-cyanopyrimidine (3 g, 0.0285 mol) in dry methanol was stirred with HCl gas for 2 hours. The reactor was plugged and kept at 4°C for 3 days. The reaction mixture was concentrated, the residue was basified with 10% sodium bicarbonate solution, and extracted with dichloromethane. The dichloromethane layer was washed with water and brine, dried over sodium sulfate, and concentrated to give the title compound.

Synthesis of 2-(5-methyl-1H-pyrazol-3-yl)-pyrimidine:

Step 1: To sodium methoxide (0.86 g, 0.0159 mol) in dry THF (20 ml) was added dry acetone (0.9 g, 0.015 mol) and stirred for about 30 minutes. Methyl pyrimidine-2-carboxylate (1.1 g, 0.007 mol) in dry THF (20 ml) was added dropwise. The reaction mixture was stirred for 30 minutes, then heated at reflux for 1 hour. The reaction mixture was cooled to room temperature, neutralized with acetic acid, and extracted with ethyl acetate. The ethyl acetate layer was washed once each with water and brine, dried over sodium sulfate, and concentrated to give the corresponding diketone.

Step 2: Following Scheme I, the diketone from Step 1 was treated with hydrazine hydrate to afford the title compound.

1-Oxo-isonicotinic acid methyl ester:

To methyl isonicotinate (44 g, 0.2913 mol) in acetic acid (135 ml) was added _H2O2 ( ₄₄ ml) dropwise and the mixture was heated at 90 °C for 12 hours. The mixture was cooled to ambient temperature, Pd/C (0.5 g) was added slowly and the mixture was stirred for 15 minutes. The reaction mixture was then filtered through celite and the filtrate was concentrated to afford the title compound.

Synthesis of 4-(5-methyl-1H-pyrazol-3-yl)-pyridine 1-oxide:

Step 1: To NaOMe (19.4 g, 0.3592 mol) in dry diethyl ether (300 ml) was added dry acetone (27.7 g, 0.4790 mol) and the reaction mixture was stirred for 20 minutes. 1-Oxo-isonicotinic acid methyl ester (40 g, 0.2395) in 300 mL of diethyl ether was slowly added and the mixture was heated to reflux and stirred for 1 hour. The reaction mixture was cooled to ambient temperature, neutralized with acetic acid and extracted with ethyl acetate. The ethyl acetate layer was washed once each with water and brine, dried over _Na2SO4 , and concentrated to give the corresponding diketone _.

Step 2: Following Scheme I, the diketone from Step 1 was treated with hydrazine hydrate to afford the title compound.

Synthesis of 4-(5-methyl-1H-pyrazol-3-yl)-pyridine-2-carbonitrile:

To 4-(5-methyl-1H-pyrazol-3-yl)-pyridine 1-oxide (7.0 g, 0.024 mol) in a water/1,4-dioxane mixture (140/175 ml) was added NaCN (3 g, 0.0614 mol). The reaction mixture was stirred for 14 hours, then extracted with ethyl acetate. _The ethyl acetate layer was washed once each with water and brine, dried over _Na2SO4 , and concentrated. The crude residue was purified by column chromatography to afford the title compound.

Synthesis of 2-methyl-5-(5-methyl-2H-pyrazol-3-yl)-pyridine:

Step 1: To sodium methoxide (1.5 g, 0.027 mol) in dry THF (20 ml) was added dry acetone (3.2 g, 0.055 mol) and the mixture was stirred for about 30 minutes. 6-Methyl-nicotinic acid methyl ester (2.3 g, 0.027 mol) in dry THF (20 ml) was added dropwise. The reaction mixture was stirred for 30 minutes, then heated at reflux for 1 hour. The reaction mixture was cooled to room temperature, neutralized with acetic acid, and extracted with ethyl acetate. The ethyl acetate layer was washed once each with water and brine, dried over sodium sulfate, and concentrated to give the corresponding diketone.

Step 2: Following Scheme I, the diketone from Step 1 was treated with hydrazine hydrate to afford the title compound.

Synthesis of 4-(5-methyl-2H-pyrazol-3-yl)-pyridine:

Step 1: To sodium methoxide (5.9 g, 0.1 mol) in anhydrous THF (100 ml) was added anhydrous acetone (12.7 g, 0.2 mol) under nitrogen atmosphere, and stirred for 30 minutes. Methyl isonicotinate (15 g, 0.1 mol) in anhydrous THF (100 ml) was added dropwise. The reaction mixture was stirred for 30 minutes, then heated at reflux for 1 hour. The reaction mixture was cooled to room temperature, neutralized with acetic acid, and extracted with ethyl acetate. The ethyl acetate layer was washed once each with water and brine, dried over sodium sulfate, and concentrated to give the corresponding diketone.

Step 2: Following Scheme I, the diketone from Step 1 was treated with hydrazine hydrate to afford the title compound.

Synthesis of 2-chloro-5-(5-methyl-1H-pyrazol-3-yl)-pyridine:

Step 1: 5 g (0.0269 mol) ethyl 6-chloronicotinate was dissolved in anhydrous THF, and this solution was added to 2.18 g (0.041 mols) sodium methoxide in anhydrous THF. In a nitrogen atmosphere, 3.96 mL (0.054 mol) of acetone was added thereto, and the mixture was refluxed at 65° C. for 12 hours. The reaction mixture was cooled to ambient temperature and quenched with water. THF was removed in vacuo, the pH was adjusted to 3.5 with acetic acid, and the mixture was extracted with chloroform. The chloroform phase was washed _once each with water and brine, dried over _Na2SO4 , and concentrated. The resulting residue is a mixture of 1-(6-chloropyridin-3-yl)butan-1,3-dione and 1-(6-ethoxypyridin-3-yl)butan-1,3-dione .

Step 2: Following Scheme I, the above mixture was treated with hydrazine hydrate to afford crude pyrazole.

Step 3: 1.7 g of the above crude pyrazole was dissolved in 20 mL of anhydrous dioxane, 10 mL of POCl ₃ was added thereto, and the mixture was heated at 80° C. for 12 hours. The reaction mixture was cooled to -20 °C, 50 mL of water was added, and the pH was adjusted to 9 with NaHCO ₃ solution. The mixture was extracted with chloroform. The chloroform phase was washed three times _with water, once with brine, dried over _Na2SO4 , and concentrated. The residue was purified by column chromatography using petroleum ether/ethyl acetate as eluent to afford the title compound.

5-furan-2-yl-3-trifluoromethyl-1H-pyrazole

Following Scheme I, using commercially available diketones, the above compound was synthesized: ¹ H NMR (400 MHz, CDCl ₃ ): δ6.51 (dd, J=1.8 & 3.3 Hz, 1H), 6.67-6.68 (m, 1H ), 6.71 (s, 1H), 7.48-7.49 (m, 1H).

Protocol L: Chlorination or bromination of pyrazoles with N-chlorosuccinimide (NCS) or N-bromosuccinimide (NBS):

4-Chloro-5-methyl-1H-pyrazole-3-carboxylic acid ethyl ester

Following Protocol L, ethyl 5-methyl-1H-pyrazole-3-carboxylate was treated with NCS to afford the title compound.

(4-Chloro-5-methyl-1H-pyrazol-3-yl)-methanol

3.0 g of ethyl 4-chloro-5-methyl-1H-pyrazole-3-carboxylate (15.9 mmol, 1.0 eq) was dissolved in 17 mL of anhydrous THF, and the solution was cooled in an ice-water bath. Under nitrogen, 1.2g _LiAlH4 (31.8mmol, 2.0eq) was added in portions, being careful not to make the reaction too vigorous. The gray slurry was refluxed for 3 hours. The mixture was cooled in an ice water bath and carefully quenched with 1M NaOH. The solvent was removed in vacuo and the solid was washed with hot MeOH and discarded. The methanol solution was concentrated in vacuo and purified by preparative HPLC.

5-(4-Chloro-5-methyl-1H-pyrazol-3-yl)-pyridine-2-carbonitrile

Following Scheme L, 5-(5-Methyl-1H-pyrazol-3-yl)-pyridine-2-carbonitrile was treated with N-chlorosuccinimide to afford the title compound.

Synthesis of 2-(4-chloro-5-trifluoromethyl-2H-pyrazol-3-yl)-pyridine:

Following Protocol L, 2-(5-trifluoromethyl-2H-pyrazol-3-yl)-pyridine was treated with N-chlorosuccinimide. The crude product was purified by recrystallization from hexane and ethyl acetate (9:1): ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.35-7.38 (m, 1H), 7.85-7.90 (m, 1H) , 8.20 (d, J=8.1 Hz, 1H), 8.63 (d, J=4.0 Hz, 1H).

6-(4-Chloro-5-methyl-1H-pyrazol-3-yl)-pyridine-2-carboxylic acid methylamide

Following Scheme L, 6-(5-Methyl-1H-pyrazol-3-yl)-pyridine-2-carboxylic acid methylamide was treated with N-chlorosuccinimide to afford the title compound.

4-(4-Chloro-5-methyl-1H-pyrazol-3-yl)-pyridine-2-carbonitrile

Following Protocol L, 4(5-Methyl-1H-pyrazol-3-yl)-pyridine-2-carbonitrile was treated with NCS to afford the title compound.

2-(4-Chloro-5-methyl-1H-pyrazol-3-yl)-6-trifluoromethyl-pyridine

Following Protocol L, 2-(5-Methyl-1H-pyrazol-3-yl)-6-trifluoromethyl-pyridine was treated with NCS to afford the title compound.

3-Bromoindazole

Following Scheme L, indazole was converted to 3-bromoindazole.

Synthesis of 3-(2-pyridyl)-4-chloro-5-methylpyrazole:

Following Scheme L, 3-(2-pyridyl)-5-methylpyrazole was treated with N-chlorosuccinimide to afford the title compound as a pale yellow solid.

Synthesis of 2-(4-chloro-5-methyl-1H-pyrazol-3-yl)-6-methyl-pyridine:

Following Scheme L, 2-methyl-6-(5-methyl-1H-pyrazol-3-yl)-pyridine was treated with N-chlorosuccinimide to afford the title compound.

Synthesis of 2-(4-bromo-5methyl-1H-pyrazol-3-yl)6-methyl-pyridine:

Following Scheme L, 2-methyl-6-(5-methyl-1H-pyrazol-3-yl)-pyridine was treated with N-bromosuccinimide to afford the title compound.

Synthesis of 3-methyl-4-iodo-5-(trifluoromethyl)pyrazole

3-Methyl-5(trifluoromethyl)pyrazole (1.5g, 10mmol), [bis(trifluoroacetoxy)iodo]benzene (4.8g, 11mmol) and iodine (2.8g, 11mmol) were mixed in 120mL in DCM, stirred at room temperature for 2 hours. To _this mixture was added 0.5L EtOAc, washed with 1M _Na2S2O5 and brine, dried over anhydrous sodium sulfate, and concentrated to form a brown _solid . The solid was washed with hexanes to provide the title compound: HPLC retention time = 3.52 minutes (Agilent Zorbax SB-C18, 2.1 x 50 mm, 5 μ, 35° C.) using a 4.5 minute gradient of 20-95% B at 95% B A 1.1 minute wash was used (A = 0.1% formic acid/5% acetonitrile/94.9% water, B = 0.08% formic acid/99.9% acetonitrile); MS (ES) M+H expected = 276.9, found = 277.1.

Synthesis of 3-methyl-4-fluoro-5(trifluoromethyl)pyrazole

3-Methyl-5-(trifluoromethyl)pyrazole (0.30 g, 2 mmol), selectfluor reagent (3.54 g, 10 mmol) were mixed in DMF and stirred overnight at 60°C. EtOAc was added, the mixture was filtered, and the filtrate was washed with saturated _NaHCO3 , brine, dried over _Na2SO4 , and concentrated to provide the product _.

6-(4-Chloro-5-methyl-1H-pyrazol-3-yl)-pyridine-2-carboxylic acid ethyl ester

Following Scheme L, ethyl 6-(5-methyl-1H-pyrazol-3-yl)-pyridine-2-carboxylate was treated with N-chlorosuccinimide to afford the title compound.

Synthesis of 4-(4-chloro-5-methyl-1H-pyrazol-3-yl)-pyrimidine:

Following Scheme L, 4-(5-methyl-1H-pyrazol-3-yl)-pyrimidine was treated with N-chlorosuccinimide in acetonitrile to afford the title compound.

Synthesis of 4-chloro-3-iodo-5-methyl-1H-pyrazole:

Add 7.0 gm (60 mmol) of 4-chloro-3-methylpyrazole, 34 gm (78 mmol) of bis-(trifluoroacetoxy) iodobenzene, and 20 gm (78 mmol) of iodine to a 350 mL of di in methyl chloride. After 14 hours, the mixture was partitioned between 3M sodium metabisulfite and hexane and the phases were separated. The hexane phase was washed once each with 3M sodium metabisulfite and brine, dried over sodium sulfate, filtered, and concentrated. The residue was crystallized from hexane to give the title compound.

Synthesis of 4-(4-bromo-5-methyl-2H-pyrazol-3-yl)-pyridine:

Following Scheme X, 4-(5-methyl-2H-pyrazol-3-yl)-pyridine was treated with NBS in acetonitrile to afford the title compound.

Synthesis of 4-(4-chloro-5-methyl-2H-pyrazol-3-yl)-pyridine:

Following Scheme X, 4-(5-methyl-2H-pyrazol-3-yl)-pyridine was treated with NCS in acetonitrile to afford the title compound.

Synthesis of 2-(4-chloro-5-methyl-1H-pyrazol-3-yl)-pyrimidine:

Following protocol L, 2-(5-methyl-1H-pyrazol-3-yl)-pyrimidine was treated with N-chlorosuccinimide at 60°C for 1 hour. The reaction mixture was cooled to room temperature, concentrated and the residue was partitioned between ethyl acetate and water. The phases were separated and the aqueous phase was back extracted twice with ethyl acetate. The combined ethyl acetate phases were washed with 1M _NaOH , brine, dried over _Na2SO4 and concentrated. The residue was slurried in ether and the solid was isolated by filtration to give the title compound.

Synthesis of 2-methyl-5-(4-chloro-5-methyl-2H-pyrazol-3-yl)-pyridine:

Following Scheme L, 2-methyl-5-(5-methyl-2H-pyrazol-3-yl)-pyridine was treated with N-chlorosuccinimide in acetonitrile to afford the title compound.

4-Chloro-3,5-dipyridin-2-yl-pyrazol-1-yl

Following Scheme L, using commercially available dipyridylpyrazole, the above compound was synthesized.

2-Methyl-4-(4-chloro-5-methyl-1H-pyrazol-3-yl)-pyridine

Following Scheme L, 2-methyl-4-(5-methyl-1H-pyrazol-3-yl)-pyridine was treated with N-chlorosuccinimide to afford the title compound.

5-(4-Chloro-5-methyl-1H-pyrazol-3-yl)-pyridine-2-carboxylic acid ethyl ester

Following Protocol L, ethyl 5-(5-methyl-1H-pyrazol-3-yl)-pyridine-2-carboxylate was treated with NCS to afford the title compound.

Synthesis of 3-bromo-4-chloro-5-methyl-1H-pyrazole:

In a closed vessel, 5.0 mL (61 mmol) of 3-methylpyrazole and 8.95 gm (67.1 mmol) of N-chlorosuccinimide were heated in 50 mL of glacial acetic acid at 60° C. for 2 hours. Afterwards, 5.5 gm (74 mmol) sodium acetate, 40 mL water and 3.2 mL (61 mmol) bromine were added, the vessel was sealed and the dark mixture was heated at 100° C. for 3 hours. The pale orange solution was cooled to ambient temperature and 100 mL of water was added slowly. The solid was isolated by filtration, washed with water and dried to give the title compound.

Scheme M: General procedure for the reduction of nitropyrazoles

Synthesis of 3-methyl-4-nitro-5(trifluoromethyl)pyrazole:

3-Methyl-5(trifluoromethyl)pyrazole (3.0 _g , 20 mmol) was dissolved in 2 mL of concentrated _H2SO4 with vigorous stirring. 6 mL of nitric acid was slowly added thereto. The reaction mixture was stirred overnight at 60 °C. The reaction mixture was cooled to room temperature, poured into 50 mL of saturated NaHCO ₃ in an ice bath, and the resulting mixture was extracted three times with ethyl acetate. The combined ethyl acetate layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated to provide the title compound (3.9 g, yield: 100%). HPLC retention time = 4.55 minutes (Agilent Zorbax SB-C18, 2.1 x 50mm, 5μ, 35°C) using a 4.5 minute gradient from 20-95% B with a 1.1 minute wash at 95% B (A = 0.1% formic acid /5% acetonitrile/94.9% water, B=0.08% formic acid/99.9% acetonitrile). MS(ES) M+H expected = 196.0, found = 196.1.

Synthesis of 3-methyl-4-amino-5(trifluoromethyl)pyrazole:

Following Protocol M, 3-methyl-4-nitro-5(trifluoromethyl)pyrazole was treated with zinc in acetic acid to provide the title compound: MS (ES) M+H expected = 166.0, found = 165.0 .

Scheme P: Coupling of arylpiperazines with pyrazolyl-acetic acid derivatives - compounds prepared by HATU-involved couplings:

2-(4-bromo-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(2,4-dichloro-5-methoxy-phenyl)- Piperazin-1-yl]-ethanone

Coupling of 1-(2,4-dichloro-5-methoxy-phenyl)-piperazine with (4-bromo-5-methyl-3-trifluoromethyl-pyrazole) using HATU following Protocol P -1-yl)-acetic acid to give the title compound: HPLC retention time = 4.96 min (Agilent Zorbax SB-C18, 2.1 x 50 mm, 5 μ, 35°C) using a 4.5 min gradient from 20-95% B at 95% B A 1.1 minute wash was used (A = 0.1% formic acid/5% acetonitrile/94.9% water, B = 0.08% formic acid/99.9% acetonitrile).

1-[4-(4-chloro-2-fluoro-5-methoxy-phenyl)-piperazin-1-yl]-2-(4-chloro-5-methyl-3-trifluoromethyl -pyrazol-1-yl)-ethanone

Coupling of 1-(4-chloro-2-fluoro-5-methoxy-phenyl)-piperazine with 4-chloro-5-methyl-3-trifluoromethyl-pyrazole using HATU following Protocol P -1-yl)-acetic acid to give the title compound: HPLC retention time = 7.38 min (Agilent Zorbax SB-C18, 2.1 x 50 mm, 5 μ, 35 °C) with 2.0 min no gradient time at 20% B followed by 20- 5.0 min gradient to 95% B with 2.5 min wash at 95% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.08% formic acid/99.9% acetonitrile); (M/Z)+ =469(M+H).

2-(4-Bromo-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-[(S)-4-(2,4-dichloro-5-methoxy- Phenyl)-2-methyl-piperazin-1-yl]-ethanone

Following Protocol P, using HATU, couple (S)-1-(2,4-dichloro-5-methoxy-phenyl)-3-methyl-piperazine with (4-bromo-5-methyl- 3-Trifluoromethyl-pyrazol-1-yl)-acetic acid to give the title compound: HPLC retention time = 6.86 min (Agilent Zorbax SB-C18, 2.1 x 50 mm, 5 μ, 35 °C) with 20% B of 2.0 min no gradient time followed by a 5.0 min gradient from 20-95% B with a 2.5 min wash at 95% B (A = 0.1% formic acid/5% acetonitrile/94.9% water, B = 0.08% formic acid/99.9% Acetonitrile); (M/Z)-=463 (M-Br).

2-(4-bromo-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-[(S)-4-(4-bromo-5-methoxy-phenyl) -2-Methyl-piperazin-1-yl]-ethanone

Following Protocol P, using HATU, couple (S)-1-(4-bromo-5-methoxy-phenyl)-3-methyl-piperazine with (4-bromo-5-methyl-3-tris Fluoromethyl-pyrazol-1-yl)-acetic acid to give the title compound: HPLC retention time = 7.32 min (Agilent Zorbax SB-C18, 2.1 x 50 mm, 5 μ, 35° C.), 2.0 min with 20% B without gradient time, followed by a 5.0 minute gradient from 20-95% B with a 2.5 minute wash at 95% B (A = 0.1% formic acid/5% acetonitrile/94.9% water, B = 0.08% formic acid/99.9% acetonitrile); (M/Z)-=473 (M-Br).

1-[4-(4-chloro-3-methoxy-phenyl)-cis-2,3-dimethyl-piperazin-1-yl]-2-(4-chloro-5-methyl- 3-Trifluoromethyl-pyrazol-1-yl)-ethanone

According to the coupling scheme P in which HATU participated, 1-(4-chloro-3-methoxy-phenyl)-2,3-cis-dimethyl-piperazine was combined with (4-chloro-5-methyl-3 -Trifluoromethyl-pyrazol-1-yl)-acetic acid coupling afforded the title compound: HPLC retention time = 7.5 minutes (Agilent Zorbax SB-C18, 2.1 x 50mm, 5μ, 35°C), using 2.0% of 20% B min no gradient time followed by a 5.0 min gradient from 20-95% B with a 2.5 min wash at 95% B (A = 0.1% formic acid/5% acetonitrile/94.9% water, B = 0.08% formic acid/99.9% acetonitrile);

2-chloro-5-{4-[2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-piperazin-1-yl}-benzene ethyl formate

Coupling of ethyl 2-chloro-5-piperazin-1-yl-benzoate with (4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl) using HATU following Protocol P - Acetic acid to give the title compound: HPLC retention time = 7.38 min (Agilent Zorbax SB-C18, 2.1 x 50 mm, 5 μ, 35° C.) with 2.0 min no gradient time for 20% B followed by 5.0 min for 20-95% B Minute gradient with a 2.5 minute wash at 95% B (A = 0.1% formic acid/5% acetonitrile/94.9% water, B = 0.08% formic acid/99.9% acetonitrile).

1-[4-(2-Bromo-4-chloro-5-methoxy-phenyl)-piperazin-1-yl]-2-(4-chloro-5-methyl-3-trifluoromethyl -pyrazol-1-yl)-ethanone

Following Protocol P, coupling of 1-(2-bromo-4-chloro-5-methoxy-phenyl)-piperazine with (4-chloro-5-methyl-3-trifluoromethyl-pyridine) using HATU Azol-1-yl)-acetic acid to give the title compound: HPLC retention time = 7.82 min (Agilent Zorbax SB-C18, 2.1 x 50 mm, 5 μ, 35 °C), 2.0 min no gradient time with 20% B followed by 20 - 5.0 minute gradient to 95% B with a 2.5 minute wash at 95% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.08% formic acid/99.9% acetonitrile).

5-chloro-2-{4-[2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-piperazin-1-yl}-4 -Methoxy-methylbenzoate

Following Protocol P, coupling of 5-chloro-4-methoxy-2-piperazin-1-yl-benzoic acid methyl ester with (4-chloro-5-methyl-3-trifluoromethyl-pyridine Azol-1-yl)-acetic acid to give the title compound: HPLC retention time = 7.44 min (Agilent Zorbax SB-C18, 2.1 x 50 mm, 5 μ, 35 °C), 2.0 min no gradient time with 20% B followed by 20 - 5.0 min gradient to 95% B with 2.5 min wash at 95% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.08% formic acid/99.9% acetonitrile): (M/Z) -=506.9 (M-H).

Synthesis of racemic 1-[4-(4-chloro-3-methoxyphenyl)-2-trifluoromethylpiperazin-1-yl]-2-(4-chloro-5-methyl-3 -Trifluoromethylpyrazol-1-yl)ethanone

The title compound was obtained following protocol P: LCMS (ES): M+H 519.0; HPLC retention time = 5.57 minutes (Agilent Zorbax SB-C18, 2.1 x 50 mm, 5 μ, 35° C.) using a 4.5 minute gradient of 20-95% B , with a 1.1 minute wash at 95% B (A = 0.1% formic acid/5% acetonitrile/94.9% water, B = 0.08% formic acid/99.9% acetonitrile).

Synthesis of 1-[4-(4-chloro-3-methoxyphenyl)-cis-2,5-dimethylpiperazin-1-yl]-2-(4-chloro-5-methyl-3 -Trifluoromethylpyrazol-1-yl)ethanone

The title compound was obtained following protocol P: LCMS (ES): M+H 479.1; HPLC retention time = 5.49 minutes (Agilent Zorbax SB-C18, 2.1 x 50 mm, 5 μ, 35° C.) using a 4.5 minute gradient of 20-95% B , with a 1.1 minute wash at 95% B (A = 0.1% formic acid/5% acetonitrile/94.9% water, B = 0.08% formic acid/99.9% acetonitrile).

Synthesis of racemic 1-[4-(4-chloro-3-methoxyphenyl)-trans-2,5-dimethylpiperazin-1-yl]-2-(4-chloro-5-methyl Base-3-trifluoromethylpyrazol-1-yl)ethanone

The title compound was obtained following protocol P: LCMS (ES): M+H 479.1; HPLC retention time = 5.47 minutes (Agilent Zorbax SB-C18, 2.1 x 50 mm, 5 μ, 35° C.) using a 4.5 minute gradient of 20-95% B , with a 1.1 minute wash at 95% B (A = 0.1% formic acid/5% acetonitrile/94.9% water, B = 0.08% formic acid/99.9% acetonitrile).

Synthesis of 2-(3-cyano-4-chloro-5-methyl-pyrazol-1-yl)-1-[4-(4-chloro-3-methoxy-phenyl)-[1,4 ]diazepan-1-yl]-ethanone:

Step 1: At room temperature, tert-butyl 1-[4-(4-chloro-3-methoxy-phenyl)-[1,4]diazepane-1-carboxylate (68 mg, 0.2 mmol, 1 equiv) The sample was treated with 2 mL of 4N HCl in dioxane for 2 hours and then evaporated.

Step 2: To a solution of this residue in 1 mL DMF at room temperature was added (4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid (48 mg, 1 equiv), HATU (84 mg, 1.1 equiv), TEA (84 μL, 3 equiv) overnight. The mixture was diluted with EtOAc, washed with saturated aqueous NaHCO ₃ and brine. The organic layer was dried over Na2SO4, filtered, evaporated and subjected to reverse phase HPLC (acetonitrile- _H2O with 0.1% TFA as eluent) to yield the title compound: the NMR signal from the major isomer ^is1H NMR (400MHz, CDCl ₃ )δ7.33(d, 1H), 6.76(d, 1H), 6.60(dd, 1H), 5.00(s, 2H), 3.84(s, 3H), 4.00-3.50(m, 8H ), 2.33 (m, 2H), 2.08 (s, 3H). LCMS: (M+H) ⁺ Observations: 466.

4-chloro-1-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-5-methyl-1H -pyrazole-3-carboxylic acid methylamide

4-Chloro-1-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl was coupled using HATU following Protocol P }-5-methyl-1H-pyrazole-3-carboxylic acid and methylamine hydrochloride to obtain the title compound: HPLC retention time=4.78 minutes (Agilent Zorbax SB-C18, 2.1×50mm, 5μ, 35°C), using 20 2.0 minute no gradient time for %B, followed by a 5.0 minute gradient from 20-95% B with a 2.5 minute wash at 95% B (A = 0.1% formic acid/5% acetonitrile/94.9% water, B = 0.08% Formic acid/99.9% acetonitrile); (M/Z)+=440.1 (M+H).

4-chloro-1-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-5-methyl-1H -pyrazole-3-carboxylic acid dimethylamide

4-Chloro-1-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl was coupled using HATU following Protocol P }-5-methyl-1H-pyrazole-3-carboxylic acid and dimethylamine to obtain the title compound: HPLC retention time=4.899 minutes (Agilent Zorbax SB-C18, 2.1×50mm, 5μ, 35°C), using 20 2.0 minute no gradient time for %B, followed by a 5.0 minute gradient from 20-95% B with a 2.5 minute wash at 95% B (A = 0.1% formic acid/5% acetonitrile/94.9% water, B = 0.08% Formic acid/99.9% acetonitrile); (M/Z)+=454.1 (M+H).

4-chloro-1-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-5-methyl-1H -Pyrazole-3-carboxylic acid ethylamide

4-Chloro-1-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl was coupled using HATU following Protocol P }-5-methyl-1H-pyrazole-3-carboxylic acid and ethylamine to obtain the title compound: HPLC retention time=5.02 minutes (Agilent Zorbax SB-C18, 2.1×50mm, 5μ, 35°C), using 20% 2.0 min no gradient time for B, followed by a 5.0 min gradient from 20-95% B with a 2.5 min wash at 95% B (A = 0.1% formic acid/5% acetonitrile/94.9% water, B = 0.08% formic acid /99.9% acetonitrile); (M/Z)+=454.1 (M+H).

Synthesis of 2-(4-chloro-5-methyl-3-trifluoromethylpyrazol-1-yl)-1-[4-(2,4-dimethyl-phenyl)piperazin-1-yl ] ethyl ketone

The title compound was obtained following protocol P: LCMS (ES): M+H 415.1; HPLC retention time = 5.374 minutes (Agilent Zorbax SB-C18, 2.1 x 50 mm, 5 μ, 35° C.) using a 4.5 minute gradient of 20-95% B , with a 1.1 minute wash at 95% B (A = 0.1% formic acid/5% acetonitrile/94.9% water, B = 0.08% formic acid/99.9% acetonitrile).

1-[4-(4-chloro-3-methoxy-phenyl)-trans-2,5-dimethyl-piperazin-1-yl]-2-(4-chloro-5-methyl- 3-pyridin-2-yl-pyrazol-1-yl)-ethanone

Following Protocol P, the title compound was prepared: ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.87-8.92 (m, 3H), 6.02-6.95 (s, 2H), 5.11 (s, 2H), 4.18 (q, 1H) , 3.68(q, 1H), 3.41(q, 1H), 2.45(s, 3H), 1.52(t, 3H), 1.42(d, 3H), 1.21(d, 3H); LCMS(ES) M+H =488.4, RT4.364min (acetonitrile/H ₂ O 20-95% method).

1-[4-(4-chloro-3-methoxyphenyl)piperazin-1-yl]-2-[4-chloro-5-methyl-3-(1-oxypyridin-4-yl) Pyrazol-1-yl]ethanone

The title compound was obtained following Protocol P: LCMS (ES): M+H 476.0; HPLC retention time = 4.00 min (Agilent Zorbax SB-C18, 2.1 x 50 mm, 5 μ, 35° C.) using a 4.5 min gradient of 20-95% B , with a 1.1 minute wash at 95% B (A = 0.1% formic acid/5% acetonitrile/94.9% water, B = 0.08% formic acid/99.9% acetonitrile).

Synthesis of 1-[(4-chloro-3-methoxyphenyl)-2-(S)-methylpiperazin-1-yl]-2-[4-chloro-5-methyl-3-(1 -Oxidized pyridin-4-yl)pyrazol-1-yl]ethanone

The title compound was obtained following protocol P: LCMS (ES): M+H 490.1; HPLC retention time = 4.36 minutes (Agilent Zorbax SB-C18, 2.1 x 50 mm, 5 μ, 35° C.) using a 4.5 minute gradient of 20-95% B , with a 1.1 minute wash at 95% B (A = 0.1% formic acid/5% acetonitrile/94.9% water, B = 0.08% formic acid/99.9% acetonitrile).

Synthesis of 1-[4-(4-chloro-3-methoxy-phenyl)-2-(S)-methyl-piperazin-1-yl]-2-[4-chloro-5-methyl- 3-(1-Oxo-pyridin-3-yl)-pyrazol-1-yl]-ethanone:

Following Scheme P, [4-Chloro-5-methyl-3-(1-oxido-pyridin-3-yl)-pyrazol-1-yl]-sodium acetate was mixed with 1-(4-chloro-3-methoxy Base-phenyl)-3-(S)-methyl-piperazine coupling to obtain the title compound: MS (M+H ⁺ ): 490.1; HPLC retention time = 4.06 minutes (Agilent Zorbax SB-C18, 2.1×50mm, 5 μ, 35° C.) with a 4.5-minute gradient of 20-95% B, with a 1.1-minute wash at 95% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.08% formic acid/99.9% acetonitrile).

Synthesis of 1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-[4-chloro-5-methyl-3-(1-oxo-pyridine -3-yl)-pyrazol-1-yl]-ethanone:

Following Scheme P, [4-Chloro-5-methyl-3-(1-oxy-pyridin-3-yl)-pyrazol-1-yl]-sodium acetate and 1-(4-chloro-3-methoxy (Agilent Zorbax SB-C18, 2.1× ^50mm , 5μ, 35°C), using 20- 4.5 minute gradient to 95% B with a 1.1 minute wash at 95% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.08% formic acid/99.9% acetonitrile).

1-[4-(4-chloro-3-methoxybenzyl)piperazin-1-yl]-2-(4-chloro-5-methyl-3-trifluoromethylpyrazol-1-yl ) ethyl ketone

The title compound was obtained according to protocol P: LCMS (ES) M+H: M+H=465.0; HPLC retention time=3.733 minutes (Agilent Zorbax SB-C18, 2.1×50mm, 5μ, 35°C), using 20-95%B A 4.5 minute gradient at 95% B with a 1.1 minute wash (A = 0.1% formic acid/5% acetonitrile/94.9% water, B = 0.08% formic acid/99.9% acetonitrile).

4-chloro-1-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-5-methyl-1H -Pyrazole-3-carboxylic acid isopropylamide

Following Protocol P, using HATU, 4-chloro-1-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl }-5-Methyl-1H-pyrazole-3-carboxylic acid was coupled with isopropylamine to give the title compound: HPLC retention time=5.23 minutes (Agilent Zorbax SB-C18, 2.1×50mm, 5μ, 35°C), A 2.0 minute no-gradient time at 20% B was used, followed by a 5.0 minute gradient from 20-95% B with a 2.5 minute wash at 95% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B= 0.08% formic acid/99.9% acetonitrile); (M/Z)+=468.1 (M+H).

1-[4-(4-chloro-3-methoxy-phenyl)-2-pyrrolidin-1-ylmethyl-piperazin-1-yl]-2-(4-chloro-5-methyl -3-Trifluoromethyl-pyrazol-1-yl)-ethanone

Dissolve about 0.28 mmol 4-(4-chloro-3-methoxy-phenyl)-2-pyrrolidin-1-ylmethyl-piperazine-1-carboxylic acid tert-butyl ester in 1 mL of 1/1 dichloro methane and trifluoroacetic acid. After 30 minutes, the solution was concentrated to a residue. The crude residue was dissolved in 500 μL DMF, and 82 mg 4-chloro-3-trifluoromethyl-5-methylpyrazole-1-acetic acid (0.34 mmol), 293 μL DIEA (1.7 mmol) and 128 mg HATU (0.34 mmol) were sequentially added ). The vial was stirred at room temperature for several hours, then placed in a 60°C oil bath overnight. The crude mixture was purified by preparative HPLC. LC/MS(ES) (M+H) 534.5; HPLC retention time = 6.47 min (Agilent Zorbax SB-C18, 2.1 x 50 mm, 5 μ, 35°C) with 2.0 min no gradient time at 20% B followed by 20 - 5.0 minute gradient to 95% B with a 2.5 minute wash at 95% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.08% formic acid/99.9% acetonitrile).

1-[4-(4-chloro-3-methoxy-phenyl)-2-morpholin-4-ylmethyl-piperazin-1-yl]-2-(4-chloro-5-methyl -3-Trifluoromethyl-pyrazol-1-yl)-ethanone

Dissolve about 0.28 mmol tert-butyl 4-(4-chloro-3-methoxy-phenyl)-2-morpholin-4-ylmethyl-piperazine-1-carboxylate in 1 mL 1/1 dichloro methane and trifluoroacetic acid. After 30 minutes, the solution was concentrated to a residue. The residue was dissolved in 500 μL DMF, and 82 mg 4-chloro-3-trifluoromethyl-5-methylpyrazole-1-acetic acid (0.34 mmol), 293 μL DIEA (1.7 mmol) and 128 mg HATU (0.34 mmol) were added sequentially . The vial was stirred at room temperature for several hours, then placed in a 60°C oil bath overnight. The crude mixture was purified by preparative HPLC. LC/MS(ES) (M+H) 550.5; HPLC retention time = 6.33 min (Agilent Zorbax SB-C18, 2.1 x 50 mm, 5 μ, 35°C) with 2.0 min no gradient time at 20% B followed by 20 - 5.0 minute gradient to 95% B with a 2.5 minute wash at 95% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.08% formic acid/99.9% acetonitrile).

1-[4-(4-chloro-3-methoxy-phenyl)-2-(4-methyl-piperazin-1-ylmethyl)-piperazin-1-yl]-2-(4 -Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-ethanone

About 0.28 mmol of 4-(4-chloro-3-methoxy-phenyl)-2-(4-methyl-piperazin-1-ylmethyl)-piperazine-1-carboxylic acid tert-butyl ester Dissolve in 1 mL of 1/1 dichloromethane and trifluoroacetic acid. After 30 minutes, the solution was concentrated to a residue. The residue was dissolved in 500 μL DMF, and 82 mg 4-chloro-3-trifluoromethyl-5-methylpyrazole-1-acetic acid (0.34 mmol), 293 μL DIEA (1.7 mmol) and 128 mg HATU (0.34 mmol) were added sequentially . The vial was stirred at room temperature for several hours, then placed in a 60°C oil bath overnight. The crude mixture was purified by preparative HPLC.

LC/MS(ES) (M+H) = 563.5; HPLC retention time = 7.25 minutes (Agilent Zorbax SB-C18, 2.1 x 50mm, 5μ, 35°C) with 2.0 minutes no gradient time at 20% B followed by 5.0 minute gradient from 20-95% B with a 2.5 minute wash at 95% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.08% formic acid/99.9% acetonitrile).

1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-[4-chloro-5-methyl-3-(morpholine-4-carbonyl) -pyrazol-1-yl]-ethanone

Following Protocol P, using HATU, 4-chloro-1-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl }-5-methyl-1H-pyrazole-3-carboxylic acid was coupled with morpholine to obtain the title compound: HPLC retention time=4.90 minutes (Agilent Zorbax SB-C18, 2.1×50mm, 5μ, 35°C), using 20 2.0 minute no gradient time for %B, followed by a 5.0 minute gradient from 20-95% B with a 2.5 minute wash at 95% B (A = 0.1% formic acid/5% acetonitrile/94.9% water, B = 0.08% Formic acid/99.9% acetonitrile); (M/Z)+=496.1 (M+H).

Scheme S: Preparation of Chloroacetylarylpiperazines

4-Chloromethylcarbonyl-1-(4-chloro-3-(2-fluoro)ethoxy-phenyl)-piperazine

Following Protocol S, 1-(4-chloro-3-(2-fluoro)ethoxy-phenyl)-piperazine dihydrochloride

(1.53mmol, 1.0eq) _, 1.0g _K2CO3 (7.5mmol, 5.0eq) were mixed with 4mL NMP in a vial. The vial was cooled in an ice-water bath, then 197 μL of chloroacetyl chloride (1.8 mmol, 1.2 eq) was added, and the mixture was stirred at room temperature overnight. The material was purified by column chromatography to give 100 mg of pure product.

4-Chloromethylcarbonyl-1-(4-chloro-3-(2,2,2-trifluoro)ethoxy-phenyl)-piperazine

Following Scheme S, 1-(4-chloro-3-(2,2,2-trifluoro)ethoxy-phenyl)-piperazine dihydrochloride was reacted with chloroacetyl chloride to afford the title compound.

4-Chloromethylcarbonyl-1-(4-chloro-3-propoxy-phenyl)-piperazine

Following Scheme S, 1-(4-chloro-3-propoxy-phenyl)-piperazine dihydrochloride was reacted with chloroacetyl chloride to afford the title compound.

Scheme T: Coupling reaction of chloroacetylarylpiperazine and pyrazole via K ₂ CO ₃

1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-(4-chloro-5-methyl-3-pyridin-4-yl-pyrazole -1-yl)-ethanone

The title compound was prepared following Protocol T using 1-(4-chloro-3-methoxy-phenyl)-piperazine: HPLC retention time = 5.57 minutes (Agilent Zorbax SB-C18, 2.1 x 50mm, 5μ, 35°C ), with a 2.0-minute no-gradient time at 20% B, followed by a 5.0-minute gradient from 20-95% B, with a 2.5-minute wash at 95% B (A = 0.1% formic acid/5% acetonitrile/94.9% water, B=0.08% formic acid/99.9% acetonitrile); (M/Z)+=460.1 (M+H).

Synthesis of 1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-(5-hydroxy-3-methyl-pyrazol-1-yl)-ethyl Ketone and 1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-(3-hydroxy-5-methyl-pyrazol-1-yl)- ethyl ketone

The title compound was prepared following Scheme T using (3-methyl-5-(hydroxy)pyrazole: 1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl ]-2-(3-Hydroxy-5-methyl-pyrazol-1-yl)-ethanone: HPLC retention time = 2.89 minutes (Agilent Zorbax SB-C18, 2.1×50mm, 5μ, 35°C), using 20 - 4.5 min gradient to 95% B with 1.1 min wash at 95% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.08% formic acid/99.9% acetonitrile); MS(ES)M +H expected = 365.1, found = 365.4. 1-[4-(4-Chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-(5-hydroxy-3-methan yl-pyrazol-1-yl)-ethanone: HPLC retention time = 3.33 min (Agilent Zorbax SB-C18, 2.1 x 50 mm, 5 μ, 35 °C) with a 4.5 min gradient of 20-95% B at 95% A 1.1 minute wash was used for B (A = 0.1% formic acid/5% acetonitrile/94.9% water, B = 0.08% formic acid/99.9% acetonitrile); MS(ES) M+H expected = 365.1, found = 365.4; ¹ HNMR (DMSO, 400MHz) 7.20(d, 1H), 70(s1H), 6.52(d, 1H), 5.50(s, 1H), 4.84(s, 2H), 3.83(s, 3H), 3.5-3.6 (Par. Obsc. s, 4H), 3.1-3.3 (d, 4H), 2.15 (s, 3H) ppm.

1-[4-(4-chloro-3-methoxy-phenyl)-2-methyl-piperazin-1-yl]-2-[4-chloro-5-methyl-3-(4- Methyl-pyridin-2-yl)-pyrazol-1-yl]-ethanone

Following protocol T, combine 2-chloro-1-[4-(4-chloro-3-methoxy-phenyl)-2-(S)-methylpiperazin-1-yl]-ethanone and 2- (4-Chloro-5-methyl-1H-pyrazol-3-yl)-4-methyl-pyridine to give the title compound: HPLC retention time=6.76 minutes (Agilent Zorbax SB-C18, 2.1×50mm, 5μ, 35°C) with a 2.0-minute no-gradient time at 20% B, followed by a 5.0-minute gradient from 20-95% B with a 2.5-minute wash at 95% B (A = 0.1% formic acid/5% acetonitrile/94.9% Water, B=0.08% formic acid/99.9% acetonitrile); (M/Z)+=488.1 (M+H).

4-(1-{2-[4-(4-chloro-3-methoxy-phenyl)-2-(S)-methyl-piperazin-1-yl]-2-oxo-ethyl }-5-Methyl-1H-pyrazol-3-yl)-pyridine-2-carbonitrile

The title compound was prepared following Protocol T: HPLC retention time = 6.90 minutes (Agilent Zorbax SB-C18, 2.1 x 50 mm, 5 μ, 35° C.) with 2.0 minutes no gradient time for 20% B, followed by 5.0 minutes for 20-95% B Minute gradient with 2.5 min wash at 95% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.08% formic acid/99.9% acetonitrile); (M/Z)+=465.3(M+ h).

4-(4-chloro-1-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-5-methyl Base-1H-pyrazol-3-yl)-pyridine-2-carbonitrile

Following protocol T, combine 2-chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone and 2-(4-chloro-5-methanone (Agilent Zorbax SB-C18, 2.1×50mm, 5 μ, 35°C), using 20% B A 2.0-minute no-gradient time followed by a 5.0-minute gradient from 20-95% B with a 2.5-minute wash at 95% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.08% formic acid/ 99.9% acetonitrile); (M/Z)+=486.2 (M+H).

4-(4-chloro-1-{2-[4-(4-chloro-3-methoxy-phenyl)-2-methyl-piperazin-1-yl]-2-oxo-ethyl }-5-methyl-1H-pyrazol-3-yl)-pyridine-2-carbonitrile

Following protocol T, combine 2-chloro-1-[4-(4-chloro-3-methoxy-phenyl)-2-(S)-methyl-piperazin-1-yl]-ethanone and 2 -(4-Chloro-5-methyl-1H-pyrazol-3-yl)-4-methyl-pyridine to give the title compound: HPLC retention time=7.42 minutes (Agilent Zorbax SB-C18, 2.1×50mm, 5 μ , 35°C) with a 2.0-minute no-gradient time at 20% B, followed by a 5.0-minute gradient from 20-95% B, with a 2.5-minute wash at 95% B (A = 0.1% formic acid/5% acetonitrile/94.9 % water, B=0.08% formic acid/99.9% acetonitrile); (M/Z)+=499.2 (M+H).

1-{4-[4-chloro-3-(2-fluoro-ethoxy)-phenyl]-piperazin-1-yl}-2-(4-chloro-5-methyl-3-pyridine- 2-yl-pyrazol-1-yl)-ethanone

Following protocol T, the title compound was prepared: LC/MS (ES) (M+H) 492.4; HPLC retention time = 5.91 min (Agilent Zorbax SB-C18, 2.1 x 50 mm, 5 μ, 35°C) using 2.0 of 20% B min no gradient time followed by a 5.0 min gradient from 20-95% B with a 2.5 min wash at 95% B (A = 0.1% formic acid/5% acetonitrile/94.9% water, B = 0.08% formic acid/99.9% acetonitrile).

2-(4-chloro-5-methyl-3-pyridin-2-yl-pyrazol-1-yl)-1-{4-[4-chloro-3-(2,2,2-trifluoro- Ethoxy)-phenyl]-piperazin-1-yl}-ethanone

Following protocol T, the title compound was prepared: LC/MS (ES) (M+H) 528.4; HPLC retention time = 6.47 min (Agilent Zorbax SB-C18, 2.1 x 50mm, 5μ, 35°C) using 2.0 of 20% B min no gradient time followed by a 5.0 min gradient from 20-95% B with a 2.5 min wash at 95% B (A = 0.1% formic acid/5% acetonitrile/94.9% water, B = 0.08% formic acid/99.9% acetonitrile).

2-(4-Chloro-5-methyl-3-pyridin-2-yl-pyrazol-1-yl)-1-[4-(4-chloro-3-propoxy-phenyl)-piperazine -1-yl]-ethanone

Following protocol T, the title compound was prepared: LC/MS (ES) (M+H) 488.4; HPLC retention time = 6.52 minutes (Agilent Zorbax SB-C18, 2.1 x 50mm, 5μ, 35°C) using 2.0% of 20% B min no gradient time followed by a 5.0 min gradient from 20-95% B with a 2.5 min wash at 95% B (A = 0.1% formic acid/5% acetonitrile/94.9% water, B = 0.08% formic acid/99.9% acetonitrile).

1-[4-(4-Chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-(5-methyl-3-trifluoromethyl-pyrazol-1-yl) - ethyl ketone

Following Protocol T, 2-Chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone was mixed with 3-methyl-5-trifluoromethane Coupling with pyrazole gave the title compound: HPLC retention time = 7.18 min (Agilent Zorbax SB-C18, 2.1 x 50 mm, 5 μ, 35 °C) with 2.0 min no gradient time for 20% B followed by 20-95% B 5.0 minute gradient with 2.5 minute wash at 95% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.08% formic acid/99.9% acetonitrile); (M/Z)+=417.2 (M +H).

1-[4-(4-Chloro-2-fluoro-5-methoxy-phenyl)-piperazin-1-yl]-2-(5-methyl-3-trifluoromethyl-pyrazole- 1-yl)-ethanone

According to protocol T, 2-chloro-1-[4-(4-chloro-6-fluoro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone was mixed with 3-methyl-5 - trifluoromethylpyrazole reaction to give the title compound: HPLC retention time = 7.35 min (Agilent Zorbax SB-C18, 2.1 x 50 mm, 5 μ, 35 °C), 2.0 min no gradient time with 20% B followed by 20- 5.0 min gradient to 95% B with 2.5 min wash at 95% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.08% formic acid/99.9% acetonitrile); (M/Z)+ =435.2 (M+H).

2-(4-chloro-3-hydroxymethyl-5-methyl-pyrazol-1-yl)-1-[4-(4-chloro-3-methoxy-phenyl)-piperazine-1 -yl]-ethanone

According to protocol T, (4-chloro-5-methyl-1H-pyrazol-3-yl)-methanol was mixed with 2-chloro-1-[4-(4-chloro-3-methoxy-phenyl) -Piperazin-1-yl]-ethanone coupling afforded the title compound: HPLC retention time = 6.45 minutes (Agilent Zorbax SB-C18, 2.1 x 50 mm, 5 μ, 35°C), 2.0 minutes no gradient time with 20% B , followed by a 5.0 minute gradient of 20-95% B with a 2.5 minute wash at 95% B (A = 0.1% formic acid/5% acetonitrile/94.9% water, B = 0.08% formic acid/99.9% acetonitrile); ( M/Z)+=413.2(M+H).

1-[4-(4-chloro-3-methoxyphenyl)-2-(S)-methylpiperazin-1-yl]-2-(4-chloro-5-methyl-3-pyridine -4-ylpyrazol-1-yl)ethanone

The title compound was obtained following protocol T: LCMS (ES): M+H 474.1; HPLC retention time = 3.645 minutes (Agilent Zorbax SB-C18, 2.1 x 50 mm, 5 μ, 35° C.) using a 4.5 minute gradient of 20-95% B , with a 1.1 minute wash at 95% B (A = 0.1% formic acid/5% acetonitrile/94.9% water, B = 0.08% formic acid/99.9% acetonitrile).

6-(4-chloro-1-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-5-methanol Base-1H-pyrazol-3-yl)-pyridine-2-carboxylic acid methylamide

The title compound was prepared according to Protocol T: LCMS (ES) M+H = 518.4; HPLC RT = 4.308 min (Agilent Zorbax SB-C18, 2.1 x 50 mm, 5 μ, 35 °C) using a 4.5 min gradient of 20-95% B, A 1.1 minute wash was used at 95% B (A = 0.1% formic acid/5% acetonitrile/94.9% water, B = 0.08% formic acid/99.9% acetonitrile).

Synthesis of 1-[4-(4-chloro-3-methoxyphenyl)piperazin-1-yl]-2-(4-chloro-5-methyl-3-pyridin-2-yl-pyrazole- 1-yl) ethyl ketone

The title compound was obtained following protocol T: LCMS (ES): M+H 460.1; HPLC retention time = 3.77 minutes (Agilent Zorbax SB-C18, 2.1 x 50 mm, 5 μ, 35° C.) using a 4.5 minute gradient of 20-95% B , with a 1.1 minute wash at 95% B (A = 0.1% formic acid/5% acetonitrile/94.9% water, B = 0.08% formic acid/99.9% acetonitrile).

6-(4-chloro-1-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-5-methanol Base-1H-pyrazol-3-yl)-pyridine-2-carboxylic acid dimethylamide

The title compound was prepared following Scheme T: ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.98-7.41 (m, 3H), 6.47 (m, 3H), 5.05 (s, 1H), 3.89 (q, 2H), 3.89 ( s, 3H), 3.21-3.13 (dt, 2H), 2.34 (s, 3H), 2.18 (s, 3H), 1.63 (s, 1H); LCMS (ES) M+H = 531.5; HPLC RT = 4.113 minutes (Agilent Zorbax SB-C18, 2.1×50 mm, 5 μ, 35° C.), using a 4.5-minute gradient of 20-95% B with a 1.1-minute wash at 95% B (A=0.1% formic acid/5% acetonitrile/94.9 % water, B = 0.08% formic acid/99.9% acetonitrile).

Synthesis of 2-(3-methylsulfonyl-4-chloro-5-methyl-pyrazol-1-yl)-1-[4-(4-chloro-3-methoxy-phenyl)-2( S)-Methyl-piperazin-1-yl]-ethanone

According to protocol T, 2-chloro-1-[4-(4-chloro-3-methoxy-phenyl)-2(S)-methyl-piperazin-1-yl]-ethanone and 3- Methylsulfonyl-4-chloro-5-methyl-pyrazol-1-yl coupling gave the title compound: ¹ H NMR (400MHz, CDCl ₃ ) δ7.30(d, 1H), 7.18(br, 1H) , 6.80(br, 1H), 6.05(bt, 3H), 5.50(br, 1H), 4.95(br, 1H), 4.42(br, 1H), 3.90(s, 3H), 3.42(br, 3H), 3.18 (s, 3H), 2.30 (s, 3H), 1.70 (d, 1.5H), 1.58 (d, 1.5H); LCMS: (M+H) ⁺ observed 475.

1-[4-(4-chloro-3-methoxyphenyl)-2-(S)-methylpiperazin-1-yl]-2-(4-chloro-5-methyl-3-pyridine -2-ylpyrazol-1-yl)ethanone

The title compound was prepared following protocol T: LCMS (ES) M+H = 474.1; HPLC retention time = 4.95 minutes (Agilent Zorbax SB-C18, 2.1 x 50 mm, 5 μ, 35° C.) using a 4.5 minute gradient of 20-95% B , with a 1.1 minute wash at 95% B (A = 0.1% formic acid/5% acetonitrile/94.9% water, B = 0.08% formic acid/99.9% acetonitrile).

Synthesis of 1-[4-(4-chloro-2-fluoro-5-methoxyphenyl)piperazin-1-yl]-2-(4-chloro-5-methyl-3-pyridin-2-yl Pyrazol-1-yl)ethanone

The title compound was obtained following protocol T: LCMS (ES): M+H 478.1; HPLC retention time = 3.92 minutes (Agilent Zorbax SB-C18, 2.1 x 50 mm, 5 μ, 35° C.) using a 4.5 minute gradient of 20-95% B , with a 1.1 minute wash at 95% B (A = 0.1% formic acid/5% acetonitrile/94.9% water, B = 0.08% formic acid/99.9% acetonitrile).

Synthesis of 1-[4-(4-chloro-3-methoxyphenyl)-2-methylpiperazin-1-yl]-2-[4-chloro-5-methyl-3-(6-methyl ylpyridin-3-yl)pyrazol-1-yl]ethanone

The title compound was obtained following protocol T: LCMS (ES): M+H 488.1; HPLC retention time = 4.32 minutes (Agilent Zorbax SB-C18, 2.1 x 50 mm, 5 μ, 35° C.) using a 4.5 minute gradient of 20-95% B , with a 1.1 minute wash at 95% B (A = 0.1% formic acid/5% acetonitrile/94.9% water, B = 0.08% formic acid/99.9% acetonitrile).

Synthesis of 1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-(4-chloro-5-pyridin-2-yl-3-trifluoromethyl -pyrazol-1-yl)-ethanone and 1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-(4-chloro-3-pyridine -2-yl-5-trifluoromethyl-pyrazol-1-yl)-ethanone:

The above two isomers were synthesized using the same scheme T. These isomers were purified by preparative TLC (50% EtOAc:n-hexane).

1-(4-(4-chloro-3-methoxyphenyl)-piperazin-1-yl)-2-(4-chloro-5-pyridin-2-yl-3-trifluoromethyl-pyridine Azol-1-yl)-ethanone (main isomer): LC MS 514 (M ⁺ , method 20-95, RT=4.99 minutes); ¹ HNMR (400MHz, CDCl ₃ ): δ3.06(t, J =4.7Hz, 2H), 3.19(t, J=4.7Hz, 2H), 3.63(apparent q, J=7.5Hz, 4H), 3.87(s, 3H), 5.63(s, 2H), 6.39(dd, J=2.6 &8.8Hz, 1H), 6.46(d, J=2.6Hz, 1H), 7.20(d, J=8.8Hz, 1H), 7.29-7.32(m, 1H), 7.81(dt, J=1.8 & 8.1Hz, 1H), 7.92(d, J=7.7Hz, 1H), 8.60(d, J=5.1Hz, 1H).

1-(4-(4-chloro-3-methoxyphenyl)-piperazin-1-yl)-2-(4-chloro-3-pyridin-2-yl-5-trifluoromethyl-pyridine Azol-1-yl)-ethanone (minor isomer): LC MS 514 (M ⁺ , method 20-95, RT=4.68 minutes); ¹ HNMR (400MHz, CDCl ₃ ): δ3.06(t, J=4.3Hz, 2H), 3.21(t, J=4.3Hz, 2H), 3.60(apparent q, J=6.5Hz, 2H), 3.76(apparent q, J=6.5Hz, 2H), 3.85(s, 3H ), 5.24(s, 2H), 6.39(dd, J=2.6 & 8.8Hz, 1H), 6.46(d, J=2.6Hz, 1H), 7.20(d, J=8.8Hz, 1H), 7.29-7.32 (m, 1H), 7.76 (dt, J=1.8 & 8.1Hz, 1H), 7.98 (d, J=7.7Hz, 1H), 8.74 (d, J=5.1Hz, 1H).

Synthesis of 1-[4-(4-chloro-3-methoxyphenyl)-2-(S)-methylpiperazin-1-yl]-2-(4-chloro-5-methyl-3- Pyrimidin-4-ylpyrazol-1-yl)ethanone

The title compound was obtained following protocol T: LCMS (ES): M+H 475.1; HPLC retention time = 4.59 minutes (Agilent Zorbax SB-C18, 2.1 x 50 mm, 5 μ, 35° C.) using a 4.5 minute gradient of 20-95% B , with a 1.1 minute wash at 95% B (A = 0.1% formic acid/5% acetonitrile/94.9% water, B = 0.08% formic acid/99.9% acetonitrile).

Synthesis of 1-(4-(4-chloro-3-methoxyphenyl)-2(S)-methylpiperazin-1-yl)-2-(4-chloro-5-pyridin-2-yl- 3-trifluoromethyl-pyrazol-1-yl)ethanone and 1-(4-(4-chloro-3-methoxyphenyl)-2(S)-methylpiperazin-1-yl) -2-(4-Chloro-3-pyridin-2-yl-5-trifluoromethyl-pyrazol-1-yl)-ethanone:

1-(4-(4-chloro-3-methoxyphenyl)-2(S)-methylpiperazin-1-yl)-2-(4-chloro-5-pyridin-2-yl-3 -Trifluoromethyl-pyrazol-1-yl)ethanone: The above compound was synthesized using the same protocol T: LCMS 528 (M ⁺ H); HPLC RT=5.29 minutes (Agilent Zorbax SB-C18, 2.1×50mm, 5 μ, 35° C.) with a 4.5-minute gradient of 20-95% B, with a 1.1-minute wash at 95% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.08% formic acid/99.9% acetonitrile).

1-(4-(4-chloro-3-methoxyphenyl)-2(S)-methylpiperazin-1-yl)-2-(4-chloro-3-pyridin-2-yl-5 -Trifluoromethyl-pyrazol-1-yl)-ethanone: The above compound was synthesized using the same protocol T: LCMS 528 (M ⁺ H); HPLC RT=4.95 minutes (Agilent Zorbax SB-C18, 2.1×50mm , 5μ, 35°C), using a 4.5-minute gradient of 20-95% B with a 1.1-minute wash at 95% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.08% formic acid/99.9 % acetonitrile).

Synthesis of 1-(4-(4-chloro-2-fluoro-5-methoxyphenyl)-2(S)-methylpiperazin-1-yl)-2-(4-chloro-5-pyridine- 2-yl-3-trifluoromethyl-pyrazol-1-yl)-ethanone and 1-(4-(4-chloro-2-fluoro-5-methoxyphenyl)-2(S)- Methylpiperazin-1-yl)-2-(4-chloro-3-pyridin-2-yl-5-trifluoromethyl-pyrazol-1-yl)-ethanone:

1-(4-(4-chloro-2-fluoro-5-methoxyphenyl)-2(S)-methylpiperazin-1-yl)-2-(4-chloro-5-pyridine-2 -yl-3-trifluoromethyl-pyrazol-1-yl)-ethanone: The above compound was synthesized using Scheme T: LC MS546 (M ⁺ H); HPLC RT = 5.52 minutes (Agilent Zorbax SB-C18, 2.1 ×50mm, 5μ, 35°C), using a 4.5-minute gradient of 20-95% B, with a 1.1-minute wash at 95% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.08% formic acid /99.9% acetonitrile).

1-(4-(4-chloro-2-fluoro-5-methoxyphenyl)-2(S)-methylpiperazin-1-yl)-2-(4-chloro-3-pyridine-2 -yl-5-trifluoromethyl-pyrazol-1-yl)ethanone: The above compound was synthesized using the same protocol XX: LC MS546 (M ⁺ H); HPLC RT = 5.19 minutes (Agilent Zorbax SB-C18, 2.1 x 50mm, 5μ, 35°C) with a 4.5 minute gradient of 20-95% B, with a 1.1 minute wash at 95% B (A = 0.1% formic acid/5% acetonitrile/94.9% water, B = 0.08% formic acid/99.9% acetonitrile).

Synthesis of 1-[4-(4-chloro-3-methoxyphenyl)-2-(S)-methylpiperazin-1-yl]-2-(4-chloro-5-methyl-3- Pyrimidin-2-ylpyrazol-1-yl)ethanone

The title compound was obtained following Scheme T: ¹ H NMR: δ (400 MHz, CDCl ₃ ) 8.95 (d, 2H), 7.60 (ddd, 1H), 7.39 (m, 1H), 6.52 (br, 2H), 5.28-4.77 ( br, 2H), 4.47-4.18(br, 2H), 3.89(s, 3H), 3.78-2.73(br, 5H), 2.36(s, 3H), 1.53-0.78(br, 3H); LCMS(ES) : M+H 475.1; HPLC retention time = 4.41 minutes (Agilent Zorbax SB-C18, 2.1 x 50 mm, 5 μ, 35° C.) using a 4.5 minute gradient from 20-95% B with a 1.1 minute wash at 95% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.08% formic acid/99.9% acetonitrile).

Synthesis of 1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-(4-fluoro-5-methyl-3-trifluoromethyl-pyrazole -1-yl)-ethanone

The title compound was prepared according to Scheme T, using 1-(3-methoxyphenyl-4-chloro)piperazin-4-chloromethyl-one and (3-methyl-4-fluoro-5-(tri Fluoromethyl)pyrazole as coupling component: HPLC retention time = 4.69 minutes (Agilent Zorbax SB-C18, 2.1×50 mm, 5 μ, 35° C.), using a 4.5-minute gradient of 20-95% B at 95% B A 1.1 minute wash was used (A = 0.1% formic acid/5% acetonitrile/94.9% water, B = 0.08% formic acid/99.9% acetonitrile); MS (ES) M+H expected = 435.1, found = 435.3.

6-(4-chloro-1-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-5-methanol Base-1H-pyrazol-3-yl)-pyridine-2-carbonitrile

The title compound was prepared according to Protocol T: LCMS (ES) M+H = 485.4; HPLC RT = 6.859 min (Agilent Zorbax SB-C18, 2.1 x 50 mm, 5 μ, 35 °C) using a 4.5 min gradient of 20-95% B, A 1.1 minute wash was used at 95% B (A = 0.1% formic acid/5% acetonitrile/94.9% water, B = 0.08% formic acid/99.9% acetonitrile).

Synthesis of 1-[4-(4-chloro-3-methoxyphenyl)piperazin-1-yl]-2-(4-chloro-5-methyl-3-pyrimidin-4-ylpyrazole-1 -yl) ethyl ketone

The title compound was obtained following Protocol T: LCMS (ES): M+H 461.1; HPLC retention time = 4.37 minutes (Agilent Zorbax SB-C18, 2.1 x 50 mm, 5 μ, 35° C.) using a 4.5 minute gradient of 20-95% B , with a 1.1 minute wash at 95% B (A = 0.1% formic acid/5% acetonitrile/94.9% water, B = 0.08% formic acid/99.9% acetonitrile).

Synthesis of 1-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-5methyl-3-trifluoromethyl Amyl-1H-pyrazole-4-carbonitrile

The title compound was prepared according to Scheme T, using 1-(3-methoxyphenyl-4-chloro)piperazin-4-chloromethyl-one and (3-methyl-4-cyano-5-( Trifluoromethyl)pyrazole as coupling component: HPLC retention time = 4.59 minutes (Agilent Zorbax SB-C18, 2.1×50 mm, 5 μ, 35° C.), using a 4.5-minute gradient of 20-95% B at 95% B (A = 0.1% formic acid/5% acetonitrile/94.9% water, B = 0.08% formic acid/99.9% acetonitrile); MS (ES) M+H expected = 442.1, found = 442.4.

Synthesis of 1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-(4-iodo-5-methyl-3-trifluoromethyl-pyrazole -1-yl)-ethanone

The title compound was prepared following protocol T: HPLC retention time = 4.89 minutes, (Agilent Zorbax SB-C18, 2.1 x 50 mm, 5 μ, 35° C.) using a 4.5 minute gradient from 20-95% B at 95% B in 1.1 minutes (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.08% formic acid/99.9% acetonitrile); MS(ES) M+H expected = 543.2, found = 543.3.

Synthesis of N-(1-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-5-methyl-3 -Trifluoromethyl-1H-pyrazol-4-yl)-acetamide

The title compound was prepared according to Scheme T using 1-(3-methoxyphenyl-4-chloro)piperazin-4-chloromethyl-one and 3-methyl-4-acetylamino-5-( Trifluoromethyl)pyrazole as coupling component: HPLC retention time = 3.66 min, (Agilent Zorbax SB-C18, 2.1 x 50mm, 5μ, 35°C) using a 4.5 min gradient of 20-95% B at 95% A 1.1 minute wash was used for B (A = 0.1% formic acid/5% acetonitrile/94.9% water, B = 0.08% formic acid/99.9% acetonitrile); MS (ES) M+H expected = 474.1, found = 474.4.

Synthesis of 2-(2-phenylimidazol-1-yl)-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone

Following Scheme T, coupling of 2-chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone and 2-phenylimidazole gave the title compound : LCMS retention time: 2.86 min (Agilent Zorbax SB-C18, 2.1×50 mm, 5 μ, 35° C.), using a 4.5 min gradient from 20-95% B with a 1.1 min wash at 95% B (A=0.1% Formic acid/5% acetonitrile/94.9% water, B=0.08% formic acid/99.9% acetonitrile); LCMS: (M+H) ⁺ observed 411.

Synthesis of 2-benzimidazol-1-yl-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone

2-Chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone was reacted with benzimidazole following Scheme T to afford the title compound: LCMS Retention time: 2.57 minutes (Agilent Zorbax SB-C18, 2.1×50 mm, 5 μ, 35° C.), using a 4.5-minute gradient of 20-95% B with a 1.1-minute wash at 95% B (A=0.1% formic acid/ 5% acetonitrile/94.9% water, B = 0.08% formic acid/99.9% acetonitrile); LCMS: (M+H) ⁺ observed 385.

5-(4-chloro-1-{2-[4-(4-chloro-3-methoxy-phenyl)-2-(S)-methyl-piperazin-1-yl]-2-oxo Substitute-ethyl}-5-methyl-1H-pyrazol-3-yl)-pyridine-2-carboxylic acid methylamide

The title compound was prepared following Scheme T: ¹ H NMR (400 MHz, CDCl ₃ ): δ 9.21-8.12 (m, 3H), 6.47 (m, 3H), 4.64 (s, 2H), 3.81 (q, 2H), 3.89 (s, 1H), 3.89(d, 2H), 3.79-3.32(dt, 2H), 2.35(s, 3H), 2.18(s, 3H); LCMS (ES) M+H=531.5; HPLC RT=4.360 min (Agilent Zorbax SB-C18, 2.1×50mm, 5μ, 35°C), using a 4.5 min gradient from 20-95% B, with a 1.1 min wash at 95% B (A = 0.1% formic acid/5% acetonitrile/ 94.9% water, B = 0.08% formic acid/99.9% acetonitrile).

2-[4-Chloro-3-(6-methylsulfonyl-pyridin-2-yl)-5-methyl-pyrazol-1-yl]-1-[4-(4-chloro-3-methoxy Base-phenyl)-2-(S)-methyl-piperazin-1-yl]-ethanone

The title compound was prepared following Scheme T: ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.12-7.82 (m, 3H), 6.47 (m, 3H), 5.51 (s, 2H), 3.89 (s, 1H), 3.89 ( s, 3H), 3.81(d, 2H), 3.79(d, 2H), 3.36(s, 3H), 3.18-3.13(dt, 2H), 2.35(s, 3H), 2.34(s, 3H), 1.60 (s, 1H); LCMS (ES) M+H = 532.5; HPLC RT = 4.582 minutes (Agilent Zorbax SB-C18, 2.1 x 50 mm, 5 μ, 35° C.) with a 4.5 minute gradient of 20-95% B, A 1.1 minute wash was used at 95% B (A = 0.1% formic acid/5% acetonitrile/94.9% water, B = 0.08% formic acid/99.9% acetonitrile).

Synthesis of 1-[4-(4-chloro-2-fluoro-5-methoxyphenyl)piperazin-1-yl]-2-(4-chloro-5-methyl-3-pyrimidin-2-yl Pyrazol-1-yl)ethanone

The title compound was obtained following Protocol T: LCMS (ES): M+H 479.1; HPLC retention time = 4.65 minutes (Agilent Zorbax SB-C18, 2.1 x 50 mm, 5 μ, 35° C.) using a 4.5 minute gradient of 20-95% B , with a 1.1 minute wash at 95% B (A = 0.1% formic acid/5% acetonitrile/94.9% water, B = 0.08% formic acid/99.9% acetonitrile).

2-[4-chloro-3-(6-chloro-pyridin-3-yl)-5-methyl-pyrazol-1-yl]-1-[4-(4-chloro-3-methoxy- Phenyl)-2-(S)-methyl-piperazin-1-yl]-ethanone

According to scheme T, 2-chloro-1-[4-(4-chloro-3-methoxy-phenyl)-2-(S)-methylpiperazin-1-yl]-ethanone and 2-chloro -5-(4-Chloro-5-methyl-1H-pyrazol-3-yl)-pyridine coupling to obtain the title compound: HPLC retention time=7.83 minutes (Agilent Zorbax SB-C18, 2.1×50mm, 5 μ, 35 °C) with a 2.0-minute no-gradient time at 20% B, followed by a 5.0-minute gradient from 20-95% B with a 2.5-minute wash at 95% B (A = 0.1% formic acid/5% acetonitrile/94.9% water , B=0.08% formic acid/99.9% acetonitrile); (M/Z)-=506 (M-H).

4-chloro-1-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-5-methyl-1H - Ethyl pyrazole-3-carboxylate

Following protocol T, combine 2-chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone and 4-chloro-5-methyl-1H - Ethyl pyrazole-3-carboxylate to give the title compound: HPLC retention time = 7.14 min (Agilent Zorbax SB-C18, 2.1 x 50 mm, 5 μ, 35 °C), 2.0 min no gradient time with 20% B, followed by A 5.0 minute gradient of 20-95% B with a 2.5 minute wash at 95% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.08% formic acid/99.9% acetonitrile); (M/ Z)+=455.1 (M+H).

Synthesis of 1-[4-(4-chloro-3-methoxyphenyl)piperazin-1-yl]-2-[4-chloro-5-methyl-3-(6-methylpyridine-2- Base) pyrazol-1-yl] ethyl ketone

The title compound was obtained following protocol T: LCMS (ES): M+H 474.1; HPLC retention time = 4.39 minutes (Agilent Zorbax SB-C18, 2.1 x 50 mm, 5 μ, 35° C.) using a 4.5 minute gradient of 20-95% B , with a 1.1 minute wash at 95% B (A = 0.1% formic acid/5% acetonitrile/94.9% water, B = 0.08% formic acid/99.9% acetonitrile).

Synthesis of 1-[4-(4-chloro-3-methoxyphenyl)-2-(S)-methylpiperazin-1-yl]-2-[4-chloro-5-methyl-3- (6-methylpyridin-2-yl)pyrazol-1-yl]ethanone

The title compound was obtained following protocol T: LCMS (ES): M+H 488.1; HPLC retention time = 4.42 minutes (Agilent Zorbax SB-C18, 2.1 x 50 mm, 5 μ, 35° C.) using a 4.5 minute gradient of 20-95% B , with a 1.1 minute wash at 95% B (A = 0.1% formic acid/5% acetonitrile/94.9% water, B = 0.08% formic acid/99.9% acetonitrile).

Synthesis of 2-[4-bromo-5-methyl-3-(6-methylpyridin-2-yl)pyrazol-1-yl]-1-[4-(4-chloro-3-methoxybenzene Base) piperazin-1-yl] ethanone

The title compound was obtained following Protocol T: LCMS (ES): M+H 518.1; HPLC retention time = 4.43 minutes (Agilent Zorbax SB-C18, 2.1 x 50 mm, 5 μ, 35° C.) using a 4.5 minute gradient of 20-95% B , with a 1.1 minute wash at 95% B (A = 0.1% formic acid/5% acetonitrile/94.9% water, B = 0.08% formic acid/99.9% acetonitrile).

Synthesis of 2-[4-bromo-5-methyl-3-(6-methylpyridin-2-yl)pyrazol-1-yl]-1-[4-(4-chloro-3-methoxybenzene Base)-2-(S)-methylpiperazin-1-yl]ethanone

The title compound was obtained following protocol T: LCMS (ES): M+H 532.1; HPLC retention time = 4.25 minutes (Agilent Zorbax SB-C18, 2.1 x 50 mm, 5 μ, 35° C.) using a 4.5 minute gradient of 20-95% B , with a 1.1 minute wash at 95% B (A = 0.1% formic acid/5% acetonitrile/94.9% water, B = 0.08% formic acid/99.9% acetonitrile).

Synthesis of 1-[4-(4-chloro-3-methoxyphenyl)piperazin-1-yl]-2-[4-chloro-5-methyl-3-(2-methylpyridine-4- Base) pyrazol-1-yl] ethyl ketone

The title compound was obtained following protocol T: LCMS (ES): M+H 474.1; HPLC retention time = 3.76 minutes (Agilent Zorbax SB-C18, 2.1 x 50 mm, 5 μ, 35° C.) using a 4.5 minute gradient of 20-95% B , with a 1.1 minute wash at 95% B (A = 0.1% formic acid/5% acetonitrile/94.9% water, B = 0.08% formic acid/99.9% acetonitrile).

Synthesis of 1-[4-(4-chloro-3-methoxyphenyl)piperazin-1-yl]-2-[4-chloro-5-methyl-3-(6-trifluoromethylpyridine- 2-yl)pyrazol-1-yl]ethanone

According to scheme T, combine 2-(4-chloro-5-methyl-1H-pyrazol-3-yl)-6-trifluoromethyl-pyridine and 2-chloro-1-[4-(4-chloro- 3-Methoxy-phenyl)-piperazin-1-yl]-ethanone to give the title compound: LCMS (ES): M+H 528.1; HPLC retention time = 5.36 minutes (Agilent Zorbax SB-C18, 2.1 ×50mm, 5μ, 35°C), using a 4.5-minute gradient of 20-95% B, with a 1.1-minute wash at 95% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.08% formic acid /99.9% acetonitrile).

1-[4-(4-chloro-2-fluoro-5-methoxy-phenyl)-2-(S)-methyl-piperazin-1-yl]-2-(4-chloro-5- Methyl-3-pyridin-2-yl-pyrazol-1-yl)-ethanone

According to scheme T, combine 2-chloro-1-[4-(4-chloro-2-fluoro-5-methoxy-phenyl)-2-(S)-methyl-piperazin-1-yl]- Ethanone and 2-(4-chloro-5-methyl-1H-pyrazol-3-yl)-pyridine gave the title compound: HPLC retention time=6.50 minutes (Agilent Zorbax SB-C18, 2.1×50mm, 5μ, 35°C) with a 2.0-minute no-gradient time at 20% B, followed by a 5.0-minute gradient from 20-95% B with a 2.5-minute wash at 95% B (A = 0.1% formic acid/5% acetonitrile/94.9% Water, B=0.08% formic acid/99.9% acetonitrile); (M/Z)+=492.1 (M+H).

Synthesis of 2-(4-chloro-3-iodo-5-methyl-pyrazol-1-yl)-1-[4-(4-chloro-3-methoxy-phenyl)-piperazine-1- base]-ethanone:

According to scheme T, 2-(4-chloro-5-methyl-1H-pyrazol-3-yl)-pyridine and 2-chloro-1-[4-(4-chloro-3-methoxyphenyl) -Piperazin-1-yl]-ethanone was treated with potassium carbonate in N,N-dimethylformamide to give the title compound: LCMS (ES) M+H = 509.0; HPLC retention time = 4.85 minutes (Agilent Zorbax SB-C18, 2.1 x 50 mm, 5 μ, 35°C), using a 4.5-minute gradient of 20-95% B, with a 1.1-minute wash at 95% B (A = 0.1% formic acid/5% acetonitrile/94.9% water, B = 0.08% formic acid/99.9% acetonitrile).

Synthesis of 1-[4-(4-chloro-5-ethoxy-2-fluorophenyl)piperazin-1-yl]-2-(4-chloro-5-methyl-3-pyridin-2-yl Pyrazol-1-yl)ethanone:

According to scheme T, 2-(4-chloro-5-methyl-1H-pyrazol-3-yl)-pyridine and 2-chloro-1-[4-(4-chloro-3-ethoxy-2- Fluoro-phenyl)-piperazin-1-yl]-ethanone was treated with potassium carbonate in N,N-dimethylformamide to yield the title compound: ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.87-7.12 (m, 3H), 6.47 (d, 3H), 5.11 (s, 2H), 3.8 (q, 2H), 3.21-3.83 (dt, 2H), 2.35 (s, 3H). LCMS (ES) M+H=492.1, HPLC retention time=5.469 minutes (acetonitrile/H ₂ O 20-95% method).

Synthesis of 1-(4-(4-chloro-3-methoxyphenyl)-piperazin-1-yl)-2-(3-trifluoromethyl)-5-(2-furyl)-pyrazole -1-yl)ethanone:

The above compound was synthesized according to scheme T: LCMS M+H=469; HPLC RT=4.81 minutes (Agilent Zorbax SB-C18, 2.1×50mm, 5 μ, 35° C.), using a 4.5-minute gradient of 20-95% B at 95 A 1.1-minute wash was used for %B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.08% formic acid/99.9% acetonitrile); ¹ H NMR (400 MHz, CDCl ₃ ) δ3.14-3.21 (m , 4H), 3.65-3.78(m, 4H), 3.88(s, 3H), 5.30(s, 2H), 6.42(dd, J=2.4 & 6.7Hz, 1H), 6.48-6.50(m, 2H), 6.70 (d, J = 3.3 Hz, 1H), 6.75 (s, 1H), 7.21 (s, 1H), 7.46 (d, J = 1.8 Hz, 1H).

Synthesis of 2-(4-chloro-3,5-dipyridin-2-yl-pyrazol-1-yl)-1-(4-(4-chloro-3-methoxyphenyl)-piperazine-1 -yl) ethyl ketone:

The above compound was synthesized according to scheme T: LCMS M+H=523; HPLC RT=4.29 minutes (Agilent Zorbax SB-C18, 2.1×50mm, 5 μ, 35° C.), using a 4.5-minute gradient of 20-95% B at 95 A 1.1 minute wash was used for %B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.08% formic acid/99.9% acetonitrile); ¹ H NMR (400 MHz, DMSO-d ₆ ): δ3.10 ( br, 2H), 3.25(br, 2H), 3.51(br, 2H), 3.68(br, 2H), 3.87(s, 3H), 5.65(s, 2H), 6.52(dd, J=2.6 & 8.8Hz , 1H), 6.71(d, J=2.6Hz, 1H).7.23(d, J=8.8Hz, 1H) 6.48-6.50(m, 2H), 6.70(d, J=3.3Hz, 1H), 6.75( s, 1H), 7.21(s, 1H), 7.46(d, J=1.8Hz, 1H), 7.43-7.50(m, 2H), 7.90-7.94(m, 2H), 8.01(dt, J=1.8 & 7.7Hz, 1H), 8.70-8.73(m, 2H).

Synthesis of 2-(4-chloro-3,5-dipyridin-2-yl-pyrazol-1-yl)-1-(4-(4-chloro-2-fluoro-5-methoxyphenyl)- 2-(S)-Methylpiperazin-1-yl)ethanone:

The above compound was synthesized according to scheme T: LCMS M+H=555; HPLC RT=4.77 minutes (Agilent Zorbax SB-C18, 2.1×50mm, 5 μ, 35° C.), using a 4.5-minute gradient of 20-95% B at 95 A 1.1 minute wash was used for %B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.08% formic acid/99.9% acetonitrile); ¹ H NMR (400 MHz, DMSO-d ₆ ): δ1.11 ( d, J=6.3Hz, 1.5H), 1.41(d, J=6.5Hz, 1.5H), 3.25(br, 2H), 2.67-3.01(m, 3H), 3.43-3.50(m, 1H), 3.88( s, 3H), 4.10-4.13(m, 1H), 4.28(br, 1H), 4.45(br, 1H), 5.60(s, 1H), 5.68(s, 1H), 6.74(d, J=8Hz, 1H), 7.38-7.56 (m, 3H), 7.90-7.97 (m, 2H), 8.02 (t, J=7.7Hz, 1H), 8.71-8.75 (m, 2H).

Synthesis of 1-[4-(4-chloro-3-ethoxyphenyl)-2-methylpiperazin-1-yl]-2-(4-chloro-5-methyl-3-pyridine-2- (Pyrazol-1-yl)ethanone:

Following Scheme T, combining 2-(4-chloro-5-methyl-1H-pyrazol-3-yl)-pyridine and 2-chloro-1-[4-(4-chloro-3-ethoxyphenyl )-2-(S)-methylpiperazin-1-yl]-ethanone, yielding the title compound: ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.87-7.12 (m, 3H), 6.47 (d, 3H ), 5.11(s, 2H), 3.8(q, 2H), 3.21-3.83(dt, 2H), 2.35(s, 3H), 1.52(d, 3H); LCMS (ES) M+H=488.1; HPLC RT = 5.993 min (Agilent Zorbax SB-C18, 2.1 x 50 mm, 5 μ, 35° C.), using a 4.5 min gradient from 20-95% B, with a 1.1 min wash at 95% B (A = 0.1% formic acid/5 % acetonitrile/94.9% water, B=0.08% formic acid/99.9% acetonitrile).

Synthesis of 6-(4-chloro-1-{2-[4-(4-chloro-3-ethoxyphenyl)piperazin-1-yl]-2-oxo-ethyl}-5-methyl -1H-pyrazol-3-yl)pyridine-2-carbonitrile:

Following Scheme T, 2-(4-chloro-5-methyl-1H-pyrazol-3-yl)-6-cyanopyridine and 2-chloro-1-[4-(4-chloro-3-ethoxy phenyl)-piperazin-1-yl]-ethanone was treated with potassium carbonate in N,N-dimethylformamide to yield the title compound: ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.87-8.92 ( m, 3H), 6.57-6.45(m, 3H), 5.11(s, 2H), 4.18(q, 2H), 3.21-3.68(dt, 4H), 2.45(s, 3H), 1.52(t, 3H) ; LCMS (ES) M+H = 499.2; HPLC RT = 4.807 minutes (Agilent Zorbax SB-C18, 2.1 x 50 mm, 5 μ, 35° C.) using a 4.5 minute gradient of 20-95% B at 95% B 1.1 minute wash (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.08% formic acid/99.9% acetonitrile).

Synthesis of 6-(4-chloro-1-{2-[4-(4-chloro-3-ethoxyphenyl)-2-(S)-methylpiperazin-1-yl]-2-oxo -Ethyl}-5-methyl-1H-pyrazol-3-yl)pyridine-2-carbonitrile:

Following Scheme T, 2-(4-chloro-5-methyl-1H-pyrazol-3-yl)-6-cyanopyridine and 2-chloro-1-[4-(4-chloro-3-ethoxy (Phenylphenyl)-2-(S)-methylpiperazin-1-yl]-ethanone was treated with potassium carbonate in N,N-dimethylformamide to yield the title compound. ¹ H NMR (400MHz, CDCl ₃ ) δ8.87-8.92(m, 3H), 6.57-6.45(m, 3H), 5.11(s, 2H), 4.18(q, 2H), 3.21-3.68(dt, 4H ), 2.45 (s, 3H), 1.52 (d, 3H), 1.40 (q, 1H); LCMS (ES) M+H = 513.4; HPLC RT = 5.192 min. (Agilent Zorbax SB-C18, 2.1×50 mm, 5 μ, 35° C.), using a 4.5-minute gradient of 20-95% B with a 1.1-minute wash at 95% B (A=0.1% formic acid/5% acetonitrile/94.9 % water, B = 0.08% formic acid/99.9% acetonitrile).

Synthesis of 2-[4-chloro-1-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxoethyl}-5-methanol Ethyl-1H-pyrazol-3-yl)-isonicotinic acid ethyl ester

The title compound was prepared following protocol T: HPLC retention time = 5.9 minutes (Agilent Zorbax SB-C18, 2.1 x 50 mm, 5 μ, 35° C.) using a 4.5 minute gradient from 20-95% B and a 1.1 minute gradient at 95% B Washes (A = 0.1% formic acid/5% acetonitrile/94.9% water, B = 0.08% formic acid/99.9% acetonitrile); MS (ES) M+H expected = 532.14, found = 532.2.

Synthesis of 2-[4-chloro-3-(6-methylsulfonyl-pyridin-2-yl)-5-methyl-pyrazol-1-yl]-1-[4-(4-chloro-3-methyl Oxyphenyl)-piperazin-1-yl]-ethanone

The title compound was prepared following protocol T: HPLC retention time = 5.55 minutes (Agilent Zorbax SB-C18, 2.1 x 50 mm, 5 μ, 35° C.) using a 4.5 minute gradient from 20-95% B and a 1.1 minute gradient at 95% B Washes (A = 0.1% formic acid/5% acetonitrile/94.9% water, B = 0.08% formic acid/99.9% acetonitrile); MS (ES) M+H expected = 538.1, found = 538.1.

Synthesis of 1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-(4-chloro-5-methyl-3-pyrimidin-2-yl-pyridine Azol-1-yl)-ethanone (isomer I) and 1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-(4-chloro -3-Methyl-5-pyrimidin-2-yl-pyrazol-1-yl)-ethanone (isomer II)

The title compound was prepared following Protocol T: Isomer I: HPLC retention time = 3.8 min (Agilent Zorbax SB-C18, 2.1 x 50 mm, 5 μ, 35 °C) using a 4.5 min gradient from 20-95% B at 95% B A 1.1 minute wash was used (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.08% formic acid/99.9% acetonitrile). MS(ES) M+H expected = 461.1, found = 461.3.

Isomer II: HPLC retention time = 4.16 min (Agilent Zorbax SB-C18, 2.1 x 50 mm, 5 μ, 35 °C) with a 4.5 min gradient from 20-95% B, with a 1.1 min wash at 95% B ( A = 0.1% formic acid/5% acetonitrile/94.9% water, B = 0.08% formic acid/99.9% acetonitrile). MS(ES) M+H expected = 461.1, found = 461.3.

Synthesis of 1-[4-(4-chloro-3-ethoxy-phenyl)-piperazin-1-yl]-2-(4-chloro-5-methyl-3-pyrimidin-2-yl-pyridine Azol-1-yl)-ethanone (isomer I) and 1-[4-(4-chloro-3-ethoxy-phenyl)-piperazin-1-yl]-2-(4-chloro -3-Methyl-5-pyrimidin-2-yl-pyrazol-1-yl)-ethanone (isomer II)

The title compound was prepared following Protocol T: Isomer I: HPLC retention time = 4.09 minutes (Agilent Zorbax SB-C18, 2.1 x 50 mm, 5 μ, 35° C.) using a 4.5 minute gradient of 20-95% B at 95% B With 1.1 min wash (A = 0.1% formic acid/5% acetonitrile/94.9% water, B = 0.08% formic acid/99.9% acetonitrile); MS(ES) M+H expected = 475.1, found = 475.4; ¹ H NMR (CDCl3, 400MHz) 8.88(d, 2H), 7.31-7.25(m, 4H), 6.64(s, 1H), 6.52(d, 1H), 5.15(s, 2H), 4.5-4.3, 4.08(q , 2H), 3.83(m, 4H), 3.25-3.19(m, 4H), 2.37(s, 3H), 1.47(t, 3H) ppm; NOESY showed α-H (5.1ppm) and CH3- (2.4ppm);

Isomer II: HPLC retention time = 4.45 minutes (Agilent Zorbax SB-C18, 2.1 x 50 mm, 5 μ, 35° C.) using a 4.5 minute gradient from 20-95% B with a 1.1 minute wash at 95% B ( A = 0.1% formic acid/5% acetonitrile/94.9% water, B = 0.08% formic acid/99.9% acetonitrile). MS(ES) M+H expected = 475.1, found = 475.4; ¹ H NMR (CDCl3, 400 MHz) ¹ H NMR (CDCl ₃ , 400 MHz) 8.80 (d, 2H), 7.2 (m, 4H), 6.62 ( s, 1H), 6.61 (d, 1H), 5.64 (s, 2H), 4.10 (d, 2H), 3.77-3.23 (d, d, 8H), 3.17 (d, 4H), 2.34 (s, 3H) , 1.48 (t,3H) ppm; NOESY showed no correlation between α-H (5.64 ppm) and CH ₃ - (2.34 ppm) in pyrazole.

Synthesis of 1-[4-(4-chloro-3-ethoxy-phenyl)-2-methyl-piperazin-1-yl]-2-(4-chloro-5-methyl-3-pyrimidine- 2-yl-pyrazol-1-yl)-ethanone (isomer I) and 1-[4-(4-chloro-3-ethoxy-phenyl)-2-methyl-piperazine-1 -yl]-2-(4-chloro-3-methyl-5-pyrimidin-2-yl-pyrazol-1-yl)-ethanone (isomer II)

The title compound was prepared following Protocol T: Isomer I: HPLC retention time = 4.35 min (Agilent Zorbax SB-C18, 2.1 x 50 mm, 5 μ, 35 °C) using a 4.5 min gradient from 20-95% B at 95% B A 1.1 minute wash was used (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.08% formic acid/99.9% acetonitrile). MS(ES) M+H expected = 489.2, found = 489.4.

Isomer II: HPLC retention time = 4.71 min (Agilent Zorbax SB-C18, 2.1 x 50 mm, 5 μ, 35°C) with a 4.5 min gradient from 20-95% B, with a 1.1 min wash at 95% B ( A = 0.1% formic acid/5% acetonitrile/94.9% water, B = 0.08% formic acid/99.9% acetonitrile). MS(ES) M+H expected = 461.1, found = 489.4.

Synthesis of 1-[4-(4-chloro-1-{2-[4-(4-chloro-3-ethoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl} -5-Methyl-1H-pyrazol-3-yl)-pyrimidine-2-carbonitrile

The title compound was prepared following protocol T: HPLC retention time = 4.94 min (Agilent Zorbax SB-C18, 2.1 x 50 mm, 5 μ, 35 °C) using a 4.5 min gradient from 20-95% B and a 1.1 min gradient at 95% B Washes (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.08% formic acid/99.9% acetonitrile). MS(ES) M+H expected = 499.1, found = 499.4.

Synthesis of 2-[4-chloro-3(1-hydroxy-1-methyl-ethyl)-5-methyl-pyrazol-1-yl]-1-[4-(3-methoxy-4- Chloro-phenyl)-piperazin-1-yl]-ethanone (isomer I) and 2-[4-chloro-5(1-hydroxy-1-methyl-ethyl)-3-methyl- Pyrazol-1-yl]-1-[4-(3-methoxy-4-chloro-phenyl)-piperazin-1-yl]-ethanone (isomer II):

Following protocol T, combine 2-chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone and 2-(4-chloro-5-methanone (1H-pyrazol-3-yl)-propan-2-ol to give the title compound. Isomer I: HPLC retention time = 5.34 min (Agilent Zorbax SB-C18, 2.1 x 50 mm, 5 μ, 35° C.) with a 4.5 min gradient from 20-95% B, with a 1.1 min wash at 95% B ( A = 0.1% formic acid/5% acetonitrile/94.9% water, B = 0.08% formic acid/99.9% acetonitrile); MS(ES) M+H expected = 441.1, found = 423.1 ( _-H2O ); ¹ HNMR (CDCl ₃ , 400MHz) 7.63(s, 3H), 7.32(d1H), 6.80(s, 1H), 6.65(d1H), 5.04(s, 2H), 3.89(m, 3H), 3.93-3.85(Par. Obsc.m, 4H), 3.38(t, 2H), 3.30(t, 2H), 2.27(s, 2H), 1.63(s, 6H) ppm; NOESY shown in α-H (5.0ppm) and pyrazole Correlation between CH3 (2.2ppm).

Isomer II: HPLC retention time = 5.5 minutes (Agilent Zorbax SB-C18, 2.1 x 50 mm, 5 μ, 35° C.) using a 4.5 minute gradient from 20-95% B with a 1.1 minute wash at 95% B ( A = 0.1% formic acid/5% acetonitrile/94.9% water, B = 0.08% formic acid/99.9% acetonitrile); MS(ES) M+H expected = 441.1, found = 423.1 ( _-H2O ); ¹ H NMR (CDCl ₃ , 400MHz) 9.6(s, 1H), 7.25(d, 1H), 6.5(s1H), 6.45(d, 1H), 4.86(s, 2H), 3.88(s, 3H), 3.38(m , 8H), 2.24 (s, 3H), 1.82 (s, 6H) ppm; NOESY showed no correlation between α-H (4.86 ppm) and CH ₃ - (2.24 ppm) in pyrazole.

Synthesis of 2-[4-chloro-3-isopropyl-5-methylpyrazol-1-yl]-1-[4-(4-chloro-3-methoxy-phenyl)-piperazine-1 -yl]-ethanone

The title compound was prepared following protocol T: HPLC retention time = 6.0 min (Agilent Zorbax SB-C18, 2.1 x 50 mm, 5 μ, 35 °C) using a 4.5 min gradient from 20-95% B and a 1.1 min gradient at 95% B Washes (A = 0.1% formic acid/5% acetonitrile/94.9% water, B = 0.08% formic acid/99.9% acetonitrile); MS (ES) M+H expected = 425.1, found = 425.1.

Synthesis of 1-4-(4-chloro-3-methoxyphenyl)-piperazin-1-yl)-2-(3,5-dipyridin-2-yl-pyrazol-1-yl)ethanone :

The title compound was prepared following Protocol T: LC MS 489 (M ⁺ , method 20-95, RT = 3.79 minutes); ¹ HNMR (400 MHz, CDCl ₃ ): δ3.13 (bs, 2H), 3.25 (bs, 2H) , 3.74(bs, 4H), 3.88(s, 3H), 5.82(s, 2H), 6.43(dd, J=2.6 & 8.5Hz, 1H), 6.48(d, J=2.4Hz, 1H), 7.17- 7.24(m, 3H), 7.37(d, J=1.1Hz, 1H), 7.68-7.76(m, 3H), 7.97(dd, J=0.7 &7.3Hz, 1H), 8.49-8.52(m, 1H) , 8.60-8.62 (m, 1H).

Synthesis of 6-(4-chloro-1-{2-[4-(4-chloro-5-ethoxy-2-fluorophenyl)piperazin-1-yl]-2-oxo-ethyl}- 5-Methyl-1H-pyrazol-3-yl)pyridine-2-carbonitrile:

Following protocol T, combine 2-(4-chloro-5-methyl-1H-pyrazol-3-yl)-6-cyanopyridine and 2-chloro-1-[4-(4-chloro-3-ethyl Oxy-2-fluorophenyl)-piperazin-1-yl]-ethanone, yielding the title compound: ¹ H NMR (400 MHz, CDCl ₃ ) δ8.87-8.92 (m, 3H), 6.02-6.95 (s , 2H), 5.11 (s, 2H), 4.18 (q, 2H), 3.21-3.68 (dt, 4H), 2.45 (s, 3H), 1.52 (t, 3H). LCMS (ES) M+H=517.4, RT=5.130 min (acetonitrile/H ₂ O 20-95% method).

Synthesis of 1-{2-[4-(4-chloro-3-methoxy-phenyl)-2-methyl-piperazin-1-yl]-2-oxo-ethyl}-5-methyl -3-(5-Methyl-iso-oxazol-3-yl)-1H-pyrazole-4-carboxylic acid ethyl ester:

Following protocol T, combine ethyl 5-methyl-3-(5-methyl-isoxazol-3-yl)-1H-pyrazole-4-carboxylate and 2-chloro-1-[4-(4 -Chloro-3-methoxy-phenyl)-2-(S)-methyl-piperazin-1-yl]-ethanone to give the title compound: MS (M+H ⁺ ): 488.2; HPLC retention time = 5.21 minutes (Agilent Zorbax SB-C18, 2.1 x 50mm, 5μ, 35°C) using a 4.5 minute gradient from 20-95% B with a 1.1 minute wash at 95% B (A = 0.1% formic acid/5% Acetonitrile/94.9% water, B = 0.08% formic acid/99.9% acetonitrile).

Synthesis of 2-(3-bromoindazol-1-yl)-1-(4-(4-chloro-3-methoxyphenyl)-piperazin-1-yl)ethanone

The title compound was prepared following Protocol T: LCMS M+H = 464; HPLC RT = 4.73 min. (Agilent Zorbax SB-C18, 2.1 x 50 mm, 5 μ, 35 °C) using a 4.5 min gradient of 20-95% B at 95% B with 1.1 minute wash (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.08% formic acid/99.9% acetonitrile); ¹ H NMR (400 MHz, CDCl ₃ ): δ3.07 (apparent q, J = 4.4Hz, 4H), 3.75 (apparent q, J = 4.4Hz, 4H), 3.87 (s, 3H), 5.23 (s, 2H), 6.37 (dd, J = 1.4 & 8.4Hz, 1H) , 6.48 (d, J=1.8Hz, 1H), 7.18-7.24 (m, 2H), 7.42-7.45 (m, 2H), 7.59 (d, J=8.0Hz, 1H).

5-(4-chloro-1-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-5-methanol Base-1H-pyrazol-3-yl)-pyridine-2-carboxylic acid dimethylamide

The title compound was prepared following Scheme T: ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.21-8.12 (m, 3H), 6.47 (m, 3H), 4.48 (s, 2H), 3.8 (q, 2H), 3.89 ( s, 1H), 3.79-3.32 (dt, 2H), 2.35 (s, 3H), 2.18 (s, 3H); LCMS (ES) M+H = 532.4; HPLC RT = 4.483 minutes (Agilent Zorbax SB-C18, 2.1 ×50mm, 5μ, 35°C), using a 4.5-minute gradient of 20-95% B, with a 1.1-minute wash at 95% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.08% formic acid /99.9% acetonitrile).

5-(4-chloro-1-{2-[4-(4-chloro-3-methoxy-phenyl)-2-methyl-piperazin-1-yl]-2-oxo-ethyl }-5-Methyl-1H-pyrazol-3-yl)-pyridine-2-carboxylic acid dimethylamide

The title compound was prepared following Scheme T: ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.21-8.12 (m, 3H), 6.47 (m, 3H), 4.64 (s, 2H), 3.81 (q, 2H), 3.89 ( s, 1H), 3.89(d, 2H), 3.79-3.32(dt, 2H), 2.35(s, 3H), 2.18(s, 3H); LCMS (ES) M+H=546.5; HPLC RT=6.887 min (Agilent Zorbax SB-C18, 2.1×50 mm, 5 μ, 35° C.), using a 4.5-minute gradient of 20-95% B with a 1.1-minute wash at 95% B (A=0.1% formic acid/5% acetonitrile/94.9 % water, B = 0.08% formic acid/99.9% acetonitrile).

Synthesis of 1-[4-(4-chloro-3-methoxy-phenyl)-2-methyl-piperazin-1-yl]-2-(4-chloro-5-methyl-3-pyridine- 2-yl-pyrazol-1-yl)-ethanone

4-Chloro-5-methyl-3-pyridylpyrazole (3.61 g, 18.7 mmol), phenylpiperazine-carbonylmethyl chloride (5.75 g, 19.0 mmol) and _K2CO3 ( _27.6 g, 200 mmol) A mixture in _CH3CN (50 mL) and DMF (5 mL) was heated to 80 °C for 2 h. Filter and evaporate the mixture in vacuo. The remaining residue of DMF was further removed by overnight under high vacuum. After recrystallization from hot ethanol, the title compound was provided as a white solid. This solid was dissolved in ethanol (200 mL) and hydrogen chloride in ether (2.0 M, 400 mL) was added with slow stirring. The precipitate formed was filtered off to obtain the title compound as a white solid. ¹ H NMR: δ (400MHz, d-DMSO) major rotamers: 8.69 (br d, 1H), 8.15 (br, 1H), 8.07 (br d, 1H), 7.59 (br, d, 1H), 7.20 (d, 1H), 6.64 (br, 1H), 6.41 (br d, 1H), 5.55-5.18 (br m, 2H), 3.83 (s, 3H), 3.74-3.48 (br m, 4H), 3.18 -2.59 (br m, 3H), 2.22 (s, 3H), 1.42-1.16 (br m, 3H). MS (M+H ⁺ ): 474.1.

1-[4-(4-chloro-3-methoxy-phenyl)-2-(S)-methyl-piperazin-1-yl]-2-(4-chloro-5-methyl-3 -pyridin-3-yl-pyrazol-1-yl)-ethanone:

According to scheme T, 3-(4-chloro-5-methyl-1H-pyrazol-3-yl)-pyridine and 2-chloro-1-[4-(4-chloro-3-methoxy-phenyl )-2-(S)-Methyl-piperazin-1-yl]-ethanone was treated with potassium carbonate in N,N-dimethylformamide to give the title compound: MS (M+H ⁺ ): 474.1 ; HPLC retention time = 3.96 min (Agilent Zorbax SB-C18, 2.1 x 50 mm, 5 μ, 35° C.) using a 4.5 min gradient from 20-95% B with a 1.1 min wash at 95% B (A = 0.1% Formic acid/5% acetonitrile/94.9% water, B=0.08% formic acid/99.9% acetonitrile).

1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-(4-chloro-5-methyl-3-pyridin-3-yl-pyrazole -1-yl)-ethanone:

According to scheme T, 3-(4-chloro-5-methyl-1H-pyrazol-3-yl)-pyridine and 2-chloro-1-[4-(4-chloro-3-methoxy-phenyl )-piperazin-1-yl]-ethanone was treated with potassium carbonate in N,N-dimethylformamide to give the title compound: MS (M+H ⁺ ): 460.1; HPLC retention time = 3.59 minutes (Agilent Zorbax SB-C18, 2.1 x 50mm, 5μ, 35°C) with a 4.5 minute gradient of 20-95% B, with a 1.1 minute wash at 95% B (A = 0.1% formic acid/5% acetonitrile/94.9% water , B=0.08% formic acid/99.9% acetonitrile).

Scheme V: Preparation of Compounds by Acid or Base Involved Deprotection

4-chloro-1-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-5-methyl-1H -Pyrazole-3-carboxylic acid.

4-chloro-1-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-5-methyl- 1H-Pyrazole-3-carboxylic acid ethyl ester (100 mg) was dissolved in THF (7 ml), to this solution was added 5 mL of 1N NaOH, and the reaction mixture was stirred overnight. Then, it was acidified with 1N HCl and extracted with ethyl acetate. Then drying and removal of solvent gave pure product: ¹ H NMR (CDCl ₃ , 400 MHz) 7.18-7.22 (d, 1H), 6.74-6.76 (d, 1H), 6.54-6.58 (dd, 2H), 5.3 (s, 2H), 3.88 (s, 3H), 3.68-3.82 (m, 4H), 3.22-3.38 (m, 4H), 2.24 (s, 3H) ppm. MS(ES) M+H expected = 427, found = 427.

6-(4-Chloro-5-methyl-1H-pyrazol-3-yl)-pyridine-2-carboxylic acid amide:

To ethyl 6-(4-chloro-5-methyl-1H-pyrazol-3-yl)-pyridine-2-carboxylate (1.0 gm, 0.78 mmol) in 10 mL of anhydrous THF was added 10 mL of liquid ammonia. It was then heated to 60° C. and refluxed for 6 hours, at which time the reaction ended and solid product precipitated. The reaction was cooled and the THF was spun off to yield 0.5 gm of the title compound.

6-(4-Chloro-5-methyl-1H-pyrazol-3-yl)-pyridine-2-carbonitrile:

Dissolve 6-(4-chloro-5-methyl-1H-pyrazol-3-yl)-pyridine-2-carboxylic acid amide (0.15 gm, 0.63 mmol) in 5 mL of anhydrous CH ₂ Cl ₂ and add 1 mL TEA (7.29 mmol). It was then cooled to 0°C and treated with ( _CF3CO ) _2O (0.2ml, 0.952mmol). The reaction mixture was slowly warmed to ambient temperature and stirred for an additional 4 hours. The mixture was washed once each with 10% NaHCO ₃ , 5% citric acid, and finally with saturated brine. The dichloromethane phase was concentrated and the residue was purified by chromatography to give the title compound.

6-(4-Chloro-5-methyl-1H-pyrazol-3-yl)-pyridine-2-carboxylic acid:

Dissolve ethyl 6-(4-chloro-5-methyl-1H-pyrazol-3-yl)-pyridine-2-carboxylate (0.23 gm, 0.78 mmol) in 5 mL of anhydrous THF and 5 mL of water, in which LiOH (0.3 gm) was added. After 6 hours, THF was spun off and the residue was acidified with citric acid. The solid formed was isolated to give the title compound.

Scheme W: Preparation of compounds by borohydride-involved reductive alkylation

1-(4-Chloro-3-methoxybenzyl)piperazine

Following Protocol W, using 4-chloro-3-methoxybenzaldehyde and 1-Boc-piperazine, followed by N-Boc cleavage with HCl in isopropanol afforded the title compound.

tert-butyl 4-(4-chloro-3-methoxy-phenyl)-2-formyl-piperazine-1-carboxylate

Dissolve 500 mg (1.40 mmol) tert-butyl 4-(4-chloro-3-methoxy-phenyl)-2-hydroxymethyl-piperazine-1-carboxylate in 5 mL dichloromethane, and cool the solution to At 0 °C, 7.3 mL (1.82 mmol) of 0.25M Des-Martin periodinane in dichloromethane was slowly added. After 2 hours, the mixture was washed with saturated sodium metabisulfite, brine, and dried over sodium sulfate. Crude aldehyde is available.

tert-butyl 4-(4-chloro-3-methoxy-phenyl)-2-pyrrolidin-1-ylmethyl-piperazine-1-carboxylate

Add 0.5 mL of methanol, 0.1 mL (1.1 mmol) of pyrrolidine and 35 mg (0.56 mmol) of sodium cyanoborohydride. After 4 hours, the reaction was quenched with 50 μL of acetic acid. After 1 hour, the mixture was washed with saturated sodium bicarbonate and brine, dried over sodium sulfate, and concentrated to a residue.

tert-butyl 4-(4-chloro-3-methoxy-phenyl)-2-morpholin-4-ylmethyl-piperazine-1-carboxylate

To about 0.28 mmol of tert-butyl 4-(4-chloro-3-methoxy-phenyl)-2-formyl-piperazine-1-carboxylate in 2.4 mL of dichloromethane was added 0.5 mL of methanol, 0.1 mL (1.1 mmol) of morpholine and 35 mg (0.56 mmol) of sodium cyanoborohydride. After 4 hours, the reaction was quenched with 50 μL of acetic acid. After 1 hour, the mixture was washed with saturated sodium bicarbonate and brine, dried over sodium sulfate, and concentrated to a residue.

tert-butyl 4-(4-chloro-3-methoxy-phenyl)-2-(4-methyl-piperazin-1-ylmethyl)-piperazine-1-carboxylate

To about 0.28 mmol tert-butyl 4-(4-chloro-3-methoxy-phenyl)-2-formyl-piperazine-1-carboxylate in 2.4 mL of dichloromethane was added 0.5 mL of methanol, 0.12 mL (1.1 mmol) 1-methylpiperazine and 35 mg (0.56 mmol) sodium cyanoborohydride. After 4 hours, the reaction was quenched with 50 μL of acetic acid. After 1 hour, the mixture was washed with saturated sodium bicarbonate and brine, dried over sodium sulfate, and concentrated to a residue.

Scheme X: Preparation of compounds by acylation or sulfonylation

N-(4-chloro-1-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-5-methyl -1H-pyrazol-3-yl)-methanesulfonamide

To 2-(3-amino-4-chloro-5-methyl-pyrazol-1-yl)-1-[4-(4-chloro-3-methoxy- To phenyl)-piperazin-1-yl]-ethanone (1.0 g) were added triethylamine (0.7 ml) and MeSO ₂ Cl (0.19 ml), and the mixture was stirred at 0°C for 5 hours. The resulting disulfonylated compound was dissolved in methanol (10 mL), added NaOH (0.42 g in 5 mL of water), and stirred at 60°C for 2 hours. Methanol was removed in vacuo, water was added, and the pH was adjusted to acidic with citric acid. The solid compound was filtered and purified by chromatography to afford the title compound.

Synthesis of 3-methyl-4-acetylamino-5(trifluoromethyl)pyrazole

To 3-methyl-4-amino-5(trifluoromethyl)pyrazole (165 mg, 1 mmol) in ACN was added 0.1 mL of acetic anhydride. A precipitate formed after addition and was isolated by filtration to afford the title compound: HPLC retention time = 0.36 min (Agilent Zorbax SB-C18, 2.1 x 50 mm, 5 μ, 35°C) using a 4.5 min gradient of 20-95% B at 95% A 1.1 minute wash was used for B (A = 0.1% formic acid/5% acetonitrile/94.9% water, B = 0.08% formic acid/99.9% acetonitrile); MS (ES) M+H expected = 208.1, found = 208.2.

Scheme Y: Preparation of Compounds by Alkylation

Synthesis of 2-(4-chloro-5-methyl-1H-pyrazol-3-yl)-propan-2-ol

Dissolve ethyl 4-chloro-5-methyl-1H-pyrazole-3-carboxylate (0.14g, 0.8mmol) in 6mL of anhydrous THF, cool to 0°C, add dropwise 3mL (9.0mmol ) 3M MeMgBr. The reaction was then removed from the ice bath and stirred at ambient temperature for 1 hour. The reaction mixture was poured into 1M phosphate buffer (pH=7), the mixture was extracted with EtOAc, the phases were separated, the ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated to provide the title compound: MS( ES) M-OH expected = 157.1, found = 157.1; ¹ H NMR (CDCL ₃ , 400 MHz) δ 2.25 (s, 3H), 1.64 (s, 6H) ppm.

Synthesis of 4-chloro-3-isopropyl-5-methyl-1H-pyrazole:

2-(4-Chloro-5-methyl-1H-pyrazol-3-yl)-propan-2-ol (52mg, 0.3mmol), 2mL DCM, 1mL triethylsilane and 0.1mL TFA were added together , stirred at 80°C overnight, then the solvent was removed in vacuo. The residue was dissolved in ethyl acetate, washed with saturated NaHCO ₃ and brine, dried over anhydrous sodium sulfate, and concentrated to provide the title compound. HPLC retention time = 4.9 minutes (Agilent Zorbax SB-C18, 2.1 x 50mm, 5μ, 35°C) using a 4.5 minute gradient from 20-95% B with a 1.1 minute wash at 95% B (A = 0.1% formic acid /5% acetonitrile/94.9% water, B = 0.08% formic acid/99.9% acetonitrile); MS (ES) M+H expected = 159.1, found = 159.1.

Scheme AA: Synthesis of Trisubstituted Pyrazoles by Suzuki Coupling

2-[4-chloro-3-(5-fluoro-2-methoxy-pyridin-4-yl)-5-methyl-pyrazol-1-yl]-1-[4-(4-chloro- 3-Methoxy-phenyl)-piperazin-1-yl]-ethanone

The title compound was prepared according to Protocol AA: LCMS (ES) M+H = 509.3; HPLC RT = 4.714 min (Agilent Zorbax SB-C18, 2.1 x 50 mm, 5 μ, 35 °C) using a 4.5 min gradient of 20-95% B, A 1.1 minute wash was used at 95% B (A = 0.1% formic acid/5% acetonitrile/94.9% water, B = 0.08% formic acid/99.9% acetonitrile).

2-[4-Chloro-3-(3-methoxy-phenyl)-5-methyl-pyrazol-1-yl]-1-[4-(4-chloro-3-methoxy-benzene Base)-piperazin-1-yl]-ethanone

Step 1: 3-Methyl-4-chloro-5-bromopyrazole (222.5mg) was dissolved in DMF (10ml). To this mixture was added Pd( _PPh3 )4 (44.6 mg), aqueous _Na2CO3 ( _306.16 in 2 mL of _H2O ) and finally 3-methoxyphenylboronic acid (190 mg). The reaction mixture was heated in an oil bath at about 140°C for 14 hours. After complete consumption of the starting material, it was cooled and the solid residue was filtered off. EtOAc was added to the reaction mixture, followed by washing with water to remove DMF. The organic layer was then dried and the solvent was removed to give the crude product.

Step 2: The product was dissolved in DMF (7ml) and mixed with _K2CO3 (123.2mg) and _2- chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazine-1 -yl]-ethanone A (278 mg). It was then heated at about 80°C for 16 hours, cooled, quenched with water, and extracted with ethyl acetate. The solvent was removed and the crude product was purified by chromatography to give the title compound: R _f : 0.7; ¹ H NMR (CDCl ₃ , 400 MHz) 7.4-7.48 (2H, m), 7.28-7.34 (t, 1H), 7.2-7.22 ( d, 1H), 6.86-6.91(m, 1H), 6.4-6.48(m, 2H), 5.0(2H, s), 3.84(s, 3H), 3.82(s, 3H), 3.72-3.8(m, 4H), 3.12-3.18 (m, 4H), 2.3 (s, 3H) ppm. ¹³ CNMR (400MHz, CDCl ₃ ) δ161, 160, 158, 152, 148, 140, 134, 130, 128, 120, 112, 111.5, 110, 109, 100, 58, 56, 54, 50.2, 50, 46, 42, 10.

2-(4-chloro-3-furan-2-yl-5-methyl-pyrazol-1-yl)-1-[4-(4-chloro-3-methoxy-phenyl)-2- (S)-Methyl-piperazin-1-yl]-ethanone

According to Scheme AA, 2-(3-bromo-4-chloro-5-methyl-pyrazol-1-yl)-1-[4-(4-chloro-3-methoxy-phenyl)-2- (S)-Methyl-piperazin-1-yl]-ethanone is cross-coupled with furan-2-boronic acid to give the title compound: HPLC retention time=7.42 minutes (Agilent Zorbax SB-C18, 2.1×50mm, 5 μ, 35 °C) with a 2.0-minute no-gradient time at 20% B, followed by a 5.0-minute gradient from 20-95% B with a 2.5-minute wash at 95% B (A = 0.1% formic acid/5% acetonitrile/94.9% water, B=0.08% formic acid/99.9% acetonitrile); (M/Z)+=463.2 (M+H).

Synthesis of 2-[4-chloro-3-(2,4-difluoro-phenyl)-5-methyl-pyrazol-1-yl]-1-[4-(4-chloro-3-methoxy -Phenyl)-2-(S)-methylpiperazin-1-yl]-ethanone:

According to Scheme AA, 2,4-difluorophenylboronic acid and 2-(3-bromo-4-chloro-5-methyl-pyrazol-1-yl)-1-[4-(4-chloro-3- Coupling of methoxy-phenyl)-2-(S)-methyl-piperazin-1-yl]-ethanone affords the title compound. HPLC retention time = 5.39 min (Agilent Zorbax SB-C18, 2.1 x 50 mm, 5 μ, 35°C) with a 4.5 min gradient from 20-95% B with a 1.1 min wash at 95% B (A = 0.1% formic acid /5% acetonitrile/94.9% water, B=0.08% formic acid/99.9% acetonitrile).

2-[4-Chloro-3-(3-fluoro-pyridin-4-yl)-5-methyl-pyrazol-1-yl]-1-[4-(4-chloro-3-methoxy- Phenyl)-piperazin-1-yl]-ethanone

The title compound was prepared according to Suzuki protocol AA: LCMS (ES) M+H = 478.3; HPLC RT = 4.724 min (Agilent Zorbax SB-C18, 2.1 x 50 mm, 5 μ, 35 °C) using a 4.5 min gradient of 20-95% B , with a 1.1 minute wash at 95% B (A = 0.1% formic acid/5% acetonitrile/94.9% water, B = 0.08% formic acid/99.9% acetonitrile).

2-[4-chloro-3-(2-chloro-pyridin-3-yl)-5-methyl-pyrazol-1-yl]-1-[4-(4-chloro-3-methoxy- Phenyl)-piperazin-1-yl]-ethanone

The title compound was prepared following Suzuki Protocol AA: ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.87-7.12 (m, 3H), 6.47 (d, 3H), 4.64 (s, 2H), 3.89 (s, 1H), 3.21 -3.83 (dt, 2H), 2.85 (s, 3H); LCMS (ES) M+H = 494.4; HPLC RT = 4.514 minutes (Agilent Zorbax SB-C18, 2.1 * 50mm, 5 μ, 35 ℃), adopt 20- 4.5 minute gradient to 95% B with a 1.1 minute wash at 95% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.08% formic acid/99.9% acetonitrile).

2-[4-chloro-3-(2,4-dimethoxy-pyrimidin-5-yl)-5-methyl-pyrazol-1-yl]-1-[4-(4-chloro-3 -methoxy-phenyl)-piperazin-1-yl]-ethanone

The title compound was prepared according to Suzuki protocol AA: LCMS (ES) M+H = 521.4; HPLC retention time = 4.499 minutes (Agilent Zorbax SB-C18, 2.1 x 50 mm, 5 μ, 35°C), 4.5 minutes with 20-95% B Gradient with a 1.1 minute wash at 95% B (A = 0.1% formic acid/5% acetonitrile/94.9% water, B = 0.08% formic acid/99.9% acetonitrile).

1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-[4-chloro-5-methyl-3-(1-methyl-1H- Indol-6-yl)-pyrazol-1-yl]-ethanone

The title compound was prepared according to Suzuki protocol AA: LCMS (ES) M+H = 512.4; HPLC RT = 5.038 min (Agilent Zorbax SB-C18, 2.1 x 50 mm, 5 μ, 35 °C) using a 4.5 min gradient of 20-95% B , with a 1.1 minute wash at 95% B (A = 0.1% formic acid/5% acetonitrile/94.9% water, B = 0.08% formic acid/99.9% acetonitrile).

1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-[4-chloro-5-methyl-3-(5-methyl-furan- 2-yl)-pyrazol-1-yl]-ethanone

The title compound was prepared according to Suzuki protocol AA: LCMS (ES) M+H = 463.4; HPLC retention time = 4.961 min (Agilent Zorbax SB-C18, 2.1 x 50 mm, 5 μ, 35 °C), 4.5 min with 20-95% B Gradient with a 1.1 minute wash at 95% B (A = 0.1% formic acid/5% acetonitrile/94.9% water, B = 0.08% formic acid/99.9% acetonitrile).

2-(4-chloro-3-furan-3-yl-5-methyl-pyrazol-1-yl)-1-[4-(4-chloro-3-methoxy-phenyl)-2- (S)-Methyl-piperazin-1-yl]-ethanone

According to Suzuki scheme AA, 2-(3-bromo-4-chloro-5-methyl-pyrazol-1-yl)-1-[4-(4-chloro-3-methoxy-phenyl)-2 -(S)-Methyl-piperazin-1-yl]-ethanone is cross-coupled with furan-3-boronic acid to give the title compound: HPLC retention time = 7.49 minutes (Agilent Zorbax SB-C18, 2.1×50mm, 5μ, 35°C) with a 2.0-minute no-gradient time at 20% B, followed by a 5.0-minute gradient from 20-95% B with a 2.5-minute wash at 95% B (A = 0.1% formic acid/5% acetonitrile/94.9% water , B=0.08% formic acid/99.9% acetonitrile); (M/Z)+=463.2 (M+H).

2-[4-chloro-3-(4-fluoro-phenyl)-5-methyl-pyrazol-1-yl]-1-[4-(4-chloro-3-methoxy-phenyl) -Piperazin-1-yl]-ethanone

According to Scheme AA, 2-[4-chloro-3-bromo-5-methyl-pyrazol-1-yl]-1-[4-(4-chloro-3-methoxy-phenyl)-piperazine Cross-coupling of -1-yl]-ethanone with 4-fluoroboronic acid gave the title compound: R _f =0.57; ¹ H NMR (CDCl ₃ , 400 MHz) 7.8-7.9 (2H, m), 7.2-7.22 (d, 1H ), 7.05-7.12(m, 2H), 6.4-6.48(m, 2H), 5.0(2H, s), 3.82(s, 3H), 3.7-3.8(m, 4H), 3.1-3.2(m, 4H ), 2.3 (s, 3H) ppm. ¹³ CNMR (400 MHz, CDCl ₃ ) δ162, 160, 155, 152, 148, 140, 134, 130, 118, 112, 110, 109, 100, 58, 56, 54, 52, 46, 42, 10 ppm.

2-[4-chloro-3-(2-fluoro-phenyl)-5-methyl-pyrazol-1-yl]-1-[4-(4-chloro-3-methoxy-phenyl) -Piperazin-1-yl]-ethanone.

According to Scheme AA, 2-[4-chloro-3-bromo-5-methyl-pyrazol-1-yl]-1-[4-(4-chloro-3-methoxy-phenyl)-piperazine -1-yl]-ethanone is coupled with 2-fluoroboronic acid to give the title compound: R _f : 0.521; ¹ H NMR (CDCl ₃ , 400MHz) 7.5-7.56 (1H, m), 7.32-7.38 (m, 1H) , 7.1-7.21(m, 3H), 7.12-7.22(d, 1H), 6.4-6.48(m, 2H), 5.0(2H, s), 3.83(s, 3H), 3.7-3.8(m, 4H) , 3.08-3.18 (m, 4H), 2.3 (s, 3H) ppm. ¹³ CNMR (400 MHz, CDCl ₃ ) δ162, 160, 158, 155, 138, 131, 130, 124, 118, 112, 110, 109, 100, 58, 56, 54, 52, 46, 42, 10 ppm.

2-[4-chloro-3-(3-fluoro-phenyl)-5-methyl-pyrazol-1-yl]-1-[4-(4-chloro-3-methoxy-phenyl) -Piperazin-1-yl]-ethanone

According to Scheme AA, 2-[4-chloro-3-bromo-5-methyl-pyrazol-1-yl]-1-[4-(4-chloro-3-methoxy-phenyl)-piperazine -1-yl]-ethanone is coupled with 3-fluoroboronic acid to give the title compound: R _f : 0.68; ¹ H NMR (CDCl ₃ , 400MHz) 7.68-7.72 (1H, m), 7.58-7.62 (m, 1H) , 7.32-7.38(m, 1H), 7.18-7.22(d, 1H), 6.98-7.04(m, 1H), 6.38-6.48(m, 2H), 4.98(2H, s), 3.88(s, 3H) , 3.7-3.8 (m, 4H), 3.1-3.2 ( ^m , 4H), 2.3 ( _s , 3H) ppm; , 114-116(m), 110, 100, 56, 52, 50, 49, 46, 42, 10ppm.

2-[4-chloro-3-(2,4-difluoro-phenyl)-5-methyl-pyrazol-1-yl]-1-[4-(4-chloro-3-methoxy- Phenyl)-piperazin-1-yl]-ethanone

According to Scheme AA, 2-[4-chloro-3-bromo-5-methyl-pyrazol-1-yl]-1-[4-(4-chloro-3-methoxy-phenyl)-piperazine -1-yl]-ethanone was cross-coupled with 2,4-difluoroboronic acid to give the title compound: R _f : 0.7; ¹ HNMR (CDCl ₃ , 400MHz) 7.48-7.56 (1H, m), 7.18-7.22 (d , 1H), 6.86-6.94(m, 2H), 6.38-6.48(m, 2H), 5.00(2H, s), 3.88(s, 3H), 3.68-3.8(m, 4H), 3.1-3.2(m , 4H), 2.3 (s, 3H) ppm; ¹³ CNMR (400MHz, CDCl ₃ ) δ164, 156, 150, 138, 132, 130, 122, 118, 114-116 (m), 102, 56, 52, 50 , 49, 46, 42, 10ppm.

1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-(4-chloro-5-methyl-3-pyrimidin-5-yl-pyrazole -1-yl)-ethanone

According to Scheme AA, 2-[4-chloro-3-bromo-5-methyl-pyrazol-1-yl]-1-[4-(4-chloro-3-methoxy-phenyl)-piperazine Cross-coupling of -1-yl]-ethanone with 4-pyrimidine boronic acid gave the title compound: R _f : 0.7; ¹ HNMR (CDCl ₃ , 400 MHz) 9.15 (s, 1H), 9.23 (s, 2H), 7.2-7.25 (d, 1H), 6.38-6.48(m, 2H), 5.02(s, 2H), 3.88(s, 3H), 3.72-3.82(m, 4H), 3.12-3.22(m, 4H), 2.32(s , 3H) ppm; MS (ES) M+H expected = 461, found = 461.1.

2-(4-chloro-3-furan-3-yl-5-methyl-pyrazol-1-yl)-1-[4-(4-chloro-3-methoxy-phenyl)-piperazine -1-yl]-ethanone

According to Scheme AA, 2-[4-chloro-3-bromo-5-methyl-pyrazol-1-yl]-1-[4-(4-chloro-3-methoxy-phenyl)-piperazine -1-yl]-ethanone was cross-coupled with 3-furan boronic acid to give the title compound: R _f : 0.7; ¹ HNMR (CDCl ₃ , 400MHz) 8.00 (s, 1H), 7.42-7.44 (t, 1H), 7.18 -7.22(d, 1H), 6.82-6.84(d, 2H), 6.38-6.48(m, 2H), 4.84(s, 2H), 3.88(s, 3H), 3.68-3.8(m, 4H), 3.1 -3.2 (m, 4H), 2.3 (s, 3H) ppm; ¹³ CNMR (400MHz, CDCl ₃ ) δ164, 156, 151, 143, 141, 138, 130, 118, 116, 110, 111, 102, 56, 52, 50, 49, 46, 42, 10ppm.

2-(4-Chloro-3-furan-2-yl-5-methyl-pyrazol-1-yl)-1-[4-(4-chloro-3-methoxy-phenyl)-piperazine -1-yl]-ethanone.

According to Scheme AA, 2-[4-chloro-3-bromo-5-methyl-pyrazol-1-yl]-1-[4-(4-chloro-3-methoxy-phenyl)-piperazine -1-yl]-ethanone was cross-coupled with 2-furan boronic acid to give the title compound: R _f : 0.7; ¹ HNMR (CDCl ₃ , 400MHz) 7.48-7.52 (d, 1H), 7.18-7.22 (d, 1H) , 6.91-6.92(d, 1H), 6.38-6.48(m, 3H), 5.00(s, 2H), 3.88(s, 3H), 3.68-3.78(m, 4H), 3.1-3.2(m, 4H) , 2.3 (s, 3H) ppm; ¹³ CNMR (400MHz, CDCl ₃ ) δ164, 156, 151, 146, 142, 138, 130, 114, 111, 109, 108, 100, 56, 52, 50, 49, 46 , 42, 10ppm.

1-[4-(4-chloro-3-methoxy-phenyl)-2-(S)-methyl-piperazin-1-yl]-2-(4-chloro-5-methyl-3 -pyrimidin-5-yl-pyrazol-1-yl)-ethanone

According to Scheme AA, 2-[4-chloro-3-bromo-5-methyl-pyrazol-1-yl]-1-[4-(4-chloro-3-methoxy-phenyl)-2- Cross-coupling of methyl-piperazin-1-yl]-ethanone with 4-pyrimidine boronic acid gave the title compound: R _f : 0.7; ¹ HNMR (CDCl ₃ , 400MHz) 9.15(s, 1H), 9.23(s, 2H ), 7.2-7.25(d, 1H), 6.38-6.48(m, 2H), 4.32-5.2(m, 5H), 3.88(s, 3H), 2.52-3.52(m, 7H), 2.3-2.4(s , 4H) ppm; MS (ES) M+H expected = 475, found = 475.1.

1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-(4-chloro-5-methyl-3-quinolin-3-yl-pyridine Azol-1-yl)-ethanone

The title compound was prepared following Suzuki Protocol AA: ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.21-7.43 (m, 6H), 6.47 (d, 3H), 4.64 (s, 2H), 3.89 (s, 1H), 3.21 -3.83 (dt, 2H), 2.85 (s, 3H); LCMS (ES) M+H=510.3, HPLC RT=4.718 minutes (Agilent Zorbax SB-C18, 2.1 * 50mm, 5 μ, 35 ℃), adopt 20- 4.5 minute gradient to 95% B with a 1.1 minute wash at 95% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.08% formic acid/99.9% acetonitrile).

Synthesis of 1-[4-(4-chloro-2-fluoro-5-methoxyphenyl)piperazin-1-yl]-2-(4-chloro-3-furan-3-yl-5-methyl Pyrazol-1-yl)ethanone

The title compound was obtained following Protocol AA: LCMS (ES): M+H 467.1; HPLC retention time = 4.98 minutes (Agilent Zorbax SB-C18, 2.1 x 50 mm, 5 μ, 35° C.) using a 4.5 minute gradient of 20-95% B , with a 1.1 minute wash at 95% B (A = 0.1% formic acid/5% acetonitrile/94.9% water, B = 0.08% formic acid/99.9% acetonitrile).

Scheme CC: One-pot HATU-involved coupling and azide reduction reactions

2-(5-aminomethyl-4-chloro-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(2,4-dichloro-5-methoxy-phenyl) -Piperazin-1-yl]-ethanone

In a 4 mL vial, 50 mg 1-(2,4-dichloro-5-methoxy-phenyl)-piperazine di-HCl salt (0.14 mmol, 1.0 eq), 48 mg (5-azidomethyl- 4-Chloro-3-trifluoromethyl-pyrazol-1-yl)-acetic acid (0.17mmol, 1.2eq), 100μL DIEA (0.57mmol, 4.0eq) and 65mg HATU (0.17mmol, 1.2eq) were mixed in 250μL DMF. After 4 hours, 157 mg (0.7 mmol) tin(II) chloride was added, the vial was sealed and heated in a 60°C oil bath overnight. The reaction was purified by preparative HPLC to afford the title compound: HPLC retention time = 5.01 min (Agilent Zorbax SB-C18, 2.1 x 50 mm, 5 μ, 35 °C), 2.0 min no gradient time with 20% B followed by 20-95 5.0 minute gradient of %B with 2.5 minute wash at 95% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.08% formic acid/99.9% acetonitrile); (M/Z)+= 496.7 (M+H).

2-(5-Aminomethyl-4-chloro-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(4-bromo-3-methoxy-phenyl)-piperazine -1-yl]-ethanone

1-(4-Bromo-5-methoxy-phenyl)-piperazine dihydrochloride and (5-azidomethyl-4-chloro-3-trifluoromethyl-pyridine Azol-1-yl)-acetic acid coupling, the crude product was reduced in situ with tin(II) chloride to give the title compound: HPLC retention time = 5.46 minutes (Agilent Zorbax SB-C18, 2.1×50mm, 5μ, 35°C), A 2.0 minute no-gradient time at 20% B was used, followed by a 5.0 minute gradient from 20-95% B with a 2.5 minute wash at 95% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B= 0.08% formic acid/99.9% acetonitrile); (M/Z)+=509.0 (M+H).

2-(5-aminomethyl-4-chloro-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(4-bromo-3-methoxy-phenyl)-2- Methyl-piperazin-1-yl]-ethanone

Using HATU, (S)-1-(4-bromo-3-methoxy-phenyl)-3-methyl-piperazine was reacted with (5-azidomethyl-4-chloro-3 -trifluoromethyl-pyrazol-1-yl)-acetic acid coupling, the crude mixture was treated with tin(II) chloride to give the title compound: HPLC retention time = 5.58 minutes (Agilent Zorbax SB-C18, 2.1×50mm, 5 μ , 35°C) with a 2.0-minute no-gradient time at 20% B, followed by a 5.0-minute gradient from 20-95% B, with a 2.5-minute wash at 95% B (A = 0.1% formic acid/5% acetonitrile/94.9 % water, B=0.08% formic acid/99.9% acetonitrile); (M/Z)-=443.9 (M-Br).

2-(5-Aminomethyl-4-chloro-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(4-chloro-2-fluoro-5-methoxy-phenyl )-piperazin-1-yl]-ethanone

1-(4-Chloro-2-fluoro-5-methoxy-phenyl)-piperazine and (5-azidomethyl-4-chloro-3-trifluoromethyl -pyrazol-1-yl)-acetic acid coupling, the crude mixture was treated with tin(II) chloride to give the title compound: HPLC retention time = 5.84 minutes (Agilent Zorbax SB-C18, 2.1 x 50mm, 5μ, 35°C), A 2.0 minute no-gradient time at 20% B was used, followed by a 5.0 minute gradient from 20-95% B with a 2.5 minute wash at 95% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B= 0.08% formic acid/99.9% acetonitrile); (M/Z)+=481.9 (M+H).

2-(5-Aminomethyl-4-chloro-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(4-chloro-3-methoxy-phenyl)-2- (S)-Methyl-piperazin-1-yl]-ethanone

Using HATU, (S)-1-(4-chloro-3-methoxy-phenyl)-3-methyl-piperazine was reacted with (5-azidomethyl-4-chloro-3 -trifluoromethyl-pyrazol-1-yl)-acetic acid coupling, the crude mixture was treated with tin(II) chloride to give the title compound: HPLC retention time = 5.74 minutes (Agilent Zorbax SB-C18, 2.1×50mm, 5 μ , 35°C) with a 2.0-minute no-gradient time at 20% B, followed by a 5.0-minute gradient from 20-95% B, with a 2.5-minute wash at 95% B (A = 0.1% formic acid/5% acetonitrile/94.9 % water, B=0.08% formic acid/99.9% acetonitrile); (M/Z)=487.8 (M+H).

Scheme DD: Preparation of compounds by methods involving palladium and copper

Synthesis of 2-(3-morpholinyl-4-chloro-5-methyl-pyrazol-1-yl)-1-[4-(4-chloro-3-methoxy-phenyl)-piperazine- 1-yl]-ethanone

At 110°C, heat 2-(3-bromo-4-chloro-5-methyl-pyrazol-1-yl)-1-[4-(4-chloro-3-methoxy-phenyl)-piper Azin-1-yl]-ethanone (46mg, 0.1mmol, 1equiv), morpholine (44mg, 45μL, 5equiv), rac-BINAP (20mg, 0.3equiv), Pd ₂ (dba) ₃ (10mg, 0.1 equiv) and K ₃ PO ₄ ·H ₂ O (138 mg, 6 equiv) in 1 mL of DMF overnight, then cooled to room temperature, dissolved in a 1:1 mixture of methanol and EtOAc, filtered through a thin layer of celite, and concentrated. The crude product was purified by reverse phase HPLC (acetonitrile- _H2O with 0.1% TFA as eluent) to yield 2-(3-morpholine-4-chloro-5-methyl-pyrazol-1-yl)- 1-[4-(4-Chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone. ¹ H NMR (400MHz, CDCl ₃ ) δ7.23(d, 1H), 6.50(d, 1H), 6.42(dd, 1H), 4.95(s, 1H), 3.90(s, 3H), 3.78(m, 8H), 3.20 (m, 8H), 2.30 (s, 3H). LCMS: (M+H) ⁺ observed 468.

Synthesis of 2-(4-chloro-5-methyl-pyrazol-1-yl)-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-B ketone

At 110°C, heat 2-(3-bromo-4-chloro-5-methyl-pyrazol-1-yl)-1-[4-(4-chloro-3-methoxy-phenyl)-piper Azin-1-yl]-ethanone (46mg, 0.1mmol, 1equiv), pyrrolidine (42mg, 42μL, 5equiv), rac-BINAP (20mg, 0.3equiv), Pd ₂ (dba) ₃ (10mg, 0.1 equiv) and K ₃ PO ₄ ·H ₂ O (138 mg, 6 equiv) in 1 mL of DMF overnight, then cooled to room temperature, dissolved in a 1:1 mixture of methanol and EtOAc, filtered through a thin layer of celite, and concentrate. The crude product was purified by reverse phase HPLC (acetonitrile- _H2O with 0.1% TFA as eluent) to yield 2-(4-chloro-5-methyl-pyrazol-1-yl)-1-[4- (4-Chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone. ¹ H NMR (400MHz, CDCl ₃ ) δ7.46(s, 1H), 7.30(d, 1H), 6.74(d, 1H), 6.60(dd, 1H), 5.08(s, 1H), 3.90(s, 3H), 3.88(m, 2H), 3.80(m, 2H), 3.34(m, 2H), 3.25(m, 2H), 2.20(s, 3H). LCMS: (M+H) ⁺ observed 383.

Synthesis of 3-methyl-4-cyano-5(trifluoromethyl)pyrazole

Mix 3-methyl-4-iodo-5-(trifluoromethyl)pyrazole (0.28g, 1mmol) and copper (I) cyanide (0.9g, 10mmol) in 1mL DMF, stir at 150°C for 1 Hour. With stirring, the reaction mixture was poured slowly into 30 mL of heated EtOAc/MeOH, and the solids were removed by filtration. The mixture was partitioned between EtOAc and saturated NaHCO ₃ and the phases were separated. The ethyl _acetate phase was washed with brine, dried over _Na2SO4 , and concentrated to provide the title product.

Synthesis of 1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-(4-methylsulfonyl-5-methyl-3-trifluoromethyl- Pyrazol-1-yl)-ethanone

The title compound was prepared by mixing 1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-(4- Iodo-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-ethanone (109mg, 0.2mmol), _NaSO2Me (61mg, 0.6mmol) and CuI (114mg, 0.6mmol) for 3 hours . The crude reaction was purified by HPLC: HPLC retention time = 4.21 min (Agilent Zorbax SB-C18, 2.1 x 50 mm, 5 μ, 35 °C) using a 4.5 min gradient from 20-95% B at 95% B in 1.1 min (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.08% formic acid/99.9% acetonitrile); MS(ES) M+H expected = 495.1, found = 495.4.

Synthesis of 3-methylsulfonyl-4-chloro-5-methyl-pyrazole

A mixture of 3-iodo-4-chloro-5-methyl-pyrazole (48 mg, 0.2 mmol, 1 equiv), _NaSO2Me (72 mg, 3 equiv) and CuI (114 mg, 3 equiv) in 1 mL of DMSO was heated at 110 °C 3 hours, then cooled to room temperature, dissolved in a 1:1 mixture of methanol and EtOAc, filtered through a thin layer of celite, and concentrated. The residue was dissolved in EtOAc and washed with water. _The organic layer was dried over _Na2SO4 , filtered and concentrated. The crude product was used in the next step without purification.

Synthesis of 1-(4-chloro-1-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-5- Methyl-1H-pyrazol-3-yl)-pyrrolidin-2-one

110°C, heat 2-(3-bromo-4-chloro-5-methyl-pyrazol-1-yl)-1-[4-(4-chloro-3-methoxy in 1 mL of dioxane -phenyl)-piperazin-1-yl]-ethanone (92 mg, 0.2 mmol, 1 equiv), 2-pyrrolidone (17 mg, 1 equiv), N,N-dimethylethylenediamine (5.3 mg, 0.3 equiv) , CuI (12 mg, 0.3 equiv) and _Cs2CO3 (130 mg, 2 equiv) overnight, then cooled to room temperature, dissolved in a 1:1 _mixture of methanol and EtOAc, filtered through a thin layer of celite, and concentrated. The crude product was purified by reverse phase HPLC (acetonitrile- _H2O with 0.1% TFA as eluent) to yield 1-(4-chloro-1-{2-[4-(4-chloro-3-methoxy -phenyl)-piperazin-1-yl]-2-oxo-ethyl}-5-methyl-1H-pyrazol-3-yl)-pyrrolidin-2-one. ¹ H NMR (400MHz, CDCl ₃ ) δ7.32(d, 1H), 6.78(d, 1H), 6.65(dd, 1H), 4.93(s, 2H), 3.90(s, 3H), 3.88(m, 6H), 3.35(m, 2H), 3.28(m, 2H), 2.60(m, 2H), 3.30(s, 3H), 2.24(m, 2H). LCMS: (M+H) ⁺ observed 466.

Synthesis of 2-(3-methylsulfonyl-4-chloro-5-methyl-pyrazol-1-yl)-1-[4-(4-chloro-3-methoxy-phenyl)-piperazine -1-yl]-ethanone

110°C, heat 2-(3-bromo-4-chloro-5-methyl-pyrazol-1-yl)-1-[4-(4-chloro-3-methoxy-benzene) in 1 mL DMSO base)-piperazin-1-yl]-ethanone (46mg, 0.1mmol, 1equiv), a mixture of NaSO ₂ Me (36mg, 3equiv) and CuI (57mg, 3equiv) overnight, then cooled to room temperature, dissolved in 1: 1 in a mixture of methanol and EtOAc, filtered through a thin layer of celite, and concentrated. The crude product was purified by reverse phase HPLC (acetonitrile- _H2O with 0.1% TFA as eluent) to yield 2-(3-methylsulfonyl-4-chloro-5-methyl-pyrazol-1-yl )-1-[4-(4-Chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone. ¹ H NMR (400MHz, CDCl ₃ ) δ7.38(d, 1H), 6.82(d, 1H), 6.70(dd, 1H), 5.18(s, 2H), 3.92(m, 4H), 3.90(s, 3H), 3.40(m, 2H), 3.36(m, 2H), 3.19(s, 3H), 2.34(s, 3H). LCMS: (M+H) ⁺ observed 461.

Synthesis of 2-[4-chloro-3-(2-phenyl)imidazol-1-yl-5-methyl-pyrazol-1-yl]-1-[4-(4-chloro-3-methoxy -Phenyl)-piperazin-1-yl]-ethanone

110°C, heat 2-(3-iodo-4-chloro-5-methyl-pyrazol-1-yl)-1-[4-(4-chloro-3-methoxy-benzene) in 1 mL DMSO Base)-piperazin-1-yl]-ethanone (102mg, 0.2mmol, 1equiv), 2-phenylimidazole (86mg, 3equiv), 8-hydroxyquinoline (5.8mg, 0.2equiv), CuI (7.6mg , 0.2 equiv) and _K2CO3 (42 mg, 1.5 equiv) for two nights, then cooled to room temperature, dissolved in a 1:1 _mixture of methanol and EtOAc, filtered through a thin layer of celite, and concentrated. The crude product was purified by reverse phase HPLC to give the title compound: LCMS retention time: 4.04 min (Agilent Zorbax SB-C18, 2.1 x 50 mm, 5 μ, 35 °C) using a 4.5 min gradient from 20-95% B at 95% B 1.1 min wash (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.08% formic acid/99.9% acetonitrile); LCMS: (M+H) ⁺ observed 525.

Synthesis of 2-(4-chloro-3-[1,2,3]triazol-1-yl-5-methyl-pyrazol-1-yl)-1-[4-(4-chloro-3-methyl Oxy-phenyl)-piperazin-1-yl]-ethanone

110°C, heat 2-(3-iodo-4-chloro-5-methyl-pyrazol-1-yl)-1-[4-(4-chloro-3-methoxy-benzene) in 1 mL DMSO base)-piperazin-1-yl]-ethanone (102mg, 0.2mmol, 1equiv), 1,2,3-triazole (42mg, 3equiv), 8-hydroxyquinoline (5.8mg, 0.2equiv), CuI (7.6 mg, 0.2 equiv) and K ₂ CO ₃ (42 mg, 1.5 equiv) for two nights, then cooled to room temperature, dissolved in a 1:1 mixture of methanol and EtOAc, filtered through a thin layer of Celite, and concentrated. The crude product was purified by reverse phase HPLC to yield the title compound: LCMS retention time = 3.93 min (Agilent Zorbax SB-C18, 2.1 x 50 mm, 5 μ, 35 °C) using a 4.5 min gradient from 20-95% B at 95% B 1.1 min wash (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.08% formic acid/99.9% acetonitrile); LCMS: (M+H) ⁺ observed 450.

Synthesis of 2-(3-cyano-4-chloro-5-methyl-pyrazol-1-yl)-1-[4-(4-chloro-3-methoxy-phenyl)-piperazine-1 -yl]-ethanone

175°C, heat 2-(3-iodo-4-chloro-5-methyl-pyrazol-1-yl)-1-[4-(4-chloro-3-methoxy-benzene) in 1 mL DMF yl)-piperazin-1-yl]-ethanone (51 mg, 0.1 mmol, 1 equiv) and CuCN (180 mg, 20 equiv) for 1 h, then cooled to room temperature and dissolved in a 1:1 mixture of methanol and EtOAc , filtered through a thin layer of celite, and concentrated. The crude product was purified by reverse phase HPLC (acetonitrile- _H2O with 0.1% TFA as eluent) to yield 2-(3-cyano-4-chloro-5-methyl-pyrazol-1-yl)- 1-[4-(4-Chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone. ¹ H NMR (400MHz, CDCl ₃ ) δ7.30(d, 1H), 6.65(d, 1H), 6.56(dd, 1H), 5.02(s, 2H), 3.90(s, 3H), 3.88(m, 2H), 3.80(m, 2H), 3.35(m, 2H), 3.28(m, 2H), 2.32(s, 3H).

Synthesis of 2-[4-chloro-3-(2-methylimidazol-1-yl)-5-methyl-pyrazol-1-yl]-1-[4-(4-chloro-3-methoxy -Phenyl)-piperazin-1-yl]-ethanone

110°C, heat 2-(3-iodo-4-chloro-5-methyl-pyrazol-1-yl)-1-[4-(4-chloro-3-methoxy-benzene) in 1 mL DMSO Base)-piperazin-1-yl]-ethanone (102mg, 0.2mmol, 1equiv), 2-methylimidazole (32mg, 2equiv), 8-hydroxyquinoline (5.8mg, 0.2equiv), CuI (7.6mg , 0.2 equiv) and _K2CO3 (42 mg, 1.5 equiv) for two nights, then cooled to room temperature, dissolved in a 1:1 _mixture of methanol and EtOAc, filtered through a thin layer of celite, and concentrated. The crude product was purified by reverse phase HPLC (acetonitrile-H ₂ O with 0.1% TFA as eluent) to give the title compound: ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.92 (s, 1H), 7.66 (d, 1H), 7.40(d, 1H), 7.28(d, 1H), 7.21(d, 1H), 6.53(d, 1H), 6.42(dd, 1H), 5.00(s, 2H), 3.90(s, 3H ), 3.80(m, 2H), 3.71(m, 2H), 3.28(m, 2H), 3.20(m, 2H), 2.72(s, 3H), 2.37(s, 3H); LCMS: (M+H ) ⁺ observation 463.

Synthesis of 2-[4-chloro-3-(4-methylimidazol-1-yl)-5-methyl-pyrazol-1-yl]-1-[4-(4-chloro-3-methoxy -Phenyl)-piperazin-1-yl]-ethanone

According to the same method as in previous examples, 2-(3-iodo-4-chloro-5-methyl-pyrazol-1-yl)-1-[4-(4-chloro-3-methoxy-benzene Base)-piperazin-1-yl]-ethanone is coupled with 4-methylimidazole to give the title compound: ¹ HNMR (400MHz, CDCl3) δ8.93(s, 1H), 7.40(s, 1H), 7.20( d, 1H), 6.52(d, 1H), 6.44(dd, 1H), 5.00(m, 2H), 3.90(s, 3H), 3.80(m, 2H), 3.73(m, 2H), 3.28(m , 2H), 3.20 (m, 2H), 2.47 (s, 3H), 2.35 (m, 3H); LCMS: (M+H) ⁺ observed 463.

Synthesis of 2-(4-chloro-3-benzimidazol-1-yl-5-methyl-pyrazol-1-yl)-1-[4-(4-chloro-3-methoxy-phenyl) -Piperazin-1-yl]-ethanone

According to the same method as in previous examples, 2-(3-iodo-4-chloro-5-methyl-pyrazol-1-yl)-1-[4-(4-chloro-3-methoxy-benzene yl)-piperazin-1-yl]-ethanone coupled with benzimidazole to give the title compound: ¹ HNMR (400MHz, CDCl ₃ ) δ9.13(s, 1H), 8.00(m, 1H), 7.80(m , 1H), 7.53(m, 2H), 7.22(d, 1H), 6.52(d, 1H), 6.44(dd, 1H), 5.06(s, 2H), 3.88(s, 3H), 3.84(m, 2H), 3.76 (m, 2H), 3.26 (m, 2H), 3.22 (m, 2H), 2.40 (s, 3H); LCMS: (M+H) ⁺ observed 499.

Synthesis of 2-(4-chloro-3-pyrazol-1-yl-5-methyl-pyrazol-1-yl)-1-[4-(4-chloro-3-methoxy-phenyl)- Piperazin-1-yl]-ethanone

According to the same method as in previous examples, 2-(3-iodo-4-chloro-5-methyl-pyrazol-1-yl)-1-[4-(4-chloro-3-methoxy-benzene yl)-piperazin-1-yl]-ethanone is coupled with pyrazole to give the title compound: ¹ H NMR (400MHz, CDCl ₃ ) δ8.00(br, 1H), 7.63(br, 2H), 7.40(d , 1H), 7.18(d, 1H), 6.42(br, 1H), 5.40(br, 2H), 4.40(br, 2H), 4.24(br, 2H), 3.90(s, 3H), 3.55(br, 2H), 3.36 (br, 2H), 2.36 (s, 3H); LCMS: (M+H) ⁺ observed 449.

Synthesis of 2-[4-chloro-3-(3-methyl)-pyrazol-1-yl-5-methyl-pyrazol-1-yl]-1-[4-(4-chloro-3-methyl Oxy-phenyl)-piperazin-1-yl]-ethanone

According to previous examples, 2-(3-iodo-4-chloro-5-methyl-pyrazol-1-yl)-1-[4-(4-chloro-3-methoxy-phenyl)-piper Coupling of azin-1-yl]-ethanone with 3-methylpyrazole affords the title compound: ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.97 (d, 1H), 7.30 (d, 1H), 6.74 (d , 1H), 6.60(dd, 1H), 6.24(d, 1H), 5.00(s, 2H), 3.82(s, 3H), 3.80(m, 4H), 3.33(m, 2H), 3.24(m, 2H), 2.37(s, 3H), 2.30(s, 3H); LCMS: (M+H) ⁺ observed 463.

Synthesis of 2-[4-chloro-3-(3-trifluoromethyl)-pyrazol-1-yl-5-methyl-pyrazol-1-yl]-1-[4-(4-chloro-3 -methoxy-phenyl)-piperazin-1-yl]-ethanone

According to previous examples, 2-(3-iodo-4-chloro-5-methyl-pyrazol-1-yl)-1-[4-(4-chloro-3-methoxy-phenyl)-piper Coupling of oxazin-1-yl]-ethanone with 3-trifluoromethylpyrazole gave the title compound: ¹ H NMR (400MHz, CDCl ₃ ) δ8.08(d, 1H), 7.30(d, 1H), 6.73 (d, 1H), 6.70(d, 1H), 6.60(dd, 1H), 5.10(s, 2H), 3.90(s, 3H), 3.89(m, 4H), 3.30(m, 4H), 2.38( s, 3H); LCMS: (M+H) ⁺ observed 517.

Synthesis of 1-(4-chloro-1-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-5- Methyl-1H-pyrazol-3-yl)-1H-pyridin-2-one

According to the previous examples, 3-iodo-4-chloro-5-methyl-pyrazol-1-yl)-1-[4-(4-chloro-3-methoxy-phenyl)-piperazine-1 -Yl]-ethanone was coupled with 2-hydroxypyridine to give the title compound: ¹ H NMR (400MHz, CDCl ₃ ) δ8.19 (m, 1H), 7.74 (m, 1H), 7.22 (d, 1H), 7.06 (m, 2H), 6.60(d, 2H), 6.48(dd, 1H), 4.92(s, 2H), 3.90(s, 3H), 3.80(m, 4H), 3.70(m, 2H), 3.22( m, 2H), 2.32 (s, 3H); LCMS: (M+H) ⁺ observed 476.

Synthesis of 1-[4-(4-chloro-3-hydroxy-phenyl)-piperazin-1-yl]-2-[4-chloro-5-methyl-3-(pyridin-2-yloxy)- Pyrazol-1-yl]-ethanone

The title compound was isolated from the previous reaction: ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.50-7.00 (m, 5H), 6.58 (d, 1H), 6.23 (d, 1H), 4.95 (s, 2H), 4.20 -4.00(m, 4H), 3.95(s, 3H), 3.42(m, 2H), 3.36(m, 2H), 2.40(s, 3H). LCMS: (M+H) ⁺ observed 476.

Scheme EE: General procedure for oxazole substitution on pyrazoles:

4-chloro-1-{2-[4-(4-chloro-3-methoxyphenyl)piperazin-1-yl]-2-oxoethyl}-5-methyl-1H-pyrazole -3-formyl chloride

To the 4-bromo-1-{2-[4-(4-chloro-3-methoxyphenyl)-2-methylpiperazin-1-yl]-2-oxyethyl} obtained in the last-reaction - A solution of 5-methyl-1H-pyrazole-3-carboxylic acid in _CH2Cl2 (1 _mL ) was added oxalyl chloride (1 mL). The reaction mixture was stirred at 60°C for 12 hours, cooled to room temperature and evaporated in vacuo to provide the title compound which was used directly.

1-[4-(4-chloro-3-methoxyphenyl)piperazin-1-yl]-2-(4-chloro-5-methyl-3-oxazol-2-yl-pyrazole- 1-yl) ethyl ketone

Heating the 4-chloro-1-{2-[4-(4-chloro-3-methoxyphenyl)piperazin-1-yl]-2-oxoethyl}-5-methanol obtained in the last reaction A mixture of yl-1H-pyrazole-3-carbonyl chloride, 1,2,3-triazole (0.008 mL) and K ₂ CO ₃ (41 mg) in sulfolane (0.5 mL) was kept at 140° C. for 10 minutes, Cool to room temperature. The residue was purified by preparative HPLC to provide the title compound. ¹ H NMR: δ(400MHz, CDCl ₃ )(400MHz, CDCl ₃ ) 7.71(d, 1H), 7.29(d, 1H), 7.22(s, 1H), 6.48(d, 1H), 6.44(dd, 1H ), 5.06 (s, 2H), 3.89 (s, 3H), 3.86 (m, 4H), 3.19 (m, 4H), 2.35 (s, 3H). LCMS (ES): M+H 450.1; HPLC retention time = 4.45 minutes (Agilent Zorbax SB-C18, 2.1 x 50 mm, 5 μ, 35° C.) using a 4.5 minute gradient of 20-95% B at 95% B 1.1 minute wash (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.08% formic acid/99.9% acetonitrile).

Scheme FF: General synthetic method for substitution on pyrazole with 1.3,4-oxadiazole:

Synthesis of 1-[4-(4-chloro-3-methoxyphenyl)piperazin-1-yl]-2-(4-chloro-5-methyl-3-[1,3,4]-di Azol-2-yl-pyrazol-1-yl)ethanone

Step Blue 1: To a solution of pyrazole carboxylate (140 mg) in MeOH (20 mL) was added hydrazine hydrate (2 mL). The reaction mixture was stirred at 25°C for 2 hours and evaporated in vacuo to provide the corresponding hydrazine which was used directly.

Step 2: The above hydrazide was dissolved in trimethyl orthoformate (30 mL), stirred and heated to 80° C. for 3 hours under positive pressure nitrogen flow. The reaction mixture was cooled to room temperature and evaporated in vacuo. The residue was purified by preparative HPLC to provide the title compound: ¹ H NMR: δ (400 MHz, CDCl ₃ ) 8.46 (s, 1H), 7.22 (d, 1H), 6.49 (s, 1H), 6.35 (dd, 1H ), 5.09 (s, 2H), 3.89 (s, 3H), 3.76 (m, 4H), 3.20 (m, 4H), 2.36 (s, 3H). LCMS (ES): M+H 451.1; HPLC retention time = 4.13 minutes (Agilent Zorbax SB-C18, 2.1 x 50 mm, 5 μ, 35° C.), using a 4.5 minute gradient of 20-95% B at 95% B A 1.1 minute wash was used (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.08% formic acid/99.9% acetonitrile).

Synthesis of 1-[4-(4-chloro-3-methoxyphenyl)-2-(S)-methylpiperazin-1-yl]-2-(4-chloro-5-methyl-3- [1,3,4]-oxadiazol-2-ylpyrazol-1-yl)ethanone

The title compound was obtained according to the same scheme as in the preceding examples: LCMS (ES): M+H 465.1: HPLC retention time=5.02 minutes (Agilent Zorbax SB-C18, 2.1×50mm, 5μ, 35°C), using 20-95% 4.5 minute gradient of B with a 1.1 minute wash at 95% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.08% formic acid/99.9% acetonitrile).

Synthesis of 1-[4-(4-chloro-3-methoxyphenyl)piperazin-1-yl]-2-[4-chloro-5-methyl-3-(5-methyl-[1, 3,4]oxadiazol-2-yl)pyrazol-1-yl]ethanone

The title compound was obtained according to the same scheme as in previous examples: using trimethyl orthoacetate: LCMS (ES): M+H 465.3; HPLC retention time=3.90 minutes (Agilent Zorbax SB-C18, 2.1×50mm, 5 μ, 35° C. ) with a 4.5 minute gradient of 20-95% B, with a 1.1 minute wash at 95% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.08% formic acid/99.9% acetonitrile).

Scheme GG: General synthetic method for oxazole substitution on pyrazole:

Synthesis of 1-[4-(4-chloro-3-methoxyphenyl)piperazin-1-yl]-2-[4-chloro-5-methyl-3-(4-methyl-azole-2 -yl)pyrazol-1-yl]ethanone

Step 1: Following Scheme P, the pyrazole carboxylic acid is coupled with 2-aminopropanal dimethyl acetal to provide the corresponding amide.

Step 2: The above amide was dissolved in POCl ₃ and heated to 90° C. for 24 hours. The reaction mixture was cooled to room temperature and evaporated in vacuo. The residue was purified by preparative HPLC to provide the title compound: LCMS (ES): M+H 464.3; HPLC retention time = 4.22 min (Agilent Zorbax SB-C18, 2.1 x 50mm, 5μ, 35°C) using 20-95% 4.5 minute gradient of B with a 1.1 minute wash at 95% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.08% formic acid/99.9% acetonitrile).

Scheme HH: Coupling of terminal alkynes to 3-halopyrazoles via the Sonagashira method

Synthesis of 2-[4-chloro-3-(3-hydroxy-prop-1-ynyl)-5-methyl-pyrazol-1-yl]-1-[4-(4-chloro-3-methoxy Base-phenyl)-2-(S)-methyl-piperazin-1-yl]-ethanone:

In a nitrogen atmosphere, to 100mg (0.21mmol) 2-(3-bromo-4-chloro-5-methyl-pyrazole-1- Base)-1-[4-(4-chloro-3-methoxy-phenyl)-2-(S)-methyl-piperazin-1-yl]-ethanone, 0.12mL (2.0mmol) alkyne Propanol, 4mg (0.02mmol) cuprous iodide, 43mg (0.30mmol) potassium carbonate and 23mg (0.02mmol) tetrakis-triphenylphosphine palladium (O), add 0.2mL triethylamine, seal the container, and heat at 135°C The mixture was left for 4 hours. The mixture was cooled to ambient temperature and partitioned between ethyl acetate and water. The phases were separated and the aqueous phase was back extracted once with ethyl acetate. The combined ethyl acetate phases were washed once each with water, 1M phosphate buffer pH=7 and brine, dried over sodium sulfate and concentrated. The residue was purified by chromatography to give the title compound: LCMS (ES) M+H = 451.2; HPLC retention time = 4.49 minutes (Agilent Zorbax SB-C18, 2.1 x 50 mm, 5 μ, 35 °C), using 20-95% B A 4.5 minute gradient at 95% B with a 1.1 minute wash (A = 0.1% formic acid/5% acetonitrile/94.9% water, B = 0.08% formic acid/99.9% acetonitrile).

Synthesis of 2-[4-chloro-3-(3-hydroxy-prop-1-ynyl)-5-methyl-pyrazol-1-yl]-1-[4-(4-chloro-3-methoxy Base-phenyl)-piperazin-1-yl]-ethanone:

According to scheme HH, 2-(3-bromo-4-chloro-5-methyl-pyrazol-1-yl)-1-[4-(4-chloro-3-methoxy-phenyl)-piperazine -1-yl]-ethanone is cross-coupled with propargyl alcohol to obtain the title compound: LCMS (ES) M+H=437.1; HPLC retention time=4.24 minutes (Agilent Zorbax SB-C18, 2.1×50mm, 5μ, 35°C ) with a 4.5 minute gradient of 20-95% B, with a 1.1 minute wash at 95% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.08% formic acid/99.9% acetonitrile).

Synthesis of 2-(4-chloro-3-ethynyl 5-methyl-pyrazol-1-yl)-1-(4-chloro-3-methoxyphenyl)-piperazin-1-yl)ethanone

TMS acetylene cross-coupling to 2-(4-chloro-3-iodo-5-methyl-pyrazol-1-yl)-1-[4-(4-chloro-3-methoxy-benzene) following Scheme HH yl)-piperazin-1-yl]-ethanone to give a TMS-protected terminal alkyne: LC MS 479 (M ⁺ , method 20-95, RT=5.43 minutes); ¹ H NMR (400MHz, CDCl ₃ ): δ0.24(s, 9H), 2.25(s, 3H), 3.12(apparent q, J=4.8Hz, 4H), 3.68(t, J=5.1Hz, 2H), 3.74(t, J=5.1Hz, 2H), 3.87(s, 3H), 4.92(s, 2H), 6.40(dd, J=2.5 & 8.8Hz, 1H), 6.46(d, J=2.5Hz, 1H), 7.20(d, J=8.4 Hz, 1H).

To a solution of the TMS-protected alkyne from above (480 mg, 1 mmol) in THF (2 mL) was added TBAF (1.4 mL, 1.4 mmol) at 0°C under nitrogen. After 2 hours, the reaction was quenched with saturated aqueous _NH4Cl and extracted with _Et2O (4 x 20 mL). _The combined ether layers were dried ( _Na2SO4 ), and concentrated. The residue was purified by chromatography to obtain the title compound: LC MS 407 (M ⁺ , method 20-95, RT = 4.42 minutes); ¹ H NMR (400 MHz, CDCl ₃ ): δ2.23 (s, 3H), 3.14- 3.18(m, 4H), 3.22(s, 1H), 3.69(t, J=4.8Hz, 2H), 3.74(t, J=5.1Hz, 2H), 3.87(s, 3H), 4.93(s, 2H ), 6.40-6.43 (m, 1H), 6.46 (d, J=2.6Hz, 1H), 7.20 (d, J=8.3Hz, 1H).

Scheme II: Preparation of oxo-pyridine species:

Synthesis of (4-chloro-5-methyl-3-pyridin-3-yl-pyrazol-1-yl)-ethyl acetate:

1.92gm (9.95mmol) of 3-(3-pyridyl)-4-chloro-5-methylpyrazole, 1.62gm (11.75mmol) of potassium carbonate and 1.51gm (9.04mmol) of ethyl bromoacetate in 25mL of anhydrous N , N-dimethylformamide, and the mixture was heated at 85°C for 4 hours. The mixture was then cooled to ambient temperature, partitioned between 1 M phosphate buffer, pH=7, and ethyl acetate, and the phases were separated. The ethyl acetate phase was washed twice with _water , once with brine, dried over _Na2SO4 , filtered, and concentrated in vacuo. The residue was purified by chromatography to afford the title compound.

Synthesis of [4-chloro-5-methyl-3-(1-oxo-pyridin-3-yl)-pyrazol-1-yl]-acetic acid ethyl ester:

Dissolve 370 mg (1.32 mmol) of (4-chloro-5-methyl-3-pyridin-3-yl-pyrazol-1-yl)-ethyl acetate in 6 mL of anhydrous dichloromethane, and cool the solution to 0 °C, 320 mg (1.85 mmol) of about 77% m-chloroperbenzoic acid was added. After 30 minutes, the flask was removed from the ice-water bath and allowed to warm to room temperature. After 3 hours, the reaction was partitioned between ethyl acetate and saturated sodium bicarbonate and the phases were separated. The ethyl acetate phase was dried over Na2SO4, filtered and concentrated in vacuo. After triturating with ether, the solid was isolated by filtration to give the title compound.

Synthesis of [4-chloro-5-methyl-3-(1-oxo-pyridin-3-yl)-pyrazol-1-yl]-sodium acetate:

At 50°C, 170mg (0.58mmol) of [4-chloro-5-methyl-3-(1-oxidation-pyridin-3-yl)-pyrazol-1-yl]-ethyl acetate and 46mg (1.6mmol ) sodium hydroxide was mixed in 2.3 mL of anhydrous methanol. After 30 minutes, the reaction was complete and the flask was allowed to cool to room temperature. The slurry was diluted with ethyl acetate and the solid was isolated by filtration to give the title compound.

[4-Chloro-5-methyl-3-(1-oxypyridin-4-yl)-pyrazol-1-yl]-acetic acid

The title compound according to Scheme II.

Scheme JJ: Synthesis of heteroaryl-substituted pyrazoles via cycloaddition and cyclization:

Synthesis of 2-(4-chloro-3-tetrazol-5-yl-5-methyl-pyrazol-1-yl)-1-[4-(4-chloro-3-methoxy-phenyl)- Piperazin-1-yl]-ethanone

2-(3-Cyano-4-chloro-5-methyl-pyrazol-1-yl)-1-[4-(4-chloro-3-methoxy-phenyl)-piperazine-1- [Ethyl]-ethanone (41 mg, 0.1 mmol, 1 equiv), NaN ₃ (130 mg, 2 equiv) and NH ₄ Cl (110 mg, 2 equiv) in 1 mL of DMF was heated at 130° C. for 3 hours and then cooled to room temperature. The crude product was purified by reverse phase HPLC (acetonitrile- _H2O with 0.1% TFA as eluent) to yield the title compound: ¹ H NMR (400 MHz, CDCl3) δ 7.35 (d, 1H), 6.82 (d, 1H ), 6.70(dd, 1H), 5.12(s, 2H), 3.90(s, 3H), 3.88(m, 4H), 3.50(m, 2H), 3.34(m, 2H), 2.33(s, 3H) ; LCMS: (M+H) ⁺ observed 451.

Synthesis of 2-[4-chloro-5-methyl-3-[1,2,3]-oxadiazol-3-yl-pyrazol-1-yl]-1-[4-(4-chloro-3- Methoxy-phenyl)-piperazin-1-yl]-ethanone

50°C, heat 2-(3-cyano-4-chloro-5-methyl-pyrazol-1-yl)-1-[4-(4-chloro-3-methoxy- A mixture of phenyl)-piperazin-1-yl]-ethanone (41 mg, 0.1 mmol, 1 equiv), _NH2OH ·HCl (35 mg, 5 equiv) and _Et3N (140 μL, 10 equiv) for 2 h, then cooled to room temperature . The white solid was collected and treated with trimethyl formate (1 mL) and crystals 1 of PTSA at 50°C for 2 hours. Reverse phase HPLC (acetonitrile-H ₂ O with 0.1% TFA as eluent) gave the title compound: ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.80 (s, 1H), 7.30 (d, 1H), 6.72 ( d, 1H), 6.62(dd, 1H), 5.18(s, 2H), 3.90(s, 3H), 3.92(m, 2H), 3.80(m, 2H), 3.38(m, 2H), 3.30(m , 2H), 2.39 (s, 3H); LCMS: (M+H) ⁺ observed 451.

Scheme KK: Synthesis of Compounds Using Negishi Coupling Reaction

Synthesis of 1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-[4-chloro-5-methyl-3-(1-methyl-1H -imidazol-2-yl)-pyrazol-1-yl]-ethanone

1-Methylimidazole (48 mg, 1.5 equiv) in 10 mL THF was treated with BuLi (2.5 M in hexane, 0.28 mL, 1.5 equiv) for 1 h at -78 °C. _ZnCl2 (1M in ether (1.8mL, 4.5equiv) was added and the mixture was stirred at 0°C for 1 hour. 2-(3-iodo-4-chloro-5-methyl-pyrazol-1-yl)- 1-[4-(4-Chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone (204 mg, 0.4 mmol, 1 equiv) and Pd(PPh3)4 (46 mg, 0.1 equiv) The resulting mixture was refluxed overnight, cooled to room temperature, quenched with water and extracted with EtOAc. The organic layer was purified by reverse phase HPLC to yield the title compound: LCMS retention time: 3.3 min (Agilent Zorbax SB-C18, 2.1 x 50 mm, 5 μ, 35°C) with a 4.5 minute gradient of 20-95% B, with a 1.1 minute wash at 95% B (A = 0.1% formic acid/5% acetonitrile/94.9% water, B = 0.08% formic acid/99.9% acetonitrile) ; LCMS: (M+H) ⁺ observed 463.

Scheme LL: Mannich addition to aromatic ring

1-[4-(4-chloro-5-methoxy-2-methylaminomethyl-phenyl)-piperazin-1-yl]-2-(4-chloro-5-methyl-3- Trifluoromethyl-pyrazol-1-yl)-ethanone

250 mg of 1-[4-(4-chloro-5-methoxyphenyl)-piperazin-1-yl]-2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazole- 1-yl)-ethanone (0.55mmol, 1.0eq), 374mg methylamine HCl (5.5mmol, 10.0eq), 414 μL of 37% formaldehyde in _H2O (5.5mmol, 10.0eq) and 1 mL of DME in a 4mL Mix in vial. The mixture was heated in an oil bath at 60 °C overnight and purified by preparative HPLC: LC/MS (ES) (M+H) 494.4; HPLC retention time = 5.71 min (Agilent Zorbax SB-C18, 2.1 x 50 mm, 5 μ, 35 °C) , with a 2.0-minute no-gradient time at 20% B, followed by a 5.0-minute gradient from 20-95% B with a 2.5-minute wash at 95% B (A = 0.1% formic acid/5% acetonitrile/94.9% water, B = 0.08% formic acid/99.9% acetonitrile).

Example 3

The preferred protocol in the following examples is that described in Example 3.

Scheme A: Metal-catalyzed arylation of secondary amines

Synthesis of 1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-(4-chloro-5-methyl-3-piperazin-1-yl- Pyrazol-1-yl)-ethanone

According to protocol A of Example 1, at 70 ° C, heat 2-(3-iodo-4-chloro-5-methyl-pyrazol-1-yl)-1-[4-(4- Chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone (204mg, 1eq), piperazine (430mg, 10eq, 9,9-dimethyl-4,5-bis(benzene A mixture of Xantphos) (40mg, 0.3eq), Pd ₂ (dba) ₃ (72mg, 0.1eq) and Cs ₂ CO ₃ (200mg, 1.5eq) overnight, then cooled to room temperature, dissolved in EtOAc, washed with water. The organic layer was purified by reverse phase HPLC (acetonitrile-H ₂ O with 0.1% TFA as eluent) to give the title compound: LCMS retention time: 3.07 minutes (Agilent Zorbax SB-C18, 2.1×50 mm, 5 μ , 35°C), using a 4.5-minute gradient of 20-95% B, with a 1.1-minute wash at 95% B (A = 0.1% formic acid/5% acetonitrile/94.9% water, B = 0.08% formic acid/99.9% acetonitrile ); LCMS: (M+H) ⁺ observed 467.

Synthesis of 1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-(4-chloro-5-methyl-3-pyrrolidin-1-yl- Pyrazol-1-yl)-ethanone

The title compound was prepared according to one variation of Scheme A. LCMS retention time: 4.77 minutes (Agilent Zorbax SB-C18, 2.1 × 50mm, 5μ, 35°C), using a 4.5-minute gradient of 20-95% B, and a 1.1-minute wash at 95% B (A = 0.1% formic acid/ 5% acetonitrile/94.9% water, B = 0.08% formic acid/99.9% acetonitrile); LCMS: 452 observed for (M+H) ⁺ .

Synthesis of 1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-(4-chloro-5-methyl-4-piperidin-1-yl- Pyrazol-1-yl)-ethanone

The title compound was prepared according to one variation of Scheme A. LCMS retention time: 5.07 minutes (Agilent Zorbax SB-C18, 2.1 × 50mm, 5μ, 35°C), using a 4.5-minute gradient of 20-95% B, and a 1.1-minute wash at 95% B (A = 0.1% formic acid/ 5% acetonitrile/94.9% water, B = 0.08% formic acid/99.9% acetonitrile); LCMS: (M+H) ⁺ observed 466.

Synthesis of 1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-[4-chloro-5-methyl-3-(4-methyl-piper Azin-1-yl)-pyrazol-1-yl]-ethanone

The title compound was prepared according to one variation of Scheme A. LCMS retention time: 3.24 minutes (Agilent Zorbax SB-C18, 2.1 × 50mm, 5μ, 35°C), using a 4.5-minute gradient of 20-95% B, with a 1.1-minute wash at 95% B (A = 0.1% formic acid/ 5% acetonitrile/94.9% water, B = 0.08% formic acid/99.9% acetonitrile); LCMS: (M+H) ⁺ observed 481.

Synthesis of 2-[4-chloro-3-(1,1-dioxo-1λ*6*-thiomorpholin-4-yl)-5-methyl-pyrazol-1-yl]-1-[ 4-(4-Chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone

The title compound was prepared according to one variation of Scheme A. LCMS retention time: 4.26 minutes (Agilent Zorbax SB-C18, 2.1 × 50mm, 5 μ, 35°C), using a 4.5-minute gradient of 20-95% B, and a 1.1-minute wash at 95% B (A = 0.1% formic acid/ 5% acetonitrile/94.9% water, B=0.08% formic acid/99.9% acetonitrile); LCMS: (M+H) ⁺ observed 516.

Synthesis of 2-(4-chloro-3-dimethylamino-5-methyl-pyrazol-1-yl)-1-[4-(4-chloro-3-methoxy-phenyl)-piperazine -1-yl]-ethanone

The title compound was prepared according to one variation of Scheme A. LCMS retention time: 5.29 minutes (Agilent Zorbax SB-C18, 2.1×50 mm, 5 μ, 35° C.), using a 4.5-minute gradient of 20-95% B, with a 1.1-minute wash at 95% B (A=0.1% formic acid/ 5% acetonitrile/94.9% water, B = 0.08% formic acid/99.9% acetonitrile); LCMS: (M+H) ⁺ observed 426.

Scheme I: Conventional method for the synthesis of pyrazoles via the condensation of hydrazines with β-diketones:

Synthesis of tert-butyl 3-trifluoromethyl-1,4,6,7-tetrahydro-pyrrolo[4,3-c]pyridine-5-carboxylate:

Add 5g of 1-Boc-4-piperidine (25mmol), 15mg of p-TSA, 25ml of benzene and 2.2ml of morpholine (25mmol) into a 50ml round bottom flask equipped with a Dean-Stark, and heat to reflux overnight. After most of the benzene was removed by a rotary evaporator, 15ml of DCM was added, cooled in an ice bath, 0.35ml of TEA (25mmol) was added, and 0.35ml of trifluoroacetic anhydride (25mmol) was added dropwise at 0°C. After the addition, remove the ice bath. The reaction mixture was stirred overnight at room temperature. Solvent was removed by rotary evaporator. The residue was dissolved in anhydrous EtOH, 3 equivalents of hydrazine was added under ice-cooling, then the ice-bath was removed, and stirred overnight at room temperature. Solvent was removed by rotary evaporator. The compound was purified by normal phase column (column: 140 g silica gel, developing buffer: 50% EtOAc/hexanes) to give the above title product as well as some Boc-deprotected product.

Protocol L: Chlorination or bromination of pyrazoles with N-chlorosuccinimide (NCS) or N-bromosuccinimide (NBS):

4-Chloro-3-trifluoromethyl-1H-pyrazole:

The above compound was prepared using the same protocol L as in Example 1.

4-Chloro-3-iodo-5-trifluoromethylpyrazole:

The above compound was prepared using the same protocol as for the synthesis of 4-chloro-3-iodo-5-methylpyrazole.

3-iodoindazole

At room temperature, iodine (8 g, 32 mmol) and potassium hydroxide (3.36 g, 60 mmol) were sequentially added to indazole (1.88 g, 16 mmol) in DMF (30 mL), and stirring was continued for 1.5 hours. Then, the reaction mixture was diluted with diethyl ether (100 mL), washed with saturated aqueous sodium thiosulfite. The aqueous phase was back extracted with ether, and the ether layer was washed with water, brine, dried ( _MgSO4 ), and concentrated. The yield of iodoindazole was 95%, which was pure enough for further reactions.

Scheme P: Coupling of arylpiperazines with pyrazolyl-acetic acid derivatives - compounds prepared by HATU-involved couplings:

2-(4-Chloro-5-(2-hydroxypropyl)-3-trifluoromethylpyrazol-1-yl)-1-(4-(4-chloro-3-methoxyphenyl)piper Azin-1-yl)ethanone:

The above compound was synthesized using the same scheme P as in Example 1, and the crude product was purified by HPLC. LCMS: m/z 495 (M+H), retention time = 4.71 minutes (Agilent Zorbax SB-C18, 2.1 x 50 mm, 5 μ, 35° C.) with a 4.5 minute gradient of 20-95% B at 95% B A 1.1 minute wash was used (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.08% formic acid/99.9% acetonitrile).

Synthesis of 1-(4-(4-chloro-3-methoxyphenyl)-2(R)-piperazin-1-yl)-2-(4-chloro-3-(1-hydroxy-3-pyrimidine) -2-yl-pyrazol-1-yl)ethanone:

The above compound was synthesized following Scheme P, and the crude product was purified by PTLC using 70 ethyl acetate: 30% n-hexane as mobile phase. LC MS: m/z 491 (M+H), _Rt = 3.59 minutes (Agilent Zorbax SB-C18, 2.1 x 50 mm, 5 μ, 35° C.) with a 4.5 minute gradient of 20-95% B at 95% B A 1.1 minute wash was used (A = 0.1% formic acid/5% acetonitrile/94.9% water, B = 0.08% formic acid/99.9% acetonitrile).

Synthesis of 1-[4-(4-chloro-3-methoxy-phenyl)-2-(R)-hydroxymethyl-piperazin-1-yl]-2-[4-chloro-5-methyl -3-(2-Methyl-pyridin-4-yl)-pyrazol-1-yl]-ethanone:

The title compound was prepared according to Scheme P, using 1-(3-methoxyphenyl-4-chloro)-3-(R)-hydroxymethylpiperazine and ([4-chloro-5-methyl-3 -(2-Methyl-pyridin-4-yl)-pyrazol-1-yl]-acetic acid as coupling component. Purified by HPLC (column: Varian Dynamax 250×21.4 mm Microsorb 100-8 C18, buffer A: 0.1 %TFA/ _H20 , buffer B: 0.1% TFA/ACN, gradient: B from 10% to 95% in 60 minutes, flow rate: 20ml/min), the title product was obtained as a white powder: HPLC retention time = 4.94 minutes (Agilent Zorbax SB-C18, 2.1 x 50mm, 5μ, 35°C) with a 4.5 minute gradient of 20-95% B, with a 1.1 minute wash at 95% B (A = 0.1% formic acid/5% acetonitrile /94.9% water, B=0.08% formic acid/99.9% acetonitrile); MS (ES) M+H expected value = 504.1, found value = 504.1.

Synthesis of 1-[4-(4-chloro-2-fluoro-5-methoxy-phenyl)-piperazin-1-yl]-2-(4-chloro-5-methyl-3-pyrimidine-2 -yl-pyrazol-1-yl)-ethanone

The title compound was prepared according to Scheme P, using 1-(4-chloro-2-fluoro-5-methoxy-phenyl)piperazine and [4-chloro-5-methyl-3-pyrimidin-2-yl -pyrazol-1-yl]-acetic acid as coupling component. Purification by TLC (5% MeOH in DCM) afforded the title compound as a white solid: HPLC retention time = 3.41 min (Agilent Zorbax SB-C18, 2.1 x 50mm, 5μ, 35°C) with 20-95% B 4.5 min gradient at 95% B with 1.1 min wash (A = 0.1% formic acid/5% acetonitrile/94.9% water, B = 0.08% formic acid/99.9% acetonitrile); MS(ES) M+H expected = 479.1, found value = 479.1.

Synthesis of 1-[4-(4-chloro-2-fluoro-5-methoxy-phenyl)-2-(S)-methyl-piperazin-1-yl]-2-[4-chloro-3 -(1-Hydroxy-1-methyl-ethyl)-5-methyl-pyrazol-1-yl]-ethanone:

The title compound was prepared according to Scheme P, using 1-(4-chloro-2-fluoro-5-methoxy-phenyl)-3-(S)-methylpiperazine and [4-chloro-3-( 1-Hydroxy-1-methyl-ethyl)-5-methyl-pyrazol-1-yl]-acetic acid as coupling component. Purification by HPLC (column: Varian Dynamax 250×21.4mm Microsorb 100-8 C18, buffer A: 0.1% TFA/H ₂ O, buffer B: 0.1% TFA/ACN, gradient: B from 25% to 95%, flow rate: 20ml/min), the title compound was obtained: HPLC retention time = 4.48 minutes (Agilent Zorbax SB-C18, 2.1 × 50mm, 5 μ, 35 ° C), using a 4.5-minute gradient of 20-95% B at 95% B with 1.1 minute wash (A = 0.1% formic acid/5% acetonitrile/94.9% water, B = 0.08% formic acid/99.9% acetonitrile); MS(ES) M+H expected = 473.1, found = 455.1 and 473.1.

Synthesis of 2-(4-chloro-3-iodo-5-methyl-pyrazol-1-yl)-1-[4-(4-chloro-3-methoxy-phenyl)-2(S)- Methyl-piperazin-1-yl]-ethanone

Following protocol P, 1-(4-chloro-3-methoxy-phenyl)-3-(S)-methyl-piperazine was mixed with (4-chloro-3-iodo-5-methyl-pyrazole -1-yl)-acetic acid coupling afforded the title compound: LCMS retention time: 5.20 minutes (Agilent Zorbax SB-C18, 2.1×50 mm, 5 μ, 35° C.), using a 4.5-minute gradient of 20-95% B at 95% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.08% formic acid/99.9% acetonitrile); LCMS: (M+H) ⁺ observed 523.

Synthesis of 1-[4-(4-chloro-2-fluoro-5-methoxy-phenyl)-piperazin-1-yl]-2-(4-chloro-3-iodo-5-methyl-pyridine Azol-1-yl)-ethanone

Following Protocol P, 1-(4-Chloro-2-fluoro-5-methoxy-phenyl)-piperazine was combined with (4-chloro-3-iodo-5-methyl-pyrazol-1-yl) - Coupling with acetic acid afforded the title compound: LCMS retention time: 5.13 minutes (Agilent Zorbax SB-C18, 2.1 x 50 mm, 5 μ, 35° C.) using a 4.5-minute gradient from 20-95% B and a 1.1-minute gradient at 95% B Washes (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.08% formic acid/99.9% acetonitrile); LCMS: (M+H) ⁺ observed 527.

Synthesis of 1-[4-(4-chloro-2-fluoro-5-methoxy-phenyl)-2(S)-methyl-piperazin-1-yl]-2-(4-chloro-3- Iodo-5-methyl-pyrazol-1-yl)-ethanone

Following protocol P, 1-(4-chloro-2-fluoro-5-methoxy-phenyl)-3-(S)-methyl-piperazine was mixed with (4-chloro-3-iodo-5-methyl (Agilent Zorbax SB-C18, 2.1×50 mm, 5 μ, 35° C.) using a 4.5-minute gradient of 20-95% B , with a 1.1 min wash at 95% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.08% formic acid/99.9% acetonitrile); LCMS: (M+H) ⁺ observed 541.

Synthesis of 1-[4-(4-chloro-3-methoxyphenyl)-2-(S)-methylpiperazin-1-yl]-2-(4-chloro-5-methyl-3- _Azol-2-yl-pyrazol-1-yl)ethanone:

Following peptide coupling scheme P, the title compound was obtained. LCMS (ES) M+H 464.1; R _f 4.40 min (Agilent Zorbax SB-C18, 2.1 x 50 mm, 5 μ, 35 °C) with a 4.5 min gradient from 20-95% B, 1.1 min at 95% B Washes (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.08% formic acid/99.9% acetonitrile).

Synthesis of 1-[4-(4-chloro-3-methoxyphenyl)-2-(R)-hydroxymethylpiperazin-1-yl]-2-(4-chloro-5-methyl-3 -_Azol-2-ylpyrazol-1-yl)ethanone:

Following peptide coupling scheme P, the title compound was obtained. LCMS (ES) M+H 480.2; _Rf 3.95 min (Agilent Zorbax SB-C18, 2.1 x 50 mm, 5 μ, 35 °C) with a 4.5 min gradient from 20-95% B, 1.1 min at 95% B Washes (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.08% formic acid/99.9% acetonitrile).

Synthesis of 2-[4-chloro-5-methyl-3-(2-methyl-pyridin-4-yl)-pyrazol-1-yl]-1-[4-(2,4-difluoro-5 -methoxy-phenyl)-piperazin-1-yl]-ethanone:

The title compound was prepared according to Scheme P, using 2,4-difluoro-5-methoxy-phenyl)-piperazine and [4-chloro-5-methyl-3-(2-methyl-pyridine- 4-yl)-pyrazol-1-yl]-acetic acid as coupling component. Purification by HPLC afforded the title compound: HPLC retention time = 3.3 min (Agilent Zorbax SB-C18, 2.1 x 50 mm, 5 μ, 35 °C) using a 4.5 min gradient from 20-95% B at 95% B in 1.1 min (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.08% formic acid/99.9% acetonitrile); MS(ES) M+H expected = 476.1, found = 476.1.

Synthesis of 2-[4-chloro-3(1,2-dihydroxy-1-methyl-ethyl)-5-methyl-pyrazol-1-yl]-1-[4-(3-methoxy -4-Chloro-phenyl)-piperazin-1-yl]-ethanone

The title compound was prepared according to Scheme P, using 1-[4-(3-methoxy-4-chloro-phenyl)]-piperazine and 2-[4-chloro-3(1,2-dihydroxy- 1-Methyl-ethyl)-5-methyl-pyrazol-1-yl]-acetic acid as coupling component. Purify by HPLC (column: Varian Dynamax 250×21.4mm Microsorb 100-8 C18, buffer A: 0.1% TFA/H ₂ O, buffer B: 0.1% TFA/ACN, gradient: B changes from 10% in 40 minutes to 60%, flow rate: 20ml/min), the title compound was obtained. HPLC retention time = 3.41 min (Agilent Zorbax SB-C18, 2.1 x 50 mm, 5 μ, 35° C.), using a 4.5 min gradient from 20-95% B with a 1.1 min wash at 95% B (A = 0.1% formic acid/ 5% acetonitrile/94.9% water, B = 0.08% formic acid/99.9% acetonitrile); MS(ES) M+H expected = 457.1, found = 439.1 ( _-H2O ), 457.1.

Synthesis of 1-(4-(4-chloro-3-methoxyphenyl)piperazin-1-yl)-2-(4-chloro-5-pyrazol-1-ylmethyl-3-trifluoromethyl (Pyrazol-1-yl)ethanone:

The above compound was synthesized following Scheme P using (4-chloro-5-pyrazol-1-ylmethyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid. The crude product was purified by PTLC using 70% ethyl acetate: 30% n-hexane as mobile phase: LC MS m/z 517 (M+H), _Rt = 5.47 minutes (Agilent Zorbax SB-C18, 2.1 x 50mm, 5μ , 35°C), using a 4.5-minute gradient of 20-95% B, with a 1.1-minute wash at 95% B (A = 0.1% formic acid/5% acetonitrile/94.9% water, B = 0.08% formic acid/99.9% acetonitrile ); ¹ H NMR (400MHz, CDCl ₃ ): δ3.17(t, J=5.1Hz, 2H), 3.23(t, J=5.1Hz, 2H) 3.64(t, J=5.2Hz, 2H), 3.77 (t, J=5.2Hz, 2H), 3.89(s, 3H), 5.32(s, 2H), 5.38(s, 2H), 6.28(t, J=2.2Hz, 1H), 6.43(apparent dd, J = 2.9 & 8.5Hz, 1H), 6.49 (d, J = 2.6Hz, 1H), 7.22 (d, J = 8.3Hz, 1H), 7.47 (t, J = 1.9Hz, 1H).

Scheme T: Coupling reaction of chloroacetylarylpiperazine and pyrazole via K ₂ CO ₃

Synthesis of 2-(4-chloro-5-(1-hydroxy-1-methylethyl)-3-trifluoromethylpyrazol-1-yl)-1-(4-(4-chloro-3-methyl Oxyphenyl)piperazin-1-yl)ethanone:

Following Scheme T of Example 1 using 2-(4-chloro-5-trifluoromethyl-2H-pyrazol-3-yl)-propan-2-ol, the above compound was synthesized and the crude product was purified by HPLC. LC MS: m/z 495 (M+H), _Rt = 5.33 min (Agilent Zorbax SB-C18, 2.1 x 50 mm, 5 μ, 35 °C) using a 4.5 min gradient of 20-95% B at 95% B A 1.1 minute wash was used (A = 0.1% formic acid/5% acetonitrile/94.9% water, B = 0.08% formic acid/99.9% acetonitrile).

2-(4-Chloro-5-iodo-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(4-chloro-3-methoxy-phenyl)-piperazine-1 -yl]-ethanone

The above compound was prepared following Scheme T using 4-chloro-5-iodo-3-trifluoromethyl-1-H-pyrazole.

Synthesis of 1-[4-(4-chloro-2-fluoro-5-methoxy-phenyl)-2-(S)-methyl-piperazin-1-yl]-2-(4-chloro-5 -Methyl-3-pyrimidin-2-yl-pyrazol-1-yl)-ethanone and 1-[4-(4-chloro-2-fluoro-5-methoxy-phenyl)-2-( S)-Methyl-piperazin-1-yl]-2-(4-chloro-3-methyl-5-pyrimidin-2-yl-pyrazol-1-yl)ethanone

The title compound was prepared according to Scheme T using 2-chloro-1-[4-(4-chloro-2-fluoro-5-methoxy-phenyl)-2-(S)-methyl-piperazine- 1-yl]-ethanone and 4-chloro-5-methyl-3-pyrimidin-2-yl-pyrazole as coupling components. Purify by HPLC (column: Varian Dynamax 250×21.4mm Microsorb 100-8 C18, buffer A: 0.1% TFA/H ₂ O, buffer B: 0.1% TFA/ACN, gradient: B changes from 10% in 60 minutes to 95%, flow rate: 20 ml/min), the title product was obtained as a white powder.

Isomer I: HPLC retention time = 4.31 min (Agilent Zorbax SB-C18, 2.1 x 50 mm, 5 μ, 35°C) with a 4.5 min gradient from 20-95% B, with a 1.1 min wash at 95% B ( A = 0.1% formic acid/5% acetonitrile/94.9% water, B = 0.08% formic acid/99.9% acetonitrile); MS (ES) M+H expected = 493.1, found = 493.4.

Isomer II: HPLC retention time = 4.66 minutes (same conditions as above); MS(ES) M+H expected = 493.1, found = 493.4.

Synthesis of 1-[4-(4-chloro-3-methoxyphenyl)piperazin-1-yl]-2-(4-chloro-5-methyl-3-oxazol-5-ylpyrazole- 1-yl) ethyl ketone

The title compound was synthesized according to Scheme T. LCMS (ES) M+H 450.1; R _f 4.15 min (Agilent Zorbax SB-C18, 2.1 x 50 mm, 5 μ, 35 °C) with a 4.5 min gradient from 20-95% B with a 1.1 min wash at 95% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.08% formic acid/99.9% acetonitrile).

Synthesis of 2-(3-chloroindazol-1-yl)-1-(4-(4-chloro-3-methoxyphenyl)piperazin-1-yl)ethanone

The compound above was synthesized following Protocol T: LCMS 419 (M+H), _Rt = 4.79 minutes (Agilent Zorbax SB-C18, 2.1 x 50mm, 5μ, 35°C) using a 4.5 minute gradient of 20-95% B at 95% A 1.1 minute wash was used for B (A = 0.1% formic acid/5% acetonitrile/94.9% water, B = 0.08% formic acid/99.9% acetonitrile).

Synthesis of 1-(4-(4-chloro-3-methoxyphenyl)piperazin-1-yl)-2-indazol-1-yl-ethanone and 1-(4-(4-chloro-3 -Methoxyphenyl)piperazin-1-yl)-2-indazol-2-yl-ethanone:

Follow Scheme T to obtain the above compound:

N1-isomer: LC MS 385 (M+H), _Rt = 4.22 min (Agilent Zorbax SB-C18, 2.1 x 50 mm, 5 μ, 35 °C) with a 4.5 min gradient of 20-95% B at 95 A 1.1 minute wash was used for %B (A = 0.1% formic acid/5% acetonitrile/94.9% water, B = 0.08% formic acid/99.9% acetonitrile).

N2-isomer: LC MS 385 (M+H), _Rt = 4.03 min (following the same method as above).

Synthesis of 1-[4-(4-chloro-2-fluoro-5-methoxy-phenyl)-piperazin-1-yl]-2-[4-chloro-3-(1-hydroxy-1-methyl Base-ethyl)-5-methyl-pyrazol-1-yl]-ethanone:

The title compound was prepared according to Scheme T, using 1-(4-chloro-2-fluoro-5-methoxy-phenyl)piperazine-4-chloromethyl-one and 4-chloro-3-(1- Hydroxy-1-methyl-ethyl)-5-methyl-pyrazole as coupling component. Purify by HPLC (column: Varian Dynamax 250×21.4mm Microsorb 100-8 C18, buffer A: 0.1% TFA/H ₂ O, buffer B: 0.1% TFA/ACN, gradient: B changes from 25% in 40 minutes to 70%, flow rate: 20ml/min), to obtain the title compound: HPLC retention time = 5.26 minutes (Agilent ZorbaxSB-C18, 2.1 * 50mm, 5 μ, 35 ℃) using a 4.5-minute gradient of 20-95% B, at 95% B with a 1.1 minute wash (A = 0.1% formic acid/5% acetonitrile/94.9% water, B = 0.08% formic acid/99.9% acetonitrile); MS(ES) M+H expected = 459.1, found = 441.1 and 459.1.

Synthesis of 1-{2-[4-(4-chloro-3-hydroxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-3-trifluoromethyl-1,4, tert-butyl 6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylate

The title compound was prepared according to Scheme T using 1-(3-methoxyphenyl-4-chloro)piperazin-4-chloromethyl-one and 3-trifluoromethyl-1,4,6,7 - tert-butyl tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylate as coupling component. Purification was performed by recrystallization from ACN/ _H2O . HPLC retention time = 5.17 min (Agilent Zorbax SB-C18, 2.1 x 50 mm, 5 μ, 35°C) with a 4.5 min gradient from 20-95% B with a 1.1 min wash at 95% B (A = 0.1% formic acid /5% acetonitrile/94.9% water, B=0.08% formic acid/99.9% acetonitrile); MS (ES) M+H expected = 558.2, found = 502.2; ¹ H NMR (CDCl3, 400 MHz) 7.22 (d, 1H ), 6.48(s, 1H), 6.43(d, 1H), 4.96(s, 2H), 4.50(s, 2H), 3.83(s, 3H), 3.65-3.80(m, 6H), 3.12-3.22( d, 4H), 2.73 (m, 2H), 1.48 (s, 9H) ppm.

Synthesis of 1-[4-(2,4-difluoro-5-methoxy-phenyl)-piperazin-1-yl]-2-[4-chloro-3-(1-hydroxy-1-methyl -Ethyl)-5-methyl-pyrazol-1-yl]-ethanone

The title compound was prepared according to Scheme T, using 1-(2,4-difluoro-5-methoxy-phenyl)piperazine-4-chloromethyl-one and 4-chloro-3-(1-hydroxy -1-methyl-ethyl)-5-methyl-pyrazole as coupling component. Purification by conventional phase column (column: 40 g silica gel, 20%-30% EtOAc/DCM) and recrystallization by ACN/water afforded the title product as a white solid: HPLC retention time = 3.9 min (Agilent Zorbax SB-C18, 2.1 ×50mm, 5μ, 35°C), using a 4.5-minute gradient of 20-95% B, with a 1.1-minute wash at 95% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.08% formic acid /99.9% acetonitrile); MS (ES) M+H expected = 443.1, found = 425.1 ( _-H2O ) and 443.1.

Synthesis of 1-[4-(4-chloro-3-methoxy-phenyl)-2-(S)-methyl-piperazin-1-yl]-2-(4-fluoro-5-methyl- 3-pyridin-2-yl-pyrazol-1-yl)-ethanone:

The title compound was prepared according to Scheme T, using 1-(3-methoxyphenyl-4-chloro-)-3-methyl-piperazine-4-chloromethyl-one and 4-fluoro-5-methanol Base-3-1pyridin-2-yl-pyrazole as coupling component. Purification by HPLC afforded the title compound: HPLC retention time = 3.75 min (Agilent Zorbax SB-C18, 2.1 x 50 mm, 5 μ, 35 °C) using a 4.5 min gradient from 20-95% B, 1.1 min at 95% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.08% formic acid/99.9% acetonitrile); MS(ES) M+H expected = 458.2, found = 458.2.

Synthesis of 2-(3-iodoindazol-1-yl)-1-(4-(4-chloro-3-methoxyphenyl)piperazin-1-yl)ethanone:

The above compound was synthesized according to Protocol T: LC MS 511 (M+H); _Rt = 4.89 min (Agilent Zorbax SB-C18, 2.1 x 50 mm, 5 μ, 35 °C), using a 4.5 min gradient of 20-95% B at A 1.1 minute wash was used at 95% B (A = 0.1% formic acid/5% acetonitrile/94.9% water, B = 0.08% formic acid/99.9% acetonitrile).

Synthesis of 2-[4-chloro-3(1-hydroxy-1-methyl-ethyl)-5-methyl-pyrazol-1-yl]-1-[4-(3-methoxy-4- Chloro-phenyl)-2-methyl-piperazin-1-yl]-ethanone (isomer I) and 2-[4-chloro-5(1-hydroxy-1-methyl-ethyl)- 3-methyl-pyrazol-1-yl]-1-[4-(3-methoxy-4-chloro-phenyl)-2-methyl-piperazin-1-yl]-ethanone (iso Construct II):

The title compound was prepared according to Scheme T, using 1-(3-methoxyphenyl-4-chloro)2-methyl-piperazine-4-chloromethyl-one and 4-chloro-3(1-hydroxy - 1-methyl-ethyl)-5-methyl-pyrazole as a coupling component, purified by HPLC (column: Varian Dynamax 250×21.4 mm Microsorb 100-8 C18, buffer A: 0.1% TFA/H ₂ O , buffer B: 0.1% TFA/ACN, gradient: B from 10% to 95% in 60 minutes, flow rate: 20ml/min), the above 2 isomers were obtained as white powder.

Isomer I: HPLC retention time = 4.28 min (Agilent Zorbax SB-C18, 2.1 x 50 mm, 5 μ, 35° C.) using a 4.5 min gradient from 20-95% B with a 1.1 min wash at 95% B ( A = 0.1% formic acid/5% acetonitrile/94.9% water, B = 0.08% formic acid/99.9% acetonitrile); MS (ES) M+H expected = 455.1, found = 437.1 ( _-H2O ), 455.1.

Isomer II: HPLC retention time = 4.54 min (same method as Isomer I); MS(ES) M+H expected = 455.1, found = 437.1 ( _-H2O ), 455.1.

Scheme V: Preparation of Compounds by Acid or Base Involved Deprotection

Synthesis of 1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-(3-trifluoromethyl-4,5,6,7-tetrahydro- Pyrazolo[4,3-c]pyridin-1-yl)-ethanone:

Stir at room temperature 0.23g 1-{2-[4-(4-chloro-3-hydroxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-3-trifluoromethyl-1 , tert-butyl 4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylate with 2 ml 4N HCl/dioxane for 40 min. 20 mL of ether was added and the solid formed was collected and washed with ether. The compound was recrystallized from ACN/ _H2O to give 0.2 g of the title compound: HPLC retention time = 3.03 min (Agilent Zorbax SB-C18, 2.1 x 50 mm, 5 μ, 35 °C) using a 4.5 min gradient of 20-95% B, 1.1 minute wash at 95% B (A = 0.1% formic acid/5% acetonitrile/94.9% water, B = 0.08% formic acid/99.9% acetonitrile); MS(ES) M+H expected = 458.15, found = 458.1.

Synthesis of 5-chloro-2-{4-[2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-piperazin-1-yl}- 4-Methoxy-Lithium Benzoate

Following a variant of Protocol V, add 5-chloro-2-{4-[2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl yl]-piperazin-1-yl}-4-methoxy-benzoic acid methyl ester (43mg, 0.084mmol), 0.4mL MeOH, 0.9mL THF and LiOH (0.42mL, 0.25M). After stirring for 2 days, the solution was diluted with water and the volatile solvents were removed in vacuo during which lithium carboxylate precipitated. The solid was filtered and dried under reduced pressure to provide 36 mg (86%) of the title salt as a white solid: ¹ H NMR (400 MHz, CD3OD) δ 7.44 (s, 1H), 6.58 (s, 1H), 5.28 (s, 2H ), 3.89(s, 3H), 3.71-3.79(m, 4H), 3.16-3.21(m, 2H), 3.09-3.14(m, 2H), 2.26(s, 3H); MS(ES)M+H Expected 495.1, found 495.1; HPLC (80:20-5:95 0.1% TFA/H2O _: 0.08% TFA/MeCN) _Rt = 4.87 min.

Scheme X: Preparation of compounds by acylation or sulfonylation

Synthesis of 1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-(5-methylsulfonyl-3-trifluoromethyl-4,5,6 , 7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl)-ethanone:

Under ice bath, to 70 mg (0.13 mmol) 1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-(3-trifluoro Add 0.046ml TEA (0.33mmol) to the methyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl)-ethanone solution, then add 0.012ml (0.15 mmol) methanesulfonyl chloride. The reaction was stirred for 30 minutes in an ice bath. After the reaction, DCM was added, and the DCM layer was washed with saturated NaHCO ₃ , brine, dried with MgSO ₄ , and concentrated to give the title compound as a white solid: HPLC retention time = 4.78 minutes (Agilent Zorbax SB-C18, 2.1×50 mm, 5 μ, 35°C) with a 4.5 minute gradient of 20-95% B, with a 1.1 minute wash at 95% B (A = 0.1% formic acid/5% acetonitrile/94.9% water, B = 0.08% formic acid/99.9% acetonitrile) ; MS(ES) M+H expected = 536.1, found = 536.1.

N-(5-chloro-2-{4-[2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-piperazin-1-yl }-4-methoxy-benzyl)-N-methyl-methanesulfonamide:

In a 4 mL vial fitted with a stir bar, add 200 mg of 1-[4-(4-chloro-5-methoxy-2-methylaminomethyl-phenyl)-piperazine in 1.4 mL of dichloromethane -1-yl]-2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-ethanone (0.42mmol, 1.0eq) and 126μL triethylamine (0.90mmol , 2.1eq). The solution was cooled in an ice-water bath, and 34 μL of methanesulfonyl chloride (0.43 mmol, 1.05 eq) was added. The ice bath was removed and the solution was stirred overnight. The crude product was purified by HPLC, which was treated with HCl in 4M p-dioxane to give the title compound: LC/MS (ES) (M+H) = 572.1; retention time = 7.32 minutes (Agilent Zorbax SB-C18, 2.1 x 50 mm, 5 μ, 35° C.) with a 2.0-minute no-gradient time at 20% B, followed by a 5.0-minute gradient from 20-95% B, with a 2.5-minute wash at 95% B (A = 0.1% formic acid/ 5% acetonitrile/94.9% water, B = 0.08% formic acid/99.9% acetonitrile).

Synthesis of 1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-(4-chloro-5-acetylaminomethyl-3-trifluoromethyl -pyrazol-1-yl)-ethanone

Room temperature, stirring 1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-(4-chloro-5-aminomethyl-3-trifluoromethyl -A mixture of -pyrazol-1-yl)-ethanone (50 mg, 1 eq), acetyl chloride (13 mg, 1.5 eq) and TEA (50 mg, 3 eq) in 2 mL of DCM for 1 h. Reversed-phase HPLC (acetonitrile-H ₂ O containing 0.1% TFA as eluent) gave the title compound: LCMS retention time: 4.60 minutes (Agilent Zorbax SB-C18, 2.1×50mm, 5μ, 35°C), using 20- 4.5 min gradient to 95% B with 1.1 min wash at 95% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.08% formic acid/99.9% acetonitrile); LCMS: (M+H ) ⁺ observation 508.

Synthesis of 1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-(4-chloro-5-methylsulfonylaminomethyl-3-trifluoro Methyl-pyrazol-1-yl)-ethanone

Stirring 1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-(4-chloro-5-aminomethyl-3-trifluoromethyl- A mixture of pyrazol-1-yl)-ethanone (50 mg, 1 eq), MeSO2Cl (19 mg, 1.5 eq) and TEA (50 mg, 3 eq) in 2 mL of DCM for 1 h. Reverse-phase HPLC (acetonitrile-H ₂ O containing 0.1% TFA as eluent), the title compound was obtained: LCMS retention time: 4.78 minutes (Agilent Zorbax SB-C18, 2.1×50mm, 5μ, 35°C), using 20- 4.5 min gradient to 95% B with 1.1 min wash at 95% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.08% formic acid/99.9% acetonitrile); LCMS: (M+H ) ⁺ observation 544.

Synthesis of (4-chloro-2-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-5-trifluoro Methyl-2H-pyrazol-3-ylmethyl)-urea

Stirring 1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-(4-chloro-5-aminomethyl-3-trifluoromethyl- A mixture of pyrazol-1-yl)-ethanone (50 mg, 1 eq), TMSNCO (30 mg, 2.5 eqin) in 2 mL THF for 1 h. Reverse-phase HPLC (acetonitrile-H ₂ 0 containing 0.1% TFA as eluent), the title compound was obtained: LCMS retention time: 4.26 minutes (Agilent Zorbax SB-C18, 2.1×50mm, 5μ, 35°C), using 20- 4.5 min gradient to 95% B with 1.1 min wash at 95% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.08% formic acid/99.9% acetonitrile); LCMS: (M+H ) ⁺ observation 509.

Scheme Y: Preparation of Compounds by Alkylation

Synthesis of 2-(4-chloro-5-methyl-1H-pyrazol-3-yl)-propan-2-ol

Dissolve ethyl 4-chloro-5-methyl-1H-pyrazole-3-carboxylate (0.14g, 0.8mmol) in 6ml of anhydrous THF, cool to 0°C, add dropwise 3ml (9.0mmol) of 3M MeMgBr ether solution. The reaction was removed from the ice bath and stirred at ambient temperature for 1 hour. The reaction mixture was poured into 1M phosphate buffer (pH=7), and the mixture was extracted with EtOAc. The phases were separated, the ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated to provide the title compound: MS (ES) M-OH expected = 157.1, found = 157.1; 1H NMR (CDCl ₃ , 400 MHz) δ 2.25 (s, 3H), 1.64 (s, 6H) ppm.

2-(4-Chloro-5-trifluoromethyl-2H-pyrazol-3-yl)-propan-2-ol

Following the same scheme as above, using ethyl 4-chloro-5-trifluoromethyl-1H-pyrazole-3-carboxylate, the above compound was synthesized.

(4-Chloro-5-pyrazol-1-ylmethyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid

(5-Bromomethyl-4-chloro-3-trifluoromethyl-pyrazol-1-yl)-ethyl acetate was treated with excess pyrazole and potassium carbonate in DMF at 60 °C, and the product was subsequently treated with hydrogen Lithium oxide treatment affords the title compound.

1-{4-[4-chloro-2-(1-hydroxy-ethyl)-5-methoxy-phenyl]-piperazin-1-yl}-2-(4-chloro-5-methyl -3-Trifluoromethyl-pyrazol-1-yl)-ethanone:

In a 250 mL three-necked flask equipped with a stir bar, a thermometer, and an addition funnel equipped with a N _inlet tube, 10 g of 5-chloro-2-{4-[2-(4-chloro-5-methyl-3- Trifluoromethyl-pyrazol-1-yl)-acetyl]-piperazin-1-yl}-4-methoxy-benzaldehyde (20.9 mmol, 1.0 eq) was slurried in 70 mL THF. The mixture was cooled to 3° C. in an ice-water bath, then 7.3 mL of a 3.0 M MeMgBr solution in Et ₂ O (21.9 mmol, 1.05 eq) was added dropwise. LC/MS showed that the reaction was only about 50% complete. Additional MeMgBr solution was added until the aldehyde was consumed (about 5 mL was required). The reaction was quenched with a small amount of water, the solvent was removed in vacuo, and the crude product was purified by column chromatography to obtain the title compound: LC/MS (ES) (M+H) 495.1; retention time 5.41 minutes (Agilent Zorbax SB-C18, 2.1 × 50mm , 5μ, 35°C) with a 2.0-minute no-gradient time at 20% B, followed by a 5.0-minute gradient from 20-95% B, with a 2.5-minute wash at 95% B (A = 0.1% formic acid/5% acetonitrile/ 94.9% water, B = 0.08% formic acid/99.9% acetonitrile).

Synthesis of 1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-[4-chloro-5-methyl-3-(2-methyl-2H -tetrazol-5-yl)-pyrazol-1-yl]-ethanone and 1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2- [4-Chloro-5-methyl-3-(2-methyl-1H-tetrazol-5-yl)-pyrazol-1-yl]-ethanone

Room temperature, heating 2-(4-chloro-3-tetrazol-5-yl-5-methyl-pyrazol-1-yl)-1-[4-(4-chloro-3-methoxy-phenyl A mixture of )-piperazin-1-yl]-ethanone (9 mg, 1 eq), MeI (3 μL, 5 eq) and K ₂ CO ₃ (20 mg, excess) in 1 mL DMF for 3 days. The crude product was purified by reverse phase HPLC (acetonitrile- _H2O with 0.1% TFA as eluent) to give 1-[4-(4-chloro-3-methoxy-phenyl)-piperazine-1- Base]-2-[4-chloro-5-methyl-3-(2-methyl-2H-tetrazol-5-yl)-pyrazol-1-yl]-ethanone. LCMS retention time: 4.06 minutes . LCMS: (M+H) ⁺ observed 465. From this reaction, 1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-[4-chloro-5-methyl-3-( 2-Methyl-1H-tetrazol-5-yl)-pyrazol-1-yl]-ethanone. The two products eluted together from HPLC and TLC. LCMS retention time: 4.06 min for both isomers (Agilent Zorbax SB-C18, 2.1 x 50 mm, 5 μ, 35 °C) using a 4.5 min gradient from 20-95% B and a 1.1 min gradient at 95% B Washes (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.08% formic acid/99.9% acetonitrile). LCMS: (M+H) ⁺ observed 465 for both isomers.

Synthesis of 1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-(4-chloro-5-morpholin-4-ylmethyl-3-tri Fluoromethyl-pyrazol-1-yl)-ethanone

A mixture of (5-bromomethyl-4-chloro-3-trifluoromethyl-pyrazol-1-yl)-ethyl acetate (350mg, 1eq) and morpholine (0.5mL, 5eq) in 1mL DMF was stirred at room temperature Over night, diluted with ethyl acetate, washed with water. The organic layer was evaporated, diluted with 3 mL THF, and treated with 3 mL 1N LiOH for 2 hours. Preparative reverse phase HPLC afforded (4-chloro-5-morpholin-4-ylmethyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid.

1-(4-Chloro-3-methoxy-phenyl)-piperazine (30 mg, 1 eq), (4-chloro-5-morpholin-4-ylmethyl-3-trifluoromethyl- A mixture of pyrazol-1-yl)-acetic acid (44 mg, 1 eq), HATU (42 mg, 1.1 eq) and TEA (0.2 mL, 6 eq) in 1 mL of DMF for 12 hours. Diluted with EtOAc, followed by washing with saturated aqueous NaHCO ₃ , reverse phase HPLC (acetonitrile-H ₂ O containing 0.1% TFA as eluent) gave the title compound: LCMS retention time: 4.69 min (Agilent Zorbax SB-C18, 2.1 ×50mm, 5μ, 35°C), using a 4.5-minute gradient of 20-95% B, with a 1.1-minute wash at 95% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.08% formic acid /99.9% acetonitrile); LCMS: (M+H) ⁺ observed 536.

Synthesis of 1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-(4-chloro-5-dimethylaminomethyl-3-trifluoromethyl Base-pyrazol-1-yl)-ethanone

Stir (5-bromomethyl-4-chloro-3-trifluoromethyl-pyrazol-1-yl)-ethyl acetate (350 mg, 1 eq and NHMe2 (2M in THF, 2.5 mL, 5 eq) at room temperature The mixture in 1 mL of DMF overnight was diluted with ethyl acetate and washed with water. The organic layer was evaporated, diluted with 3 mL of THF and treated with 3 mL of 1N LiOH for 2 h. Preparative reverse phase HPLC gave (4-chloro-5-dimethylaminomethyl -3-trifluoromethyl-pyrazol-1-yl)-acetic acid.

1-(4-Chloro-3-methoxy-phenyl)-piperazine (30 mg, 1 eq), (4-chloro-5-dimethylaminomethyl-3-trifluoromethyl-pyrazole -1-yl)-A mixture of acetic acid (28 mg, 1 eq), HATU (42 mg, 1.1 eq) and TEA (0.2 mL, 6 eq) in 1 mL of DMF for 12 hours. Diluted with EtOAc, followed by washing with saturated aqueous NaHCO ₃ , reverse phase HPLC (acetonitrile-H ₂ O containing 0.1% TFA as eluent) gave the title compound: LCMS retention time: 3.42 minutes (Agilent Zorbax SB-C18, 2.1 ×50mm, 5μ, 35°C), using a 4.5-minute gradient of 20-95% B, with a 1.1-minute wash at 95% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.08% formic acid /99.9% acetonitrile); LCMS: (M+H) ⁺ observed 494.

Synthesis of 1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-(4-chloro-5-methylsulfonylmethyl-3-trifluoromethyl Base-pyrazol-1-yl)-ethanone

A mixture of (5-bromomethyl-4-chloro-3-trifluoromethyl-pyrazol-1-yl)-ethyl acetate (350mg, 1eq) and NaSOMe (510mg, 5eq) in 1mL DMF was stirred overnight at room temperature , diluted with ethyl acetate and washed with water. The organic layer was evaporated, diluted with 3 mL THF, and treated with 3 mL 1N LiOH for 2 hours. Preparative reverse phase HPLC gave (4-chloro-5-methylsulfonylmethyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid.

1-(4-Chloro-3-methoxy-phenyl)-piperazine (30 mg, 1 eq), (4-chloro-5-methylsulfonylmethyl-3-trifluoromethyl-pyrazole) were stirred at room temperature -1-yl)-A mixture of acetic acid (32 mg, 1 eq), HATU (42 mg, 1.1 eq) and TEA (0.2 mL, 6 eq) in 1 mL of DMF for 12 hours. Diluted with EtOAc, followed by washing with saturated aqueous NaHCO ₃ , reverse phase HPLC (acetonitrile-H ₂ O with 0.1% TFA as eluent) gave the title compound: LCMS retention time: 5.08 min (Agilent Zorbax SB-C18, 2.1 ×50mm, 5μ, 35°C), using a 4.5-minute gradient of 20-95% B, with a 1.1-minute wash at 95% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.08% formic acid /99.9% acetonitrile); LCMS: (M+H) ⁺ observed 529.

Scheme Z: Preparation of compounds by peracid-involved N-oxidation

Synthesis of 1-[4-(4-chloro-3-methoxyphenyl)-4-oxypiperazin-1-yl]-2-(4-chloro-5-methyl-3-oxazole-2- Pyrazol-1-yl)ethanone

The title compound Z was synthesized according to Scheme Z of Example 1. LCMS (ES) M+H 466.1, Rf _0.62 min (Agilent Zorbax SB-C18, 2.1 x 50 mm, 5 μ, 35 °C) with a 4.5 min gradient from 20-95% B, with a 1.1 min wash at 95% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.08% formic acid/99.9% acetonitrile).

Scheme DD: Preparation of compounds by processes involving palladium and copper

Synthesis of 2-(4-chloro-5-methylsulfonyl-3-trifluoromethylpyrazol-1-yl)-1-(4-(4-chloro-3-methoxyphenyl)piperazine-1 -yl)ethanone and 1-(4-(4-chloro-3-methoxyphenyl)piperazin-1-yl)-2-(4-chloro-3-trifluoromethylpyrazole-1- base) ethyl ketone:

According to the method that copper participates in the scheme DD of embodiment 2 obtains above compound, reaction mixture is purified by PTLC, uses 50% ethyl acetate: 50% n-hexane as mobile phase.

2-(4-Chloro-5-methylsulfonyl-3-trifluoromethylpyrazol-1-yl)-1-(4-(4-chloro-3-methoxyphenyl)piperazine-1- base) Ethanone: LC MS m/z 515 (M+H), _Rt = 5.34 min (Agilent Zorbax SB-C18, 2.1 x 50 mm, 5 μ, 35 °C) with a 4.5 min gradient of 20-95% B at A 1.1 minute wash was used at 95% B (A = 0.1% formic acid/5% acetonitrile/94.9% water, B = 0.08% formic acid/99.9% acetonitrile).

1-(4-(4-chloro-3-methoxyphenyl)piperazin-1-yl)-2-(4-chloro-3-trifluoromethylpyrazol-1-yl)ethanone: LC MS m/z 437 (M+H), _Rt = 5.22 minutes (following the same method as above); 1H NMR (400MHz, CDCl3): δ3.15 (apparent quintet, J = 5.1Hz, 4H), 3.68 ( apparent t, J=5.1Hz, 2H), 3.78 (apparent t, J=5.1Hz, 2H), 3.89s, 3H), 5.03(s, 2H), 6.42 (apparent dd, J=2.5 & 8.4Hz, 1H ), 6.48 (d, J=2.5Hz, 1H), 7.22 (d, J=8.3Hz, 1H), 7.64 (s, 1H).

Synthesis of 2-(3-phenylsulfonyl-4-chloro-5-methyl-pyrazol-1-yl)-1-[4-(4-chloro-3-methoxy-phenyl)-piperazine -1-yl]-ethanone

Heat 2-(4-chloro-3-iodo-5-methyl-pyrazol-1-yl)-1-[4-(4-chloro-3-methoxy-benzene) in 1 mL DMSO at 110°C Base)-2(S)-methyl-piperazin-1-yl]-ethanone (204mg, 1eq), NaSO2Ph (200mg, 3eq) and CuI (228mg, 3eq) overnight, cooled to room temperature, dissolved in 1: 1 in a mixture of methanol and EtOAc, filtered through a thin layer of celite, and concentrated. The crude product was purified by reverse phase HPLC (acetonitrile- _H2O with 0.1% TFA as eluent) to yield the title compound: LCMS retention time: 4.95 min (Agilent Zorbax SB-C18, 2.1 x 50 mm, 5 μ, 35 °C), 4.5 min gradient from 20-95% B with 1.1 min wash at 95% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.08% formic acid/99.9% acetonitrile); LCMS: ( M+H) ⁺ observation 523.

Synthesis of 2-(4-chloro-3-[1,2,4]triazol-1-yl-5-methyl-pyrazol-1-yl)-1-[4-(4-chloro-3-methyl Oxy-phenyl)-piperazin-1-yl]-ethanone

The title compound was prepared according to variations of Scheme DD. LCMS retention time: 3.80 min (Agilent Zorbax SB-C18, 2.1×50 mm, 5 μ, 35° C.), using a 4.5 min gradient of 20-95% B, with a 1.1 min wash at 95% B (A=0.1% formic acid/ 5% acetonitrile/94.9% water, B=0.08% formic acid/99.9% acetonitrile); LCMS: (M+H) ⁺ observed 450.

1-[4-(4-chloro-3-methoxy-phenyl)-2(S)-methyl-piperazin-1-yl]-2-(4-chloro-5-methyl-3- [1,2,3]triazol-1-yl-pyrazol-1-yl)-ethanone

The title compound was prepared according to variations of Scheme DD. LCMS retention time: 4.28 minutes (Agilent Zorbax SB-C18, 2.1 × 50mm, 5 μ, 35°C), using a 4.5-minute gradient of 20-95% B, and a 1.1-minute wash at 95% B (A = 0.1% formic acid/ 5% acetonitrile/94.9% water, B = 0.08% formic acid/99.9% acetonitrile); LCMS: (M+H) ⁺ observed 464.

1-[4-(4-chloro-3-methoxy-phenyl)-2(S)-methyl-piperazin-1-yl]-2-(4-chloro-5-methyl-3- Pyrazol-1-yl-pyrazol-1-yl)-ethanone

The title compound was prepared according to variations of Scheme DD. LCMS retention time: 4.56 minutes (Agilent Zorbax SB-C18, 2.1 × 50mm, 5 μ, 35°C), using a 4.5-minute gradient of 20-95% B, and a 1.1-minute wash at 95% B (A = 0.1% formic acid/ 5% acetonitrile/94.9% water, B=0.08% formic acid/99.9% acetonitrile); LCMS: (M+H) ⁺ observed 463.

2-(4'-chloro-3,5'-dimethyl-[1,3']bipyrazol-1'-yl)-1-[4-(4-chloro-3-methoxy-benzene Base)-2(S)-methyl-piperazin-1-yl]-ethanone

The title compound was prepared according to variations of Scheme DD. LCMS retention time: 4.59 minutes (Agilent Zorbax SB-C18, 2.1×50 mm, 5 μ, 35° C.), using a 4.5-minute gradient of 20-95% B, with a 1.1-minute wash at 95% B (A=0.1% formic acid/ 5% acetonitrile/94.9% water, B = 0.08% formic acid/99.9% acetonitrile); LCMS: (M+H) ⁺ observed 477.

1-[4-(4-chloro-2-fluoro-5-methoxy-phenyl)-piperazin-1-yl]-2-(4-chloro-5-methyl-3-[1,2 , 3] Triazol-1-yl-pyrazol-1-yl)-ethanone

The title compound was prepared according to variations of Scheme DD. LCMS retention time: 5.75 minutes (Agilent Zorbax SB-C18, 2.1 × 50mm, 5μ, 35°C), using a 4.5-minute gradient of 20-95% B, and a 1.1-minute wash at 95% B (A = 0.1% formic acid/ 5% acetonitrile/94.9% water, B = 0.08% formic acid/99.9% acetonitrile); LCMS: (M+H) ⁺ observed 468.

1-[4-(4-chloro-2-fluoro-5-methoxy-phenyl)-piperazin-1-yl]-2-(4-chloro-5-methyl-3-pyrazole-1 -yl-pyrazol-1-yl)-ethanone

The title compound was prepared according to variations of Scheme DD. LCMS retention time: 5.96 minutes (Agilent Zorbax SB-C18, 2.1 × 50mm, 5μ, 35°C), using a 4.5-minute gradient of 20-95% B, and a 1.1-minute wash at 95% B (A = 0.1% formic acid/ 5% acetonitrile/94.9% water, B = 0.08% formic acid/99.9% acetonitrile); LCMS: (M+H) ⁺ observed 467.

2-(4'-chloro-3,5'-dimethyl-[1,3']bipyrazole-1'-yl)-1-[4-(4-chloro-2-fluoro-5-methyl Oxy-phenyl)-piperazin-1-yl]-ethanone

The title compound was prepared according to variations of Scheme DD. LCMS retention time: 6.02 minutes (Agilent Zorbax SB-C18, 2.1 × 50mm, 5μ, 35°C), using a 4.5-minute gradient of 20-95% B, and a 1.1-minute wash at 95% B (A = 0.1% formic acid/ 5% acetonitrile/94.9% water, B = 0.08% formic acid/99.9% acetonitrile); LCMS: (M+H) ⁺ observed 481.

Synthesis of 1-[4-(4-chloro-2-fluoro-5-methoxy-phenyl)-piperazin-1-yl]-2-(4-chloro-3-cyano-5-methyl- Pyrazol-1-yl)-ethanone

1-[4-(4-Chloro-2-fluoro-5-methoxy-phenyl)-piperazin-1-yl]-2-(4-chloro-3 -A mixture of iodo-5-methyl-pyrazol-1-yl)-ethanone (260 mg, 1 eq) and CuCN (450 mg, 10 eq) for 1 h, cooled to room temperature, dissolved in a 1:1 mixture of methanol and EtOAc , filtered through a thin layer of celite, and concentrated. The crude product was purified by reverse phase HPLC (acetonitrile- _H2O with 0.1% TFA as eluent) to yield the title compound: LCMS retention time: 5.12 min (Agilent Zorbax SB-C18, 2.1 x 50 mm, 5 μ, 35 °C) , using a 4.5 min gradient from 20-95% B with a 1.1 min wash at 95% B (A = 0.1% formic acid/5% acetonitrile/94.9% water, B = 0.08% formic acid/99.9% acetonitrile); LCMS: (M+H) ⁺ observation 426.

Synthesis of 2-(3-benzenesulfonyl-4-chloro-5-methyl-pyrazol-1-yl)-1-[4-(4-chloro-3-methoxy-phenyl)-2(S )-methyl-piperazin-1-yl]-ethanone

At 110°C, heat 2-(3-iodo-4-chloro-5-methyl-pyrazol-1-yl)-1-[4-(4-chloro-3-methoxy- A mixture of phenyl)-2-(S)-methylpiperazin-1-yl]-ethanone (204mg, 1eq), NaSO2Ph (200mg, 3eq) and CuI (228mg, 3eq) overnight, cooled to room temperature, dissolved In a 1:1 mixture of methanol and EtOAc, filter through a thin layer of celite and concentrate. The crude product was purified by reverse phase HPLC (acetonitrile- _H2O with 0.1% TFA as eluent) to yield the title compound: LCMS retention time: 5.40 min (Agilent Zorbax SB-C18, 2.1 x 50 mm, 5 μ, 35 °C), 4.5 min gradient from 20-95% B with 1.1 min wash at 95% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.08% formic acid/99.9% acetonitrile); LCMS: ( M+H) ⁺ observation 537.

Synthesis of 1-[4-(4-chloro-2-fluoro-5-methoxy-phenyl)-piperazin-1-yl]-2-(4-chloro-3-methylsulfonyl-5-methyl -pyrazol-1-yl)-ethanone

At 110°C, heat 2-(3-iodo-4-chloro-5-methyl-pyrazol-1-yl)-1-[4-(4-chloro-2-fluoro-5- Methoxy-phenyl)-piperazin-1-yl]-ethanone (200mg, 1eq), a mixture of NaSO2Me (117mg, 3eq) and CuI (217mg, 3eq) overnight, cooled to room temperature, dissolved in 1:1 A mixture of methanol and EtOAc was filtered through a thin layer of celite, and concentrated. The crude product was purified by reverse phase HPLC (acetonitrile- _H2O with 0.1% TFA as eluent) to yield the title compound: LCMS retention time: 5.90 min (Agilent Zorbax SB-C18, 2.1 x 50 mm, 5 μ, 35 °C), 4.5 min gradient from 20-95% B with 1.1 min wash at 95% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.08% formic acid/99.9% acetonitrile); LCMS: ( M+H) ⁺ 479 observations.

Synthesis of 2-(3-cyano-4-chloro-5-methyl-pyrazol-1-yl)-1-[4-(4-chloro-3-methoxy-phenyl)-2(S) -Methyl-piperazin-1-yl]-ethanone

At 175°C, heat 2-(3-iodo-4-chloro-5-methyl-pyrazol-1-yl)-1-[4-(4-chloro-3-methoxy- A mixture of phenyl)-2-(S)-methylpiperazin-1-yl]-ethanone (260mg, 1eq) and CuCN (450mg, 10eq for 1 hour, cooled to room temperature, dissolved in 1:1 methanol and The EtOAc mixture was filtered through a thin layer of Celite and concentrated. The crude product was purified by reverse phase HPLC (acetonitrile-H ₂ O with 0.1% TFA as eluent) to give the title compound: LCMS retention time: 5.96 min (Agilent Zorbax SB-C18, 2.1 x 50mm, 5μ, 35°C) with a 4.5 minute gradient of 20-95% B, with a 1.1 minute wash at 95% B (A = 0.1% formic acid/5% acetonitrile/94.9% water , B=0.08% formic acid/99.9% acetonitrile); LCMS: (M+H) ⁺ observed 422.

Synthesis of 1-(4-(4-chloro-3-methoxyphenyl)piperazin-1-yl)-2-(3-pyrazol-1-yl-indazol-1-yl)ethanone:

Following Scheme DD for copper-involved amine arylation using 2-(3-iodoindazol-1-yl)-1-(4-(4-chloro-3-methoxyphenyl)piperazine-1- base) ethyl ketone and pyrazole to synthesize the above compound. LC MS 451 (M+H); retention time = 5.89 minutes (Agilent Zorbax SB-C18, 2.1 x 50 mm, 5 μ, 35° C.) with a 4.5 minute gradient from 20-95% B, 1.1 minutes at 95% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.08% formic acid/99.9% acetonitrile).

Synthesis of 1-(4-(4-chloro-3-methoxyphenyl)piperazin-1-yl)-2-(3-methylsulfonyl-indazol-1-yl)ethanone:

The above compounds were synthesized following the variant of Scheme DD for the preparation of sulfones involving copper. LC MS 463 (M+H), retention time = 5.46 minutes (Agilent Zorbax SB-C18, 2.1 x 50mm, 5μ, 35°C) with a gradient of 20-95% B in 4.5 minutes, at 95% B in 1.1 minutes (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.08% formic acid/99.9% acetonitrile).

Scheme EE: Conventional synthesis of pyrazoles substituted by oxazoles:

Synthesis of (5-methyl-1H-pyrazol-3-yl)methanol

To a stirred solution of the ester (308 mg) in _CH2Cl2 (8 mL) and THF (10 mL) at 0 °C was added lithium aluminum hydride solution (1M in diethyl ether, 3.0 mL ₎ slowly. The reaction mixture was stirred for another 30 min and quenched by addition of _H2O (0.1 mL), aqueous NaOH (10%, 0.2 mL) and _H2O (0.3 mL). The mixture was filtered and evaporated in vacuo to give the title compound.

Synthesis of (4-chloro-5-methyl-1H-pyrazol-3-yl)methanol

To a solution of the above alcohol (1.32 g) in _CH2Cl2 (30 _mL ) was added N-chlorosuccinimide (1.74 g). The reaction mixture was stirred overnight at room temperature and aqueous NaOH (30 mL) was added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3 x 30 mL). The combined organic phases were dried ( _Na2SO4 ), filtered and evaporated _in vacuo to give the title compound.

Synthesis of 4-chloro-5-methyl-1H-pyrazole-3-carbaldehyde

To a solution of the above alcohol (14.6 mg) in dimethoxyethane (1 mL) was added _MnO2 (51 mg) in one portion. The reaction mixture was heated to 110°C for 3 hours and cooled to room temperature. The mixture was filtered and the residual solid was washed with hot ethanol (3 mL). The combined organic solutions were evaporated in vacuo to give the title aldehyde.

Synthesis of 5-(4-Chloro-5-methyl-1H-pyrazol-3-yl)-oxazole

To a solution of the above aldehyde (14 mg) in ethanol (1 mL) was added NaOEt (14 mg) and TosMic (20 mg). The reaction mixture was stirred at room temperature for 1 hour and evaporated in vacuo. The mixture was dissolved in saturated aqueous NaHCO ₃ (1 mL), extracted with ethyl acetate (3×1 mL). The combined organic solutions were dried and evaporated to give the title compound.

Scheme JJ: Heteroaryl-substituted pyrazoles synthesized by cycloaddition and cyclization reactions:

Synthesis of 1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-[4-chloro-5-methyl-3-(5-methyl-[ 1,2,4]-oxadiazol-3-yl)-pyrazol-1-yl]-ethanone

At 50°C, heat 2-(3-cyano-4-chloro-5-methyl-pyrazol-1-yl)-1-[4-(4-chloro-3-methoxyl) in 1 mL of ethanol A mixture of -phenyl)-piperazin-1-yl]-ethanone (41 mg, 1 eq), _NH2OH ·HCl (35 mg, 5 eq) and Et3N (140 μL, 10 eq) was cooled to room temperature for 2 hours. The white solid was collected and treated with trimethyl orthoacetate (1 mL) and one crystal of PTSA at 50° C. for 2 hours. Reversed-phase HPLC (acetonitrile-H ₂ O containing 0.1% TFA as eluent) gave the title compound: LCMS retention time: 4.26 minutes (Agilent ZorbaxSB-C18, 2.1×50mm, 5μ, 35°C), using 20-95 4.5 min gradient of %B with 1.1 min wash at 95% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.08% formic acid/99.9% acetonitrile); LCMS: (M+H) ⁺ Observations 465.

Synthesis of 1-[4-(4-chloro-3-methoxy-phenyl)-2(S)-methyl-piperazin-1-yl]-2-(4-chloro-5-methyl-3 -[1,2,4]-oxadiazol-3-yl-pyrazol-1-yl)-ethanone

50°C, heat 2-(3-cyano-4-chloro-5-methyl-pyrazol-1-yl)-1-[4-(4-chloro-3-methoxy- A mixture of phenyl)-2-(S)-methyl-piperazin-1-yl]-ethanone (160 mg, 1 eq), _NH2OH ·HCl (79 mg, 3 eq) and Et3N (264 μL, 5 eq) for 2 h , cooled to room temperature. The white solid was collected and treated with trimethyl orthoformate (1 mL) and CSA crystallite 1 pellets at 50°C for 2 hours. Reversed-phase HPLC (acetonitrile-H ₂ O containing 0.1% TFA as eluent) gave the title compound: LCMS retention time: 5.24 minutes (Agilent Zorbax SB-C18, 2.1×50 mm, 5 μ, 35° C.), using 20-95 4.5 min gradient of %B with 1.1 min wash at 95% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.08% formic acid/99.9% acetonitrile); LCMS: (M+H) ⁺ Observations 465.

Synthesis of 1-[4-(4-chloro-2-fluoro-5-methoxy-phenyl)-piperazin-1-yl]-2-(4-chloro-5-methyl-3-[1, 2,4]-oxadiazol-3-yl-pyrazol-1-yl)-ethanone

50°C, heat 1-[4-(4-chloro-2-fluoro-5-methoxy-phenyl)-piperazin-1-yl]-2-(4-chloro-3- A mixture of cyano-5-methyl-pyrazol-1-yl)-ethanone (165 mg, 1 eq), _NH2OH ·HCl (79 mg, 3 eq) and Et3N (264 μL, 5 eq) was cooled to room temperature for 2 hours. The white solid was collected and treated with trimethyl orthoformate (1 mL) and one crystal of CSA at 50° C. for 2 hours. Reversed-phase HPLC (acetonitrile-H ₂ O containing 0.1% TFA as eluent) gave the title compound: LCMS retention time: 5.30 minutes (Agilent ZorbaxSB-C18, 2.1×50mm, 5μ, 35°C), using 20-95 4.5 min gradient of %B with 1.1 min wash at 95% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.08% formic acid/99.9% acetonitrile); LCMS: (M+H) ⁺ Observations 469.

Scheme KK: Synthesis of Compounds Using Negishi Coupling Reaction

Synthesis of 1-(4-(4-chloro-3-methoxyphenyl)piperazin-1-yl)-2-(3-thiazol-2-yl-indazol-1-yl)ethanone:

The above compound was synthesized according to the scheme KK of Example 2, using 1-[4-(4-chloro-3methoxy-phenyl)-piperazin-1-yl]-2-(3-iodo-indazole- 1-yl)-ethanone to give the title compound: LC MS 462 (M+H), _Rt = 5.37 min (Agilent Zorbax SB-C18, 2.1 x 50mm, 5μ, 35°C) with 20-95% B 4.5 min gradient with 1.1 min wash at 95% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.08% formic acid/99.9% acetonitrile); ¹ H NMR (400 MHz, CDCl3): δ3 .07(apparent quintet, J=4.8Hz, 4H), 3.75(t, J=5.2Hz, 2H), 3.81(t, J=4.8Hz, 2H), 3.86(s, 3H), 5.34(s, 2H ), 6.37(dd, J=2.6 & 8.4Hz, 1H), 6.42(d, J=2.5Hz, 1H), 7.18(d, J=8.5Hz, 1H), 7.30-7.35(m, 2H), 7.45 -7.53 (m, 2H), 7.96 (d, J=3.0Hz, 1H), 8.46-8.48 (m, 1H).

Synthesis of (4-chloro-5-methyl-3-oxazol-2-ylpyrazol-1-yl) tert-butyl acetate

Following the Nigishi coupling scheme KK, the title compound was obtained

Synthesis of (4-chloro-5-methyl-3-oxazol-2-yl-pyrazol-1-yl)acetic acid

To a solution of the above ester (144 mg) in _CH2Cl2 (3 mL) was added trifluoroacetic acid (0.23 mL) and triethylsilane ( ₁ mL). The reaction mixture was stirred at room temperature for 3 hours and evaporated in vacuo to give the title compound.

Synthesis of 1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-(4-chloro-5-methyl-3-thiazol-2-yl-pyridine Azol-1-yl)ethanone

According to Scheme KK, 2-(3-iodo-4-chloro-5-methyl-pyrazol-1-yl)-1-[4-(4-chloro-3-methoxy-phenyl)-piperazine A mixture of -1-yl]-ethanone (204mg, 0.4mmol, 1eq), 2-thiazolylzinc bromide (0.5M in THF, 1.6mL, 2eq) and Pd(PPh3)4 (46mg, 0.1eq) Refluxed overnight, cooled to room temperature, quenched with water, extracted with EtOAc. The organic layer was purified by reverse phase HPLC to give the title compound: LCMS retention time: 4.36 minutes (Agilent Zorbax SB-C18, 2.1 x 50 mm, 5 μ, 35° C.) using a 4.5 minute gradient of 20-95% B at 95% B LCMS for (M+H) ⁺ observed: 466.

Scheme LL: Mannich addition to aromatic rings

Synthesis of 5-chloro-2-{4-[2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-piperazin-1-yl}- 4-Methoxy-benzaldehyde:

7.6 g of anhydrous DMF (97.5 mmol, 4.4 eq) were charged into a 250 mL three-necked flask equipped with a stirring bar, a thermometer, and an addition funnel equipped with a N2 inlet tube. The flask was cooled in a brine bath until the temperature was about -10°C, then 2.3 mL POCl3 (24.4 mmol, 1.1 eq) was added in a slow stream over 5 minutes. The mixture was stirred for 15 minutes, then 10.0 g of 1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-(4-chloro - A solution of 5-methyl-3-trifluoromethyl-pyrazol-1-yl)-ethanone (22.2 mmol, 1.0 eq) in 35 mL of anhydrous DMF. The temperature was kept below 5°C during the addition. The flask was then transferred to an oil bath and warmed to 35°C. After 4 hours, the solution was poured into 200 mL of vigorously stirred _H2O , resulting in a thick beige precipitate. Adjust the pH to 8 with 40% NaOH aqueous solution, collect the solid by vacuum filtration, wash thoroughly with H ₂ O, and dry in vacuo to give the title compound: LC/MS (ES) (M+H) 479.0; retention time 7.24 minutes (Agilent Zorbax SB -C18, 2.1 x 50mm, 5μ, 35°C) with 2.0 min no gradient time at 20% B, followed by 5.0 min gradient from 20-95% B with 2.5 min wash at 95% B (A = 0.1% Formic acid/5% acetonitrile/94.9% water, B=0.08% formic acid/99.9% acetonitrile).

1-[4-(4-chloro-2-hydroxymethyl-5-methoxy-phenyl)-piperazin-1-yl]-2-(4-chloro-5-methyl-3-trifluoro Methyl-pyrazol-1-yl)-ethanone:

In a 4 mL vial equipped with a stir bar was added 100 mg of 5-chloro-2-{4-[2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazole-1- Base)-acetyl]-piperazin-1-yl}-4-methoxy-benzaldehyde (0.20mmol, 1.0eq) and 15.3mg NaBH4 (0.40mmol, 2.0eq). The vial was loosely capped and the mixture was stirred at room temperature for 3 hours. The reaction was quenched with a small amount of aqueous HCl and the white precipitate formed was collected by vacuum filtration and dried in vacuo to give the title compound: LC/MS (ES) (M+H) 481.3, retention time = 4.51 minutes (Agilent Zorbax SB-C18 , 2.1×50mm, 5μ, 35°C) with a 2.0-minute no-gradient time at 20% B, followed by a 5.0-minute gradient from 20-95% B, with a 2.5-minute wash at 95% B (A = 0.1% formic acid/ 5% acetonitrile/94.9% water, B = 0.08% formic acid/99.9% acetonitrile).

Scheme MM: Preparation of compounds via C-C and C-N triple bond transformations

Synthesis of 2-(3-acetyl-4-chloro-5-methylpyrazol-1-yl)-1-(4-(4-chloro-3-methoxyphenyl)piperazin-1-yl) Ethyl ketone:

Mercury sulfate (16mg, 0.05mmol) was added to 2-(4-chloro-3-ethynyl-5-methyl-pyrazol-1-yl)-1-(4-chloro-3-methyl A solution of oxyphenyl)-piperazin-1-yl)ethanone (90 mg, 0.22 mmol) and concentrated sulfuric acid (0.2 mL) in a THF:H2O solvent ( ₂ mL:1 mL) mixture. Stirring was continued at room temperature for 1 h, neutralized with saturated aqueous NaHCO ₃ , extracted with ethyl acetate (3×20 mL). The combined organic layers _were washed with water, brine, dried ( _Na2SO4 ), and concentrated. The residue was purified by HPLC using the 20-80% method to give pure 2-(3-acetyl-4-chloro-5-methylpyrazol-1-yl)-1-(4-(4-chloro-3 -Methoxyphenyl)piperazin-1-yl)ethanone in 60% yield: LC MS: m/z 425M ^+H , _Rt =4.33min (Agilent Zorbax SB-C18, 2.1×50mm, 5 μ, 35° C.) with a 4.5-minute gradient of 20-95% B, with a 1.1-minute wash at 95% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.08% formic acid/99.9% acetonitrile); ¹ H NMR (400MHz, CDCl ₃ ): δ2.28(s, 3H), 2.55(s, 3H), 3.18(apparent d, J=15.4Hz, 4H), 3.73(apparent d, J=15.6 Hz, 4H), 3.89(s, 3H), 5.01(s, 2H), 6.43(apparent d, J=8.7Hz, 1H), 6.49(s, 1H), 7.21(d, J=8.3Hz, 1H) .

Synthesis of 2-(4-chloro-3-(1-hydroxyethyl)-5-methylpyrazol-1-yl)-1-(4-(4-chloro-3-methoxyphenyl)piperazine- 1-yl) ethyl ketone:

Add sodium borohydride to 2-(3-acetyl-4-chloro-5-methylpyrazol-1-yl)-1-(4-(4-chloro-3-methoxyphenyl)piperazine -1-yl)ethanone (100 mg, 0.23 mmol) was stirred in methanol at 0°C. The reaction was removed from the ice/water bath and stirring was continued for 2 hours. The reaction mixture was then diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried over Na2SO4, and concentrated. The residue was purified by HPLC using the 20-80% method to give 2-(4-chloro3-(1-hydroxyethyl)-5methylpyrazol-1-yl)-1-(4-(4- Chloro-3-methoxyphenyl)piperazin-1-yl)ethanone: LC MS: m/z 427M+H, _Rt =3.91 minutes (Agilent ZorbaxSB-C18, 2.1×50mm, 5μ, 35°C) , using a 4.5 minute gradient of 20-95% B with a 1.1 minute wash at 95% B (A = 0.1% formic acid/5% acetonitrile/94.9% water, B = 0.08% formic acid/99.9% acetonitrile).

Synthesis of 2-[3-(2-aminomethylpyridin-4-yl)-4-chloro-5-methylpyrazol-1-yl]-1-[4-(4-chloro-3-methoxy Phenyl)piperazin-1-yl]ethanone

4-(4-chloro-1-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl} at 0°C -5-Methyl-1H-pyrazol-3-yl)-pyridine-2-carbonitrile (49 mg) in MeOH (1 mL) was added CoCl ₂ ·6H ₂ O (71 mg) and NaBH ₄ (114 mg). The reaction mixture was stirred for an additional 30 minutes at 0 °C and quenched by the addition of water (1 mL). The mixture was filtered and purified by preparative HPLC to afford the title compound: LCMS (ES) M+H 489.1; R _f 3.13 min (Agilent Zorbax SB-C18, 2.1 x 50 mm, 5 μ, 35 °C), 4.5 with 20-95% B Minute gradient with a 1.1 minute wash at 95% B (A = 0.1% formic acid/5% acetonitrile/94.9% water, B = 0.08% formic acid/99.9% acetonitrile).

Scheme NN: Preparation of compounds using reactions involving nickel and chromium

2-[4-Chloro-5-(1-hydroxy-ethyl)-3-trifluoromethyl-pyrazol-1-yl]-1-[4-(4-chloro-3-methoxy-benzene Base)-piperazin-1-yl]-ethanone

2-(4-chloro-5-iodo-3-trifluoromethylpyrazol-1-yl)-1-(4-(4-chloro-3-methoxyphenyl)piperazin-1-yl ) ethyl ketone (100 mg, 0.18 mmol) was added to acetaldehyde (156 mg, 3.56 mmol) and chromous chloride (218 mg, 1.78 mmol) to a 0°C stirred solution of 1% _NiCl2 (2 mg) in anhydrous DMSO . The reaction was removed from the bath and stirring was continued for 2 hours. Then, the reaction mixture was diluted with saturated aqueous ammonium chloride and extracted with ethyl acetate (3 x 20 mL). The combined organic layers _were washed with water, brine, dried ( _Na2SO4 ), and concentrated. The residue was purified by HPLC to afford the title compound in 55% yield. LC MS: m/z 481 (M+H), retention time = 4.68 min (Agilent Zorbax SB-C18, 2.1 x 50 mm, 5 μ, 35° C.) using a 4.5 min gradient from 20-95% B at 95% B A 1.1 minute wash was used (A = 0.1% formic acid/5% acetonitrile/94.9% water, B = 0.08% formic acid/99.9% acetonitrile).

Synthesis of 2-(4-chloro-5-(1-hydroxyphenylmethyl)-3-trifluoromethylpyrazol-1-yl)-1-(4-(4-chloro-3-methoxybenzene Base) piperazin-1-yl) ethanone:

The title compound was synthesized following the same scheme as above. LC MS: m/z 543 (M+H), _Rt = 5.20 min (Agilent Zorbax SB-C18, 2.1 x 50 mm, 5 μ, 35 °C) with a 4.5 min gradient of 20-95% B at 95% B 1.1 minute wash (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.08% formic acid/99.9% acetonitrile); ¹ H NMR (400MHz, CDCl ₃ ): δ3.08-3.20(m, 4H), 3.40-3.45(m, 1H), 3.51-3.58(m, 1H), 3.75(apparent t, J=5.1Hz, 2H), 3.89(s, 3H), 4.33(d, J=16.1Hz, 1H), 4.70(d, J=6.6Hz, 1H), 4.96(d, J=16.1Hz, 1H), 6.19(apparent d, J=6.2Hz, 1H), 6.40(apparent dd, J=3.6 & 8.8 Hz, 1H), 6.46 (apparent d, J=2.6Hz, 1H), 7.20-7.40 (m, 5H).

Synthesis of 2-(5-benzoyl-4-chloro-3-trifluoromethylpyrazol-1-yl)-1-(4-(4-chloro-3-methoxyphenyl)piperazine-1 -yl) ethyl ketone:

MnO ₂ (20 mg) was added to 2-(4-chloro-5-(1-hydroxyphenylmethyl)-3-trifluoromethylpyrazol-1-yl)-1-( A stirred solution of 4-(4-chloro-3-methoxyphenyl)piperazin-1-yl)ethanone (20 mg) in anhydrous dichloromethane (1 mL). Stirring was continued at the same temperature for 24 hours. Then, the reaction mixture was diluted with acetone and passed through a short column of SiO ₂ to remove inorganic impurities. The effluent was concentrated and the residue was purified by HPLC to afford the title compound in 85% yield. LC MS: m/z 541 (M+H), method 20-95, _Rt = 5.64 min (Agilent Zorbax SB-C18, 2.1 x 50 mm, 5 μ, 35 °C) with a 4.5 min gradient of 20-95% B , 1.1 min wash at 95% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.08% formic acid/99.9% acetonitrile); ¹ H NMR (400MHz, CDCl ₃ ): δ3.07 (t, J=5.1Hz, 2H), 3.21(t, J=4.8Hz, 2H), 3.60(t, J=5.1Hz, 2H), 3.65(t, J=5.1Hz, 2H), 3.89(s , 3H), 5.44(s, 2H), 4.33(d, J=16.1Hz, 1H), 4.70(d, J=6.6Hz, 1H), 6.40(apparent dd, J=2.6 & 8.3Hz, 1H), 6.46 (apparent d, J=3Hz, 1H), 7.20-7.22 (m, 1H), 7.50-7.54 (m, 2H), 7.63-7.67 (m, 1H), 7.89-7.91 (m, 2H).

Synthesis of [4-chloro-5-(2-hydroxy-propyl)-3-trifluoromethyl-pyrazol-1-yl]-acetic acid:

The above compound was synthesized by a two-step method. The first step follows the routine scheme NN involving chromous chloride followed by basic hydrolysis of the ester to give the title compound.

Scheme OO: Reductive Amination of Aryl Aldehydes Using Borohydride Reagents

1-[4-(4-chloro-2-dimethylaminomethyl-5-methoxy-phenyl)-piperazin-1-yl]-2-(4-chloro-5-methyl-3 -Trifluoromethyl-pyrazol-1-yl)ethanone:

Add 200 mg of 5-chloro-2-{4-[2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl to a 4 mL vial equipped with a stir bar ]-piperazin-1-yl}-4-methoxy-benzaldehyde (0.42mmol, 1.0eq), 5 μL AcOH (ca. Amine and 1.0 mL 1:1 (v/v) THF:MeOH; the mixture was stirred at room temperature for 0.5 h, after which 79 mg NaBH3CN (1.26 mmol, 3.0 eq) was added. The vial was then capped loosely and stirring was continued overnight at room temperature. The crude product was purified by preparative HPLC followed by treatment with 4M HCl in p-dioxane to give the title compound: LC/MS (ES) (M+H) 508.2; retention time 5.42 minutes (Agilent Zorbax SB-C18, 2.1 x 50 mm, 5 μ, 35° C.) with a 2.0-minute no-gradient time at 20% B, followed by a 5.0-minute gradient from 20-95% B, with a 2.5-minute wash at 95% B (A = 0.1% formic acid/5 % acetonitrile/94.9% water, B=0.08% formic acid/99.9% acetonitrile).

1-{4-[4-Chloro-2-(isopropylamino-methyl)-5-methoxy-phenyl]-piperazin-1-yl}-2-(4-chloro-5-methyl -3-trifluoromethyl-pyrazol-1-yl)-ethanone:

Following the above scheme OO, using isopropylamine, the title compound was obtained: LC/MS (ES) (M+H) 522.2, using the same method as above scheme, retention time 5.73 minutes.

1-{4-[4-chloro-2-(ethylamino-methyl)-5-methoxy-phenyl]-piperazin-1-yl}-2-(4-chloro-5-methyl -3-Trifluoromethyl-pyrazol-1-yl)-ethanone:

Following the above scheme OO, using ethylamine, the title compound was obtained: LC/MS (ES) (M+H) 508.2, using the same method as above scheme, retention time 5.73 minutes.

1-[4-(4-chloro-2-cyclopentylaminomethyl-5-methoxy-phenyl)-piperazin-1-yl]-2-(4-chloro-5-methyl-3 -Trifluoromethyl-pyrazol-1-yl)-ethanone:

Following the above scheme OO, using aminocyclopentane, the title compound was obtained: LC/MS (ES) (M+H) 548.2, using the same method as above scheme, retention time 5.90 minutes.

1-[4-(4-chloro-5-methoxy-2-morpholin-4-ylmethyl-phenyl)-piperazin-1-yl]-2-(4-chloro-5-methyl -3-Trifluoromethyl-pyrazol-1-yl)-ethanone:

Following the above scheme OO, using morpholine, the title compound was obtained: LC/MS (ES) (M+H) 550.2, using the same method as above scheme, retention time 5.36 minutes.

1-[4-(2-Acetyl-4-chloro-5-methoxy-phenyl)-piperazin-1-yl]-2-(4-chloro-5-methyl-3-trifluoromethane Base-pyrazol-1-yl)-ethanone:

Add 8.0 _g of 1-{4-[4-chloro-2-(1-hydroxy-ethyl)-5-methoxy -Phenyl]-piperazin-1-yl}-2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-ethanone (16.2 mmol, 1.0 eq). Add 9.1 g of PDC (24.2 mmol, 1.5 eq) and stir overnight at room temperature. The solvent was removed under vacuum and the crude product was purified by column chromatography (chloroform/hexane) to give the title compound: LC/MS (ES) (M+H) 493.1; retention time = 4.90 minutes (Agilent Zorbax SB-C18, 2.1× 50mm, 5μ, 35°C) with a 2.0-minute no-gradient time at 20% B, followed by a 5.0-minute gradient from 20-95% B with a 2.5-minute wash at 95% B (A = 0.1% formic acid/5% acetonitrile /94.9% water, B=0.08% formic acid/99.9% acetonitrile).

Scheme PP: Reductive amination of aryl ketones using borohydride reagents

1-{4-[4-chloro-5-methoxy-2-(1-methylamino-ethyl)-phenyl]-piperazin-1-yl}-2-(4-chloro-5- Methyl-3-trifluoromethyl-pyrazol-1-yl)-ethanone:

In a 4 mL vial equipped with a stir bar add 100 mg 1-[4-(2-acetyl-4-chloro-5-methoxy-phenyl)-piperazin-1-yl]-2- (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-ethanone (0.20mmol, 1.0eq), 180 μL Ti(OiPr)4 (0.60mmol, 3.0eq) and 2.5 eq methylamine (2M in THF). The mixture was stirred at room temperature for 3 hours, then 38 mg NaBH3CN (0.60 mmole, 3.0 eq) was added to the vial, and the mixture was stirred overnight. The reaction was quenched with a small amount of aqueous HCl and the white precipitate formed was vacuum filtered and discarded. The mother liquor was purified by HPLC. The product was redissolved in dichloromethane and washed with 0.5M aqueous EDTA. The organic phase was separated and dried in vacuo. The residue was treated with 4M HCl in p-dioxane to give the title compound as a solid: LC/MS (ES) (M+H) 508.1, RT = 5.08 min (Agilent Zorbax SB-C18, 2.1 x 50mm, 5 μ, 35° C.) with a 2.0-minute no-gradient time at 20% B, followed by a 5.0-minute gradient from 20-95% B with a 2.5-minute wash at 95% B (A = 0.1% formic acid/5% acetonitrile/94.9 % water, B = 0.08% formic acid/99.9% acetonitrile).

1-{4-[4-chloro-2-(1-dimethylamino-ethyl)-5-methoxy-phenyl]-piperazin-1-yl}-2-(4-chloro-5 -Methyl-3-trifluoromethyl-pyrazol-1-yl)-ethanone:

According to the above scheme PP, using dimethylamine, the title compound was obtained: LC/MS (ES) (M+H) 522.1, using the same method as the above scheme, retention time 5.02 minutes.

1-{4-[4-chloro-5-methoxy-2-(1-ethylamino-ethyl)-phenyl]-piperazin-1-yl}-2-(4-chloro-5- Methyl-3-trifluoromethyl-pyrazol-1-yl)-ethanone:

According to the above scheme PP, using ethylamine, the title compound was obtained: LC/MS (ES) (M+H) 522.1, using the same method as the above scheme, retention time 4.96 minutes.

1-{4-[4-chloro-5-methoxy-2-(1-isopropylamino-ethyl)-phenyl]-piperazin-1-yl}-2-(4-chloro-5 -Methyl-3-trifluoromethyl-pyrazol-1-yl)-ethanone:

Following the above scheme PP, using isopropylamine, the title compound was obtained: LC/MS (ES) (M+H) 536.2, using the same method as above scheme, retention time 5.10 minutes.

1-{4-[4-chloro-5-methoxy-2-(1-cyclopentylamino-ethyl)-phenyl]-piperazin-1-yl}-2-(4-chloro-5 -Methyl-3-trifluoromethyl-pyrazol-1-yl)-ethanone:

According to the above scheme PP, using cyclopentylamine, the title compound was obtained: LC/MS (ES) (M+H) 562.2, using the same method as the above scheme, retention time 5.19 minutes.

1-{4-[4-chloro-5-methoxy-2-(1-pyrrolidin-1-yl-ethyl)-phenyl]-piperazin-1-yl}-2-(4-chloro -5-methyl-3-trifluoromethyl-pyrazol-1-yl)-ethanone:

According to the above scheme PP, using cyclopentylamine, the title compound was obtained: LC/MS (ES) (M+H) 548.2, using the same method as the above scheme, retention time 5.12 minutes.

Scheme QQ: General procedure for the preparation of oxime derivatives from aromatic aldehydes and ketones

In a 4 mL vial equipped with a stir bar add 100 mg of the appropriate carbonyl compound (0.20 mmol, 1.0 eq), 90 µL of Ti(OiPr) ₄ (0.30 mmol, 1.5 eq) and 5.0 eq of the appropriate hydroxylamine hydrochloride in 500 µL of THF: The mixture was stirred overnight at 60°C. The reaction was quenched with a small amount of concentrated HCl and purified by preparative HPLC. The _free base was prepared by dissolving the product in DCM and extracting with aqueous _K2CO3 , after which the organic phase was separated and dried in vacuo. Analysis was by LCMS using the following method: (Agilent Zorbax SB-C18, 2.1 x 50 mm, 5 μ, 35° C.) with a 2.0 minute no gradient time of 20% B followed by a 5.0 minute gradient of 20-95% B at 95 A 2.5 minute wash was used for %B (A = 0.1% formic acid/5% acetonitrile/94.9% water, B = 0.08% formic acid/99.9% acetonitrile).

5-chloro-2-{4-[2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-piperazin-1-yl}-4 -Methoxy-benzaldehyde oxime:

Following protocol QQ, using 5-chloro-2-{4-[2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-piperazine-1 -YL}-4-Methoxy-benzaldehyde and hydroxylamine gave the title compound as a mixture of cis and trans isomers: LC/MS (ES) (M+H) 494.1, retention time = 4.70 min.

5-chloro-2-{4-[2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-piperazin-1-yl}-4 -Methoxy-benzaldehyde O-methyl-oxime:

Following protocol QQ, using 5-chloro-2-{4-[2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-piperazine-1 -yl}-4-methoxy-benzaldehyde and O-methylhydroxylamine gave the title compound as a mixture of cis and trans isomers: LC/MS (ES) (M+H) 508.1, retention time = 4.67 minutes.

1-{4-[4-Chloro-2-(1-(Z)-hydroxyimino-ethyl)-5-methoxy-phenyl]-piperazin-1-yl}-2-(4- Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-ethanone:

Following protocol QQ, using 1-[4-(2-acetyl-4-chloro-5-methoxy-phenyl)-piperazin-1-yl]-2-(4-chloro-5-methyl- 3-Trifluoromethyl-pyrazol-1-yl)-ethanone and hydroxylamine gave the title compound: LC/MS (ES) (M+H) 508.1, retention time = 4.73 min.

1-{4-[4-Chloro-2-(1-(E)-hydroxyimino-ethyl)-5-methoxy-phenyl]-piperazin-1-yl}-2-(4- Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-ethanone:

Following protocol QQ, using 1-[4-(2-acetyl-4-chloro-5-methoxy-phenyl)-piperazin-1-yl]-2-(4-chloro-5-methyl- 3-Trifluoromethyl-pyrazol-1-yl)-ethanone and hydroxylamine gave the title compound: LC/MS (ES) (M+H) 508.1, retention time = 4.67 min.

1-{4-[4-Chloro-5-methoxy-2-(1-(Z)-methoxyimino-ethyl)-phenyl]-piperazin-1-yl}-2-( 4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-ethanone:

Following protocol QQ, using 1-[4-(2-acetyl-4-chloro-5-methoxy-phenyl)-piperazin-1-yl]-2-(4-chloro-5-methyl- 3-Trifluoromethyl-pyrazol-1-yl)-ethanone and O-methylhydroxylamine gave the title compound: LC/MS (ES) (M+H) 522.1, retention time = 5.27 min.

1-{4-[4-Chloro-5-methoxy-2-(1-(E)-methoxyimino-ethyl)-phenyl]-piperazin-1-yl}-2-( 4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-ethanone:

Following protocol QQ, using 1-[4-(2-acetyl-4-chloro-5-methoxy-phenyl)-piperazin-1-yl]-2-(4-chloro-5-methyl- 3-Trifluoromethyl-pyrazol-1-yl)-ethanone and O-methylhydroxylamine gave the title compound: LC/MS (ES) (M+H) 522.1, retention time = 5.42 min.

Scheme RR: General scheme for addition of organometallic reagents to aldehydes followed by deprotection and Bop-involved coupling

Synthesis of 1-[4-(4-chloro-3-methoxy-phenyl)-2-(1-hydroxy-ethyl)-piperazin-1-yl]-2-(4-chloro-5-methyl -3-trifluoromethyl-pyrazol-1-yl)-ethanone:

Rapidly stirred solution of 4-(4-chloro-3-methoxy-phenyl)-2-formyl-piperazine-1-carboxylic acid tert-butyl ester (120 mg, 0.338 mmol) in 2.5 mL THF at -78 °C MeMgBr (0.17 mL, 3.0M) was added dropwise. The homogeneous mixture was stirred at -78°C for 1 hour, the cooling bath was removed, and then quenched with saturated ammonium chloride. The resulting solution was partitioned between ethyl acetate and saturated sodium bicarbonate, the organic phase was separated and the aqueous phase was extracted with ethyl acetate (3 x 25 mL). The combined organic phases were dried over sodium sulfate and concentrated in vacuo to provide 120 mg of hydroxyethylpiperazine. The crude product (110 mg, 0.296 mmol) was dissolved in 2.3 mL of dichloromethane, the temperature was lowered to 0°C, and TFA (0.228 mL, 2.96 mmol) was added dropwise. The reaction was stirred at 0°C for 15 minutes, the ice bath removed, and stirred at room temperature for an additional 265 minutes. The resulting solution was concentrated under reduced pressure to provide the deprotected amine as a dark foam. In a 10 mL flask were sequentially added crude amine salt, (4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid (86 mg, 0.355 mmol), diisopropylethylamine (0.226 mL, 1.30 mmol) and DMF (4 mL). The temperature of the solution was lowered to 0 °C, and BOP (157 mg, 0.355 mmol) was added in one portion. The reaction was stirred at 0°C for 10 minutes, warmed to room temperature, and stirred for another 3 hours. The resulting solution was diluted with ether, quenched with saturated ammonium chloride, partitioned between sodium bicarbonate and ethyl acetate, and the aqueous layer was extracted with ethyl acetate (4 x 35 mL). The combined organic layers were diluted with 30 mL of hexanes, washed with saturated sodium bicarbonate (2 x 30 mL), dried over sodium sulfate, and concentrated in vacuo. The crude product (168 mg) was purified by column chromatography (30:70 EtOAc:Hexanes) to provide 39 mg of the title compound: MS (ES) M+H expected 495.1, found 495.0; HPLC _Rt = 5.05 min using the following method: (Agilent Zorbax SB-C18, 2.1×50 mm, 5 μ, 35° C.), using a 4.5-minute gradient of 20-95% B with a 1.1-minute wash at 95% B (A=0.1% formic acid/5% acetonitrile/94.9 % water, B = 0.08% formic acid/99.9% acetonitrile).

Synthesis of 1-[4-(4-chloro-3-methoxy-phenyl)-2-(1-hydroxy-2-methyl-propyl)-piperazin-1-yl]-2-(4- Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-ethanone

Following the sequence of steps in Scheme RR using isopropylmagnesium chloride as the organometallic reagent provided the title compound: MS (ES) M+H expected 523.1, found 523.1; HPLC _Rt = 5.59 min.

Synthesis of 1-[4-(4-chloro-3-methoxy-phenyl)-2-(hydroxy-phenyl-methyl)-piperazin-1-yl]-2-(4-chloro-5- Methyl-3-trifluoromethyl-pyrazol-1-yl)-ethanone

Following the sequence of steps in Scheme RR using phenylmagnesium bromide as the organometallic reagent provided the title compound: MS (ES) M+H expected 557.1, found 557.1; HPLC _Rt = 5.59 min.

Synthesis of 1-[4-(4-chloro-3-methoxy-phenyl)-2-(1-hydroxy-2-phenyl-ethyl)-piperazin-1-yl]-2-(4- Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-ethanone

Following the sequence of steps in Scheme RR using benzylmagnesium chloride as the organometallic reagent provided the title compound: MS (ES) M+H expected 571.1, found 571.1; HPLC _Rt = 5.61 min.

Synthesis of (5-chloro-2-{4-[2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-piperazin-1-yl} -4-methoxy-phenyl)-hydroxy-acetonitrile:

Step 1: To a solution of ethanol (0.018 mL, 0.313 mmol) in 25 mL THF at 0 °C was added n-BuLi (0.125 mL, 0.313 mmol) dropwise. The solution was stirred for 10 minutes, then trimethylsilylcyanide (0.625 mL, 4.70 mmol) was added. The reaction was stirred for another 10 minutes, and 5-chloro-2-{4-[2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-piperidine was added in one portion Azin-1-yl)-4-ethoxy-benzaldehyde (1.50 g, 3.13 mmol). The resulting solution was removed from the ice bath, stirred for 2.75 hours, then quenched with saturated ammonium bicarbonate. The aqueous layer was then extracted with ethyl acetate (3 x 40 mL), the combined organics were dried over sodium sulfate, and the solvent was removed in vacuo to afford 1.78 g (98%) of crude TMS hydroxynitrile which was used directly in the next step.

Step 2: In a 50 mL flask was added crude TMS hydroxynitrile, 3.1 mL 10% HCl, 10 mL water and 10 mL THF. The resulting solution was stirred vigorously for 90 minutes, then diluted with ethyl acetate and quenched with saturated sodium bicarbonate. The mixture was stirred for 5 minutes, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate (3 x 30 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo to yield 1.32 crude hydroxynitrile, which was contaminated with about 10% of the corresponding 6-benzaldehyde. Recrystallization (EtOAc/ _CH2Cl2 /hexanes) of the crude product provided 780 mg (50% ₎ of the desired hydroxynitrile with <5% aldehyde by-product: ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.42 (s, 1H), 6.81(s, 1H), 5.52(s, 1H), 5.00(s, 2H), 3.80(s, 3H), 3.65-3.83(m, 4H), 3.02-3.20(m, 2H ), 2.85-2.98 (m, 2H), 2.60 (s, 3H); MS (ES) M+H expected 506.1, found 506.1; HPLCR _t = 4.68 min.

Synthesis of (5-chloro-2-{4-[2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-piperazin-1-yl} -4-methoxy-phenyl)-oxo-acetonitrile

(5-chloro-2-{4-[2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-piperazin-1-yl} -4-Methoxy-phenyl)-hydroxy-acetonitrile (650 mg, 1.28 mmol) was dissolved in 1 mL of MeCN, diluted with 8 mL of dichloromethane, and Dess-Martin Periodinane (5.7 mL, 0.25 M) was added dropwise (due to recrystallization The starting material is poorly soluble in dichloromethane, the hydroxynitrile was dissolved in THF, and the solvent was removed under reduced pressure to form a foam in MeCN). After stirring for 3 hours, the reaction was quenched with saturated sodium thiosulfate and stirred for 10 minutes. The resulting solution was partitioned between ethyl acetate and sodium bicarbonate, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate (3 x 40 mL). The combined organics were dried over sodium sulfate and evaporated in vacuo to provide 550 mg (85%) of the desired acylnitrile, which was contaminated with about 10% 6-benzaldehyde, which was used directly in the next step.

Scheme SS: Formation of an amide bond via the reaction of an acyl nitrile with an amine

Synthesis of 5-chloro-4-methoxy-2-{4-[2-(5-methyl-4-phenyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-piper Azin-1-yl}-benzamide:

Add (5-chloro-2-{4-[2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-piperazine to a 4 mL scintillation vial -1-yl}-4-methoxy-phenyl)-oxo-acetonitrile (82 mg, 0.163 mmol), catalytic amount of dimethylaminopyridine, ammonia (0.813 mL, 2.0 M in MeOH) and dichloro Methane (0.8 mL). The resulting solution was stirred for 5 hours, concentrated in vacuo, and purified by reverse phase HPLC to provide the title compound: MS (ES) M+H expected 494.1, found 494.1; HPLC _Rt = 4.26 min using the following method: (Agilent Zorbax SB-C18 , 2.1×50mm, 5μ, 35°C), using a 4.5-minute gradient of 20-95% B, with a 1.1-minute wash at 95% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.08 % formic acid/99.9% acetonitrile).

Synthesis of 5-chloro-2-{4-[2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-piperazin-1-yl}- 4-Methoxy-N-methyl-benzamide:

Following Protocol SS, using methylamine, gave the title compound: MS (ES) M+H expected 508.1, found 508.1; HPLC _Rt = 4.44 min.

Synthesis of 5-chloro-2-{4-[2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-piperazin-1-yl}- 4-Methoxy-N,N-dimethyl-benzamide:

Following protocol SS using dimethylamine, the title compound was obtained: MS (ES) M+H expected 522.1, found 522.1; HPLC _Rt = 4.46 min.

Synthesis of 5-chloro-2-{4-[2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-piperazin-1-yl}- N-ethyl-4-methoxy-benzamide:

Following protocol SS, using ethylamine, the title compound was obtained: MS (ES) M+H expected 522.1, found 522.1; HPLC _Rt = 4.66 min.

Synthesis of 1-{4-[4-chloro-5-methoxy-2-(pyrrolidine-1-carbonyl)-phenyl]-piperazin-1-yl}-2-(5-methyl-4- Phenyl-3-trifluoromethyl-pyrazol-1-yl)-ethanone

Following Protocol SS, using pyrrolidine, afforded the title compound: MS (ES) M+H expected 548.1, found 548.1; HPLC _Rt = 4.64 min.

Synthesis of 1-{4-[4-chloro-5-methoxy-2-(morpholine-4-carbonyl)-phenyl]-piperazin-1-yl}-2-(4-chloro-5-methoxy -3-trifluoromethyl-pyrazol-1-yl)-ethanone

Following protocol SS, using morpholine, the title compound was obtained: MS (ES) M+H expected 564.1, found 564.1; HPLC _Rt = 4.42 min.

Synthesis of 5-chloro-2-{4-[2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-piperazin-1-yl}- 4-methoxy-N-(2-methoxy-ethyl)-benzamide:

Following protocol SS using 2-methoxyethylamine gave the title compound: MS (ES) M+H expected 552.1, found 552.1; HPLC _Rt = 4.66 min.

Synthesis of 5-chloro-2-{4-[2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-piperazin-1-yl}- 4-Methoxy-N-(2-morpholin-4-yl-ethyl)-benzamide

Following protocol SS, using 2-N-morpholino-ethylamine, afforded the title compound: MS (ES) M+H expected 607.2, found 607.2; HPLC _Rt = 3.47 min.

Synthesis of 1-{4-[4-chloro-5-methoxy-2-(4-pyrimidin-2-yl-piperazin-1-carbonyl)-phenyl]-piperazin-1-yl}-2- (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-ethanone

Following protocol SS using 1-(2-pyridyl)piperazine gave the title compound: MS (ES) M+H expected 641.2, found 641.1; HPLC _Rt = 4.77 min.

Synthesis of 5-chloro-2-{4-[2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-piperazin-1-yl}- 4-Methoxy-N-(2-pyridin-2-yl-ethyl)-benzamide

Following protocol SS using 2-(2-aminoethyl)pyridine, the title compound was obtained: MS (ES) M+H expected 599.2, found 599.1; HPLC _Rt = 3.75 min.

Synthesis of 1-{4-[4-chloro-5-methoxy-2-(4-pyridin-4-yl-piperazin-1-carbonyl)-phenyl]-piperazin-1-yl}-2- (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-ethanone

Following protocol SS using 1-(4-pyridyl)piperazine gave the title compound: MS (ES) M+H expected 640.2, found 640.1; HPLC _Rt = 3.61 min.

Synthesis of 5-chloro-2-{4-[2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-piperazin-1-yl}- N-(3-Imidazol-1-yl-propyl)-4-methoxy-benzamide

Following protocol SS using 1-(3-aminopropyl)imidazole gave the title compound: MS (ES) M+H expected 602.2, found 602.1; HPLC _Rt = 3.41 min.

Synthesis of 5-chloro-2-{4-[2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-piperazin-1-yl}- 4-Methoxy-benzoic acid methyl ester:

According to a variant of protocol P, 5-chloro-4-methoxy-2-piperazin-1-yl-benzoic acid methyl ester (183 mg, 0.642 mmol), (4-chloro-5-methyl -3-Trifluoromethyl-pyrazol-1-yl)-acetic acid (218 mg, 0.899 mmol) and triethylamine (0.45 mL, 3.21 mmol) in dichloromethane (5 mL) were added in one portion with BOP (397 mg, 0.899 mmol). Stir at 0°C for 15 minutes, then at room temperature for 165 minutes, and remove the solvent in vacuo. The resulting residue was partitioned between diethyl ether and saturated sodium bicarbonate, and the aqueous layer was extracted with diethyl ether (3 x 25 mL) and ethyl acetate (3 x 25 mL). The combined organic layers were dried over _Na2SO4 , concentrated in vacuo, and the resulting crude product was purified by silica gel chromatography (30:70 EtOAc:Hexanes) to provide 188 _mg (57% yield) of the title amide as a white solid.

Synthesis of tert-butyl 4-(4-chloro-3-methoxy-phenyl)-2-(R)-formyl-piperazine-1-carboxylate

4-(4-Chloro-3-methoxy-phenyl)-2-0°C to room temperature tert-butyl methyl-piperazine-1-carboxylate (1.10g, 2.08mmol) at 0°C in di To a solution in methyl chloride (30 mL) was added dropwise Dess-Martin Periodinane (16 mL, 0.25M). The resulting solution was stirred for 1 hour at 0°C and 1 hour at room temperature, then quenched with saturated sodium thiosulfate and saturated sodium bicarbonate. The aqueous layer was then extracted with ethyl acetate (3 x 30 mL). The combined organic layers were dried over sodium sulfate and the solvent was removed in vacuo. The residue was purified by column chromatography to provide 498 mg (46%) of the desired aldehyde.

Scheme TT: Synthesis of compounds via epoxide formation and ring opening reactions

Synthesis of (4-chloro-3-isopropenyl-5-methyl-pyrazol-1-yl)-ethyl acetate

Using Dean-Stark, 1.3 g of [4-chloro-3-(1-hydroxy-1-methyl-ethyl)-5-methyl-pyrazol-1-yl]-ethyl acetate and 15 ml of benzene were mixed with catalytic The amount of p-TSA was refluxed overnight. Washed with water, dried over _MgSO4 , and the solvent was removed. Purification by normal phase column (column: 25 g silica gel, 0%-10% EtOAc/Hexanes) afforded 0.4 g of the above titled product. HPLC retention time = 5.3 minutes (Agilent Zorbax SB-C18, 2.1 x 50mm, 5μ, 35°C) using a 4.5 minute gradient from 20-95% B with a 1.1 minute wash at 95% B (A = 0.1% formic acid /5% acetonitrile/94.9% water, B = 0.08% formic acid/99.9% acetonitrile); MS (ES) M+H expected = 243.1, found = 243.1. ¹ H NMR (CDCl ₃ , 400MHz) 5.80(d, 1H), 5.25(m, 1H), 4.81(s, 2H), 4.2(q, 2H), 2.21(s, 3H), 2.13(m, 3H) ppm, 1.57 (s, 2H), 1.29 (t, 3H) ppm.

Synthesis of [4-chloro-3-(1,2-dihydroxy-1-methyl-ethyl)-5-methyl-pyrazol-1-yl]-acetic acid

To 0.4 g (4-chloro-3-isopropenyl-5-methyl-pyrazol-1-yl)-ethyl acetate dissolved in DCM was added 1.3 eq 3-chloro-perbenzoic acid at ambient temperature. After 3 hours, 1.3eq _NaHCO3 was added. After stirring for 2 hours, additional DCM was added and the mixture was washed with saturated NaHCO ₃ , brine, and dried over MgSO ₄ . After filtration, the solvent was removed in vacuo to yield 0.5 g of crude epoxide.

The crude epoxide, 3ml THF, 1ml MeOH and 0.6ml 1N NaOH were mixed and stirred overnight. The mixture was neutralized to pH 5-6, most of the solvent was removed in vacuo, the residue was partitioned between water and ethyl acetate and the phases were separated. The aqueous phase was lyophilized to give the title compound: HPLC retention time = 0.35 min (Agilent Zorbax SB-C18, 2.1 x 50 mm, 5 μ, 35 °C) using a 4.5 min gradient from 20-95% B, 1.1 min at 95% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.08% formic acid/99.9% acetonitrile); MS(ES) M-H expected = 247.1, found = 246.9.

Example 4

This example illustrates the activities associated with representative compounds of the invention.

Materials and methods

A. cells

expressing CCR1 cells

a. THP-1 cells

THP-1 cells were obtained from ATCC (TIB-202), and after adding 2mM L-glutamate, 1.5g/l sodium bicarbonate, 4.5g/l glucose, 10mM HEPES, 1mM sodium pyruvate, 0.05% 2- Cultured as a suspension in RPMI-1640 medium with mercaptoethanol and 10% FBS. Cells were grown at 37°C in 5% CO ₂ /95% air, 100% humidity, and subcultured twice a week at a ratio of 1:5 (in the density range of 2×10 ⁵ to 2×10 ⁶ cells/ml cultured cells) and collected at 1×10 ⁶ cells/ml. THP-1 cells express CCR1 and can be used in CCR1 binding and functional assays.

b. Isolated human monocytes

Monocytes were isolated from human buffy coats using the Miltenyi Bead Isolation System (Miltenyi, Auburn, CA). Briefly, peripheral mononuclear cells were isolated by Ficoll gradient using standard methods, cells were washed with PBS, and red blood cells were lysed. The remaining cells were labeled with anti-CD14 antibody (MiltenyiBiotech, Auburn, CA) bound to magnetic beads. Labeled cells were passed through AutoMACS (Miltenyi, Auburn, CA), and positive fractions were collected. Monocytes express CCR1 and can be used for CCR1 binding and function tests.

b. test

1. Inhibition of CCR1 ligand binding

Cells expressing CCR1 were centrifuged and resuspended in assay buffer (20 mM HEPES pH 7.1, 140 mM NaCl, 1 mM CaCl ₂ , 5 mM MgCl ₂ with 0.2% bovine serum albumin) to a concentration of 5 for THP-1 cells. ×10 ⁶ cells/ml, the concentration of monocytes was 5×10 ⁵ . Binding assays were performed as described below. First, 0.1 ml of cells (5 x 10 ⁵ THP-1 cells/well or 5 x 10 ⁴ monocytes) were added to the test plate containing the compounds to give a final concentration of approximately 2-10 μM for each compound to be screened (or part of the dose effect of compound _IC50 determinations). Then, 0.01 mL ¹²⁵ I-labeled MIP-1α (obtained from Perkin Elmer Life Science, Boston, MA) or 0.1 mL ¹²⁵ I-labeled CCL15/leukotactin (obtained from Perkin Elmer Life Science) diluted to a final concentration of ~50 pM in assay buffer was added. Life Science, Boston, MA to obtain custom radiolabels), forming ~30000 cpm/well (using ¹²⁵ I-labeled MIP-1α for THP-1 cells and ¹²⁵ I-labeled CCL15/leukotactin for monocytes), blocking assay plate and incubate for approximately 3 hours at 4°C on a shaker platform. In a vacuum cell harvester (Packard Instruments; Meriden, CT), the reactions were pipetted onto GF/B glass filters pre-soaked in 0.3% polyethyleneimine (PEI) solution. Scintillation fluid (40 microliters; Microscint 20, Packard Instruments) was added to each well, the plate was sealed, and radioactivity was measured in a Topcount scintillation counter (Packard Instruments). Control wells containing diluent alone (for total counts) or excess MIP-1α or MIP-1β (1 μg/ml for non-specific binding) were used to calculate the total percent inhibition of the compound. _IC50 values were calculated with the computer program Prism from GraphPad, Inc. (San Diego, Ca). The _IC50 value is the concentration required to reduce the binding of labeled MIP-la to the receptor by 50%. (further descriptions of ligand binding and other functional assays can be found in Dairaghi et al., J.Biol.Chem.274:21569-21574 (1999), Penfold, et al., Proc.Natl.Acad.Sci.USA.96: 9839-9844 (1999) and Dairaghi et al., J. Biol. Chem. 272:28206-28209 (1997)).

2. Calcium mobilization

To measure the release of calcium from intracellular stores, cells (THP-1 or monocytes) were incubated in cell culture medium with 3 μM INDO-1AM dye (Molecular Probes, Eugene, OR) for 45 min at room temperature and treated with phosphate Buffered saline (PBS) washes. After addition of INDO-1 AM, the cells were resuspended in running buffer (Hank's balanced saline (HBSS) and 1% FBS). Calcium mobilization was measured using a Photon Technology International spectrophotometer (Photon Technology International; New Jersey), with excitation at 350 nm and simultaneous recording of fluorescence emission at 400 nm and 490 nm. Relative intracellular calcium levels are expressed as the 400nm/490nm emission ratio. Experiments were performed at 37° C. in sample cells of 2 ml of flow buffer each containing 10 ⁶ cells under constant mixing conditions. The chemokine ligand can be used in the range of 1-100 nM. The emission is plotted versus time (typically 2-3 minutes). Candidate blocking ligand compounds (concentrations up to 10 μM) were added at 10 s, followed by chemokine (i.e., MIP-1α; R&D Systems; Minneapolis, MN) at 60 s and a control chemokine at 150 s (ie, SDF-la; R&D Systems; Minneapolis, MN).

3. Chemotaxis assay

Chemotaxis buffer (Hank's balanced saline (HBSS) and 1% FBS) was performed in a 96-well chemotaxis chamber (Neuroprobe; Gaithersburg, MD) using filters coated with 5 μm porous polycarbonate, polyvinylpyrrolidone. Chemotaxis assay. Compound-mediated inhibition of CCR1-mediated migration was assessed using CCR1 chemokine ligands (ie, MIP-la, CCL15 Leukotactin; R&D Systems; Minneapolis, MN). Other chemokines (ie, SDF-1α; R&D Systems; Minneapolis, MN) were used as controls for specificity. Chemokines (ie, 0.1 nM CCL15/Leukotactin) in 29 microliters were added to the lower chamber and the amount of compound varied, the upper chamber contained 100000 THP-1 or monocytes in 20 microliters. Each chamber was incubated at 37°C for 1-2 hours, and the number of cells in the lower chamber was quantified by direct cell counting at 5 high-energy fields/well, or by CyQuant assay (Molecular Probes) (i.e., a fluorescent stain that measures nucleic acid content method and microscopic observation) for quantification.

Identification of CCR1 inhibitors

A. test

For the evaluation of small organic molecules that prevent the binding of the receptor CCR1 to the ligand, one can use the ability to detect radioligand (i.e., MIP-1α or CCL15/Leukotactin) in cells (e.g., THP-1 cells or isolated human monocytes). ) Assay for binding of cells expressing CCR1 on their surface. For compounds that inhibit binding, whether or not competitively inhibiting binding, fewer radioactive counts are observed when compared to non-inhibiting controls.

THP-1 cells and monocytes lack other chemokine receptors that bind the same set of chemokine ligands as CCR1 (ie, MIP-la, MPIF-1, Leukotactin, etc.). Equal amounts of cells were added to each well in the plate. Then, the cells were incubated with radiolabeled MIP-la. Unbound ligand is removed by washing the cells, and bound ligand is determined by taking radioactivity counts. Cells not incubated with any organic compound give total counts; non-specific binding is determined by incubating cells with unlabeled ligand and labeled ligand. % inhibition is determined by the following equation: % inhibition=(1-[(sample cpm)-(non-specific cpm)]/[(total cpm)-(non-specific cpm)])×100

B. Identification of inhibitors from compound libraries using CCR1-expressing cells

In a panel of compounds screened, the normalized standard deviation was 17%, indicating that an inhibitory activity of 34% or more was significant, and a threshold of 40% could be used. These pooled compounds formed 39 wells on the plate that exhibited greater than 40% inhibition of MIP-la binding. When the pooled compounds were screened for a second time on the plate, 14 of these wells had a ligand reduction of more than 40%. To determine which compound in each well inhibited MIP-la binding to CCR1, the pool was resolved by testing the inhibitory activity of each compound individually. Since some compounds may act together to inhibit binding, whereas a resolution assay only tests compounds individually, compounds that are effective in combination but not individually cannot be found in this assay. Testing the compounds individually can identify inhibitory candidate compounds:

C. Identification of Inhibitors from Compound Libraries Using CCR1 Expressing Cells

CCX-105 was identified from compound screening work.

1. Dose-response curve

To determine the affinity of candidate compounds for CCR1 and to determine their ability to inhibit ligand binding, inhibitory activity was assayed over a compound concentration range of 1×10 ⁻¹⁰ to 1×10 ⁻⁴ M. In the assays, the amount of compound was varied while cell number and ligand concentration were kept constant. Compound CCX-105 was assayed and found to be a potent inhibitor of CCR1-specific chemokine binding (see compound 1.001 in the table).

2. CCR1 function test

CCR1 is a seven transmembrane G-protein linked receptor. Some of these receptor-ligand-induced signaling cascades are characterized by a pulse-like release of calcium ions from intracellular stores. Calcium mobilization assays are performed to determine whether candidate CCR1 inhibitory compounds also block features of CCR1 signaling. Candidate compounds that inhibit ligand binding and inhibit signaling with greater specificity than other chemokine and non-chemokine receptors are highly desirable.

Calcium ions released in response to CCR1 chemokine ligands (ie, MIP-la, MPIF-1, Leukotactin, etc.) can be measured using the calcium indicator INDO-1. INDO-1/AM was added to THP-1 cells or monocytes, and calcium release was measured in response to addition of a CCR1 chemokine ligand (ie, MIP-la). To control specificity, non-CCR1 ligands were added, specifically bradykinin, which also signals through seven transmembrane receptors. In the absence of compound, a pulse of fluorescent signal was seen when MIP-la was added. If the compound specifically inhibits CCR1-MIP-1α signaling, only a small or no signal pulse is seen when MIP-1α is added, but a pulse can be observed when bradykinin is added. However, when the compound non-specifically inhibits signaling, neither pulses are seen upon addition of MIP-1[alpha] or bradykinin.

As shown below, CCX-105 can significantly or specifically inhibit signaling from CCR1.

Table 2 Inhibition of Calcium Signal Occurrence compound MIP-1α ¹ Bradykinin ¹ evaluate CCX-105 - + specific inhibition ¹ +, pulse observed; - no pulse observed, ns, nonspecific signal (see text)

A major function of chemokines is to regulate the migratory ability of cells expressing chemokine receptors, such as white blood cells. To demonstrate that CCX-105 not only inhibits CCR1-specific binding and signaling (at least as determined as described in the calcium mobilization assay), but also CCR1-mediated migration, a chemotaxis assay was used. THP-1 myelomonocytic leukemia cells (like monocytes) as well as freshly isolated monocytes can be used as chemoattraction for CCR1 chemokine ligands (i.e., MIP-1α, CCL15/Leukotactin) ) targets. Cells are placed in the upper compartment of a microwell migration chamber, while MIP-la (or other potent CCR1 chemokine ligand) and increasing concentrations of CCX-105 or other candidate compounds are located in the lower compartment. In the absence of inhibitors, cells would migrate into the lower chamber in response to chemokine agonists; if the compound inhibited CCR1 function, the majority of cells remained in the upper chamber. In order to determine the affinity of candidate compounds for CCR1 and to determine their ability to inhibit CCR1-mediated cell migration, in this chemotaxis assay, the inhibitory activity was at a compound concentration of 1×10 ^-10 -1×10 ^-4 M measured within the range. In this assay, the amount of compound is varied while cell number and chemokine agonist concentration are held constant. After the chemotaxis chamber was incubated at 37°C for 1-2 hours, the responding cells in the lower chamber were quantified by labeling with the CyQuant assay (Molecular Probes), a fluorescent staining method for measuring nucleic acid content. Assays were performed using Spectrafluor Plus (Tecan) measurements and the computer program Prism from GraphPad, Inc. (San Diego, Ca) was used to calculate _IC50 values. The _IC50 value is the concentration of compound required to inhibit by 50% the number of cells responding to a CCR1 agonist.

3. In vivo curative effect

Rabbit Model of Destructive Arthritis

A study was conducted to evaluate the effect of CCX-105 on inhibiting the inflammatory response in rabbits to intra-articular injection of bacterial membrane component lipopolysaccharide (LPS). The study design mimics the destructive joint inflammation seen in arthritis. Intra-articular injection of LPS results in an acute inflammatory response characterized by the release of cytokines and chemokines, many of which have been identified in rheumatoid arthritis joints. Leukocytes are markedly increased in synovial fluid and synovium in response to elevated levels of these chemotactic mediators. Selective antagonists of chemokine receptors have shown efficacy in this model (see Podolin et al., J. Immunol. 169(11):6435-6444 (2002)).

In a rabbit LPS study essentially as performed by Podolin et al. (ibid), treatment with vehicle alone (phosphate-buffered saline with 1% DMSO) or also with CCX-105 (dose 1 = 50 μM or dose 2 = One knee of a female New Zealand rabbit (approximately 2 kg) was treated intra-articularly with a total volume of 1.0 ml of LPS (10 ng) at 100 μM). Sixteen hours after LPS injection, the knees were lavaged and cell counts were performed. The beneficial effect of treatment was determined by histopathological evaluation of synovial fluid inflammation. Histopathological evaluation was performed using the following inflammation score: 1-minimal, 2-mild, 3-moderate, 4-moderate-significant. As shown below, CCX-105 can significantly and specifically inhibit the inflammatory response in vivo.

table 3

Efficacy of CCX-105 in a Rabbit Model of Destructive Arthritis Synovial Fluid Inflammation Score excipient 3 CCX-105 (Dose 1) 2 CCX-105 (Dose 2) 1

Evaluation of Compound 1.028 in Rat Collagen-Induced Arthritis Model

A type II collagen arthritis study at day 17 of onset was performed to evaluate the effect of compound 1.028 on arthritis-induced clinical ankle swelling. Rat collagen arthritis is an experimental model of polyarthritis, which has been widely used in preclinical experiments of many anti-arthritic agents (see J.Exp.Med.146(3) of Trentham et al.: 857-868 (1977 ), Bendele et al., Toxicologic Pathol. 27:134-142 (1999), Bendele et al., Arthritis Rheum 42:498-506 (1999)). This model is characterized by reliable onset and progression, easily measurable polyarticular inflammation, marked cartilage destruction associated with pannus formation, mild to moderate bone resorption, and periosteal bone hyperplasia.

Female Lewis rats (approximately 0.2 kg) were anesthetized with isoflurane and injected with 2 mg/ml bovine type II Collagen in Freund's incomplete adjuvant. From day 0 to day 17, compound 1.028 was injected subcutaneously daily at a dose of 25 mg/kg in a volume of 1 ml/kg in the following vehicle: 20% N,N-dimethylacetamide, 75% corn Oil, 5% Tween-80. The diameter of the ankle joint was measured with calipers and the degree of reduction in joint swelling was measured as a measure of therapeutic effect. As shown below, compound 1.028 can significantly and specifically inhibit arthritis-induced ankle joint swelling in vivo.

Table 4

Efficacy of Compound 1.028 in Collagen-Induced Arthritis Experiments in Rats Changes in joint diameter from day 9 to day 17 excipient 15.7%+/-2.0% normal 0%+/-0.3% Compound 1.028 9.1%+/-1.8%

In the table below, the structures and activities of representative compounds herein are provided. As described above, one or both of the activities of chemotaxis assays and/or binding assays are provided as follows: +, IC ₅₀ >12.5 μM; ++, 2500 nM < IC ₅₀ < 12.5 μM; +++, 500 nM < IC ₅₀ &lt; 2500 nM; and ++++, IC ₅₀ &lt; 500 nM.

table 5

It should be understood that the examples and implementations described herein are for illustrative purposes only, and that various modifications or changes may be suggested by those skilled in the art, which may be included within the spirit and scope of the application and the purview of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference.

Claims (78)

1. a kind of compound with following formula, or its pharmaceutically acceptable salt or N- oxides：

In formula,

Subscript n represents 1-2 integer；

Subscript m represents 0-10 integer；

Each R₁It is independently selected from following substituent：C_1-8Alkyl, C_1-8Haloalkyl, C_3-6Cycloalkyl, C_2-8Alkenyl and C_2-8Alkynyl ,-COR^a、-CO₂R^a、-CONR^aR^b、-NR^aCOR^b、-SO₂R^a、-X¹COR^a、-X¹CO₂R^a、-X¹CONR^aR^b、-X¹NR^aCOR^b、-X¹SO₂R^a、-X¹SO₂NR^aR^b、-X¹NR^aR^b、-X¹OR^a, wherein X¹Selected from C_1-4Alkylidene, C_2-4Alkenylene and C_2-4Alkynylene, R^aAnd R^bIt is each independently selected from：Hydrogen, C_1-8Alkyl, C_1-8Haloalkyl, C_3-6Cycloalkyl and aryl-C_1-4Alkyl, or optionally work as R^aAnd R^bWhen being connected on same nitrogen-atoms, they are combined to form with 0-2 other hetero atoms as five yuan of annular atom or hexatomic ring with the nitrogen-atoms, wherein, each R¹The aliphatic part of substituent is optionally by 1-3 following substituent group：-OH、-OR^m、-OC(O)NHR^m、-OC(O)N(R^m)₂、-SH、-SR^m、-S(O)R^m、-S(O)₂R^m、-SO₂NH₂、-S(O)₂NHR^m、-S(O)₂N(R^m)₂、-NHS(O)₂R^m、-NR^mS(O)₂R^m、-C(O)NH₂、-C(O)NHR^m、-C(O)N(R^m)₂、-C(O)R^m、-NHC(O)R^m、-NR^mC(O)R^m、-NHC(O)NH₂、-NR^mC(O)NH₂、-NR^mC(O)NHR^m、-NHC(O)NHR^m、-NR^mC(O)N(R^m)₂、-NHC(O)N(R^m)₂、-CO₂H、-CO₂R^m、-NHCO₂R^m、-NR^mCO₂R^m、-CN、-NO₂、-NH₂、-NHR^m、-N(R^m)₂、-NR^mS(O)NH₂With-NR^mS(O)₂NHR^m, wherein, each R^mIt independently is unsubstituted C_1-6Alkyl；

Ar¹It is selected from：Phenyl, naphthyl, pyridine radicals, pyrazinyl, pyridazinyl, pyrimidine radicals, triazine radical, quinolyl, quinoxalinyl and purine radicals, each of which is optionally by 1-5 R²Substituent replaces, the R²Independently selected from：Halogen ,-OR^c、-OC(O)R^c、-NR^cR^d、-SR^c、-R^e、-CN、-NO₂、-CO₂R^c、-CONR^cR^d、-C(O)R^c、-OC(O)NR^cR^d、-NR^dC(O)R^c、-NR^dC(O)₂R^e、-NR^c-C(O)NR^cR^d、-NH-C(NH₂)=NH ,-NR^eC(NH₂)=NH ,-NH-C (NH₂)=NR^e、-NH-C(NHR^e)=NH ,-NR^eC(NHR^e)=NH ,-NR^eC(NH₂)=NR^e、-NH-C(NHR^e)=NR^e、-NH-C(NR^eR^e)=NH ,-S (O) R^e、-S(O)₂R^e、-NR^cS(O)₂R^e、-S(O)₂NR^cR^d、-N₃、-C(NOR^c)R^d、-C(NR^cW)=NW ,-N (W) C (R^c)=NW ,-NR^cC(S)NR^cR^d、-X²C(NOR^c)R^d、-X²C(NR^cW)=NW ,-X²N(W)C(R^c)=NW ,-X²NR^cC(S)NR^cR^d、-X²OR^c、-O-X²OR^c、-X²OC(O)R^c、-X²NR^cR^d、-O-X²NR^cR^d、-X²SR^c、-X²CN、-X²NO₂、-X²CO₂R^c、-O-X²CO₂R^c、-X²CONR^cR^d、-O-X²CONR^cR^d、-X²C(O)R^c、-X²OC(O)NR^cR^d、-X²NR^dC(O)R^c、-X²NR^dC(O)₂R^e、-X²NR^cC(O)NR^cR^d、-X²NH-C(NH₂)=NH ,-X²NR^eC(NH₂)=NH ,-X²NH-C(NH₂)=NR^e、-X²NH-C(NHR^e)=NH ,-X²S(O)R^e、-X²S(O)₂R^e、-X²NR^cS(O)₂R^e、-X²S(O)₂NR^cR^d、-X²N₃、-NR^d-X²OR^c、-NR^d-X²NR^cR^d、-NR^d-X²CO₂R^cWith-NR^d-X²CONR^cR^d, wherein W is selected from R^c、-CN、-CO₂R^eWith-NO₂, wherein X²Selected from C_1-4Alkylidene, C_2-4Alkenylene and C_2-4Alkynylene, R^cAnd R^dIt is each independently selected from hydrogen, C_1-8Alkyl, C_1-8Haloalkyl, C_3-6Cycloalkyl, C_2-8Alkenyl, C_2-8Alkynyl, aryl, heteroaryl, aryl-C_1-4Alkyl and aryloxy group-C_1-4Alkyl, or optionally work as R^cAnd R^dWhen being connected on same nitrogen-atoms, they are combined to form with 0-2 other hetero atoms as five yuan of annular atom or hexatomic ring with the nitrogen-atoms；Each R^eIndependently selected from C_1-8Alkyl, C_1-8Haloalkyl, C_3-6Cycloalkyl, C_2-8Alkenyl, C_2-8Alkynyl, aryl, heteroaryl, aryl-C_1-4Alkyl and aryloxy group-C_1-4Alkyl, R^c、R^dAnd R^eEach also optionally it is selected from following substituent group by 1-3：-OH、-ORⁿ、-OC(O)NHRⁿ、-OC(O)N(Rⁿ)₂、-SH、-SRⁿ、-S(O)Rⁿ、-S(O)₂Rⁿ、-SO₂NH₂、-S(O)₂NHRⁿ、-S(O)₂N(Rⁿ)₂、-NHS(O)₂Rⁿ、-NRⁿS(O)₂Rⁿ、-C(O)NH₂、-C(O)NHRⁿ、-C(O)N(Rⁿ)₂、-C(O)Rⁿ、-NHC(O)Rⁿ、-NRⁿC(O)Rⁿ、-NHC(O)NH₂、-NRⁿC(O)NH₂、-NRⁿC(O)NHRⁿ、-NHC(O)NHRⁿ、-NRⁿC(O)N(Rⁿ)₂、-NHC(O)N(Rⁿ)₂、-CO₂H、-CO₂Rⁿ、-NHCO₂Rⁿ、-NRⁿCO₂Rⁿ、-CN、-NO₂、-NH₂、-NHRⁿ、-N(Rⁿ)₂、-NRⁿS(O)NH₂With-NRⁿS(O)₂NHRⁿ, wherein each RⁿIt is independently unsubstituted C_1-6Alkyl；

HAr is heteroaryl, selected from pyrazolyl, imidazole radicals, triazolyl, tetrazole radical, _ oxazolyl, different _ oxazolyl, _ di azoly, _ thiadiazolyl group, pyrrole radicals, thiazolyl, isothiazolyl, benzimidazolyl, benzopyrazoles base and BTA base, each of which is by 1-5 R³Substituent replaces, the R³Substituent independently selected from：Halogen ,-OR^f、-OC(O)R^f、-NR^fR^g、-SR^f、-R^h、-CN、-NO₂、-CO₂R^f、-CONR^fR^g、-C(O)R^f、-OC(O)NR^fR^g、-NR^gC(O)R^f、-NR^gC(O)₂R^h、-NR^f-C(O)NR^fR^g、-NH-C(NH₂)=NH ,-NR^hC(NH₂)=NH ,-NH-C (NH₂)=NR^h、-NH-C(NHR^h)=NH ,-NR^hC(NHR^h)=NH ,-NR^hC(NH₂)=NR^h、-NH-C(NHR^h)=NR^h、-NH-C(NR^hR^h)=NH ,-S (O) R^h、-S(O)₂R^h、-NR^fS(O)₂R^h、-S(O)₂NR^fR^g、-NR^fS(O)₂NR^fR^g、-N₃、-C(NOR^f)R^g、-C(NR^fW^a)=NW^a、-N(W^a)C(R^f)=NW^a、-X³C(NOR^f)R^g、-X³C(NR^fW^a)=NW^a、-X³N(W^a)C(R^f)=NW^a、-NR^fC(S)NR^fR^g、-X³NR^fC(S)NR^fR^g、-X³OR^f、-X³OC(O)R^f、-X³NR^fR^g、-X³SR^f、-X³CN、-X³NO₂、-X³CO₂R^f、-X³CONR^fR^g、-X³C(O)R^f、-X³OC(O)NR^fR^g、-X³NR^gC(O)R^f、-X³NR^gC(O)₂R^h、-X³NR^f-C(O)NR^fR^g、-X³NH-C(NH₂)=NH ,-X³NR^hC(NH₂)=NH ,-X³NH-C(NH₂)=NR^h、-X³NH-C(NHR^h)=NH ,-X³S(O)R^h、-X³S(O)₂R^h、-X³NR^fS(O)₂R^h、-X³S(O)₂NR^fR^g、-Y、-SO₂Y、-C(O)Y、-X³Y、-X³N₃、-O-X³OR^f、-O-X³NR^fR^g、-O-X³CO₂R^f、-O-X³CONR^fR^g、-NR^g-X³OR^f、-NR^g-X³NR^fR^g、-NR^g-X³CO²R^fWith-NR^g-X³CONR^fR^g, wherein, W^aSelected from R^f、-CN、-CO₂R^hWith-NO₂, wherein, Y is 5-10 members aryl, heteroaryl or heterocycle, is optionally selected from following substituent group by 1-3：Halogen ,-OR^f、-NR^fR^g、-R^h、-SR^f、-CN、-NO₂、-CO₂R^f、-CONR^fR^g、-C(O)R^f、-NR^gC(O)R^f、-S(O)R^h、-S(O)₂R^h、-NR^fS(O)₂R^h、-S(O)₂NR^fR^g、-C(NOR^f)R^g、-C(NR^fW^a)=NW^a、-N(W^a)C(R^f)=NW^a、-X³C(NOR^f)R^g、-X³C(NR^fW^a)=NW^a、-X³N(W^a)C(R^f)=NW^a、-X³OR^f、-X³NR^fR^g、-X³NR^fS(O)₂R^hWith-X³S(O)₂NR^fR^g, wherein, each X³Independently selected from C_1-4Alkylidene, C_2-4Alkenylene and C_2-4Alkynylene, R^fAnd R^gIt is each independently selected from hydrogen, C_1-8Alkyl, C_1-8Haloalkyl, C_3-6Cycloalkyl, C_2-8Alkenyl, C_2-8Alkynyl, aryl, heteroaryl, aryl-C_1-4Alkyl and aryloxy group-C_1-4Alkyl, or combined when they are connected with same nitrogen-atoms with the nitrogen-atoms, 0-2 other hetero atoms are formed with as 5 yuan or 6 yuan of rings of annular atom, each R^hIndependently selected from C_1-8Alkyl, C_1-8Haloalkyl, C_3-6Cycloalkyl, C_2-8Alkenyl, C_2-8Alkynyl, aryl, heteroaryl, aryl-C_1-4Alkyl and aryloxy group-C_1-4Alkyl, wherein R^f、R^gAnd R^hAliphatic part optionally also replaced by 1-3 selected from following substituent：-OH、-OR^o、-OC(O)NHR^o、-OC(O)N(R^o)₂、-SH、-SR^o、-S(O)R^o、-S(O)₂R^o、-SO₂NH₂、-S(O)₂NHR^o、-S(O)₂N(R^o)₂、-NHS(O)₂R^o、-NR^oS(O)₂R^o、-C(O)NH₂、-C(O)NHR^o、-C(O)N(R^o)₂、-C(O)R^o、-NHC(O)R^o、-NR^oC(O)R^o、-NHC(O)NH₂、-NR^oC(O)NH₂、-NR^oC(O)NHR^o、-NHC(O)NHR^o、-NR^oC(O)N(R^o)₂、-NHC(O)N(R^o)₂、-CO₂H、-CO₂R^o、-NHCO₂R^o、-NR^oCO₂R^o、-CN、-NO₂、-NH₂、-NHR^o、-N(R^o)₂、-NR^oS(O)NH₂With-NR^oS(O)₂NHR^o, wherein each R^oIt is independently unsubstituted C_1-6Alkyl；

L¹It is the linker containing the 1-3 backbone atoms selected from C, N, O and S, and optionally can be replaced by 1-3 selected from following substituent：Halogen, phenyl ,-ORⁱ、-OC(O)Rⁱ、-NRⁱR^j、-SRⁱ、-R、-CN、-NO₂、-CO₂Rⁱ、-CONRⁱR^j、-C(O)Rⁱ、-OC(O)NRⁱR^j、-NR^jC(O)Rⁱ、-NR^jC(O)₂R^k、-X⁴ORⁱ、-X⁴OC(O)Rⁱ、-X⁴NRⁱR^j、-X⁴SRⁱ、-X⁴CN、-X⁴NO₂、-X⁴CO₂Rⁱ、-X⁴CONRⁱR^j、-X⁴C(O)Rⁱ、-X⁴OC(O)NRⁱR^j、-X⁴NR^jC(O)RⁱWith-X⁴NR^jC(O)₂R^k, wherein X⁴Selected from C_1-4Alkylidene, C_2-4Alkenylene and C_2-4Alkynylene, RⁱAnd R^jIt is each independently selected from：Hydrogen, C_1-8Alkyl, C_1-8Haloalkyl, C_3-6Cycloalkyl, C_2-8Alkenyl, C_2-8Alkynyl, aryl, heteroaryl, aryl-C_1-4Alkyl, aryloxy group-C_1-4Alkyl, each R^kIndependently selected from C_1-8Alkyl, C_1-8Haloalkyl, C_3-6Cycloalkyl, C_2-8Alkenyl, C_2-8Alkynyl, aryl, heteroaryl, aryl-C_1-4Alkyl and aryloxy group-C_1-4Alkyl；

On condition that, the compound is not CAS Reg.No.492422-98-7,1- [[bromo- 5- methyl -3- (the trifluoromethyl) -1H- pyrazol-1-yls of 4-] acetyl group] -4- (5- chloro-2-methyls phenyl)-piperazine；CASReg.No.351986-92-0,1- [[chloro- 5- methyl -3- (the trifluoromethyl) -1H- pyrazol-1-yls of 4-] acetyl group] -4- (4- fluorophenyls)-piperazine；CAS Reg.No.356039-23-1,1- [(3,5- dimethyl -4- nitro -1H- pyrazol-1-yls) acetyl group] -4- (4- fluorophenyls)-piperazine；1- (2- { 4- nitro -3,5- dimethyl -1H- pyrazol-1-yls } propiono) -4- phenylpiperazines；2- (2,4- dinitros-imidazoles -1- bases) -1- [4- (4- fluorophenyls)-piperazine -1- bases]-ethyl ketone；2- (2,4- dinitros-imidazoles -1- bases) -1- (4- phenyl-Piperazine -1- bases)-ethyl ketone；2- (4- nitro-imidazol -1- bases) -1- (4- phenyl-Piperazine -1- bases)-ethyl ketones and CAS Reg.No.492992-15-1,3- [the fluoro- 4- of 3- [4- [(1- pyrazolyls) acetyl group] piperazine -1- bases] phenyl] -5- [[(different _ azoles -3- bases) amino] methyl] different _ azoles.

2. compound as claimed in claim 1, it is characterised in that Ar¹It is selected from：

(i) phenyl, by 1-5 R²Substituent group；

(ii) pyridine radicals, by 1-4 R²Substituent group；With

(iii) pyrimidine radicals, by 1-3 R²Substituent group；

(iv) pyrazinyl, by 1-3 R²Substituent group；With

(v) pyridazinyl, by 1-3 R²Substituent group；

Wherein, each R²Independently selected from：Halogen ,-OR^c、-OC(O)R^c、-NR^cR^d、-SR^c、-R^e、-CN、-NO₂、-CO₂R^c、-CONR^cR^d、-C(O)R^c、-OC(O)NR^cR^d、-NR^dC(O)R^c、-NR^dC(O)₂R^e、-NR^c-C(O)NR^cR^d、-C(NOR^c)R^d、-C(NR^cW)=NW ,-N (W) C (R^c)=NW ,-S (O) R^e、-S(O)₂R^e、-NR^cS(O)₂R^e、-S(O)₂NR^cR^dWith-N₃。

3. compound as claimed in claim 1, it is characterised in that Ar¹It is selected from：

(i) phenyl, by 1-5 R²Substituent group；

(ii) pyridine radicals, by 1-4 R²Substituent group；With

(iii) pyrimidine radicals, by 1-3 R²Substituent group；

(iv) pyrazinyl, by 1-3 R²Substituent group；

(v) pyridazinyl, by 1-3 R²Substituent group；

Wherein, each R²Independently selected from：Halogen ,-X²OR^c、-O-X²OR^c、-X²OC(O)R^c、-X²NR^cR^d、-O-X²NR^cR^d、-X²SR^c、-X²CN、-X²NO₂、-X²CO₂R^c、-O-X²CO₂R^c、-X²CONR^cR^d、-O-X²CONR^cR^d、-X²C(O)R^c、-X²OC(O)NR^cR^d、-X²NR^dC(O)R^c、-X²NR^dC(O)₂R^e、-X²NR^cC(O)NR^cR^d、-X²NH-C(NH₂)=NH ,-X²NR^eC(NH₂)=NH ,-X²NH-C(NH₂)=NR^e、-X²NH-C(NHR^e)=NH ,-X²C(NOR^c)R^d、-X²C(NR^cW)=NW ,-X²N(W)C(R^c)=NW ,-X²S(O)R^e、-X²S(O)₂R^e、-X²NR^cS(O)₂R^e、-X²S(O)₂NR^cR^dWith-X²N₃。

4. compound as claimed in claim 1, it is characterised in that Ar¹It is by 1-3 R²The phenyl of substituent group.

5. compound as claimed in claim 4, it is characterised in that L¹It is-CH₂-, and optionally by phenyl ,-R^k、-X⁴ORⁱ、-X⁴OC(O)Rⁱ、-X⁴NRⁱR^j、-X⁴SRⁱ、-X⁴CN or-X⁴NO₂Substitution.

6. compound as claimed in claim 5, it is characterised in that HAr is selected from pyrazolyl and triazolyl, and they can be optionally by 1-3 R³Substituent group, the R³Group independently selected from：Halogen ,-OR^f、-OC(O)R^f、-NR^fR^g、-SR^f、-R^h、-CN、-NO₂、-CO₂R^f、-CONR^fR^g、-C(O)R^f、-OC(O)NR^fR^g、-NR^gC(O)R^f、-NR^gC(O)₂R^h、-NR^f-C(O)NR^fR^g、-NH-C(NH₂)=NH ,-NR^hC(NH₂)=NH ,-NH-C (NH₂)=NR^h、-NH-C(NHR^h)=NH ,-S (O) R^h、-S(O)₂R^h、-NR^fS(O)₂R^h、-S(O)₂NR^fR^g、-NR^fS(O)₂R^h、-NR^fS(O)₂NR^fR^g、-N₃、-X³OR^f、-X³OC(O)R^f、-X³NR^fR^g、-X³SR^f、-X³CN、-X³NO₂、-X³CO₂R^f、-X³CONR^fR^g、-X³C(O)R^f、-X³OC(O)NR^fR^g、-X³NR^gC(O)R^f、-X³NR^gC(O)₂R^h、-X³NR^f-C(O)NR^fR^g、-X³NH-C(NH₂)=NH ,-X³NR^hC(NH₂)=NH ,-X³NH-C(NH₂)=NR^h、-X³NH-C(NHR^h)=NH ,-X³S(O)R^h、-X³S(O)₂R^h、-X³NR^fS(O)₂R^h、-X³S(O)₂NR^fR^g、-Y、-X³Y and-X³N₃, wherein Y is aryl, heteroaryl or the heterocycle of 5-1O members, is optionally replaced by 1-3 selected from following substituent：Halogen ,-OR^f、-NR^fR^g、-R^h、-SR^f、-CN、-NO₂、-CO₂R^f、-CONR^fR^g、-C(O)R^f、-NR^gC(O)R^f、-S(O)R^h、-S(O)₂R^h、-NR^fS(O)₂R^h、-S(O)₂NR^fR^g、-X³OR^f、-X³NR^fR^g、-X³NR^fS(O)₂R^hWith-X³S(O)₂NR^fR^g, wherein each X³Independently selected from C_1-4Alkylidene, C_2-4Alkenylene and C_2-4Alkynylene, R^fAnd R^gIt is each independently selected from：Hydrogen, C_1-8Alkyl, C_1-8Haloalkyl, C_3-6Cycloalkyl, C_2-8Alkenyl, C_2-8Alkynyl, aryl, heteroaryl, aryl-C_1-4Alkyl and aryloxy group-C_1-4Alkyl, or combined when they are connected with same nitrogen-atoms with the nitrogen-atoms, 0-2 other hetero atoms are formed with as 5 yuan or 6 yuan of rings of annular atom, each R^hIndependently selected from C_1-8Alkyl, C_1-8Haloalkyl, C_3-6Cycloalkyl, C_2-8Alkenyl, C_2-8Alkynyl, aryl, heteroaryl, aryl-C_1-4Alkyl and aryloxy group-C_1-4Alkyl, R^f、R^gAnd R^hEach aliphatic part following substituent group is optionally also selected from by 1-3：-OH、-OR^o、-OC(O)NHR^o、-OC(O)N(R^o)₂、-SH、-SR^o、-S(O)R^o、-S(O)₂R^o、-SO₂NH₂、-S(O)₂NHR^o、-S(O)₂N(R^o)₂、-NHS(O)₂R^o、-NR^oS(O)₂R^o、-C(O)NH₂、-C(O)NHR^o、-C(O)N(R^o)₂、-C(O)R^o、-NHC(O)R^o、-NR^oC(O)R^o、-NHC(O)NH₂、-NR^oC(O)NH₂、-NR^oC(O)NHR^o、-NHC(O)NHR^o、-NR^oC(O)N(R^o)₂、-NHC(O)N(R^o)₂、-CO₂H、-CO₂R^o、-NHCO₂R^o、-NR^oCO₂R^o、-CN、-NO₂、-NH₂、-NHR^o、-N(R^o)₂、-NR^oS(O)NH₂With-NR^oS(O)₂NHR^o, wherein R^oIt is unsubstituted C_1-6Alkyl.

7. compound as claimed in claim 6, it is characterised in that n is that 1, m is 0-2, Ar¹It is by 1-3 R²The phenyl of substituent group, HAr is by 3 R³The pyrazolyl of substituent group, L¹It is-CH₂-。

8. compound as claimed in claim 7, it is characterised in that the Ar¹Substituted-phenyl part selected from Figure 1A into 1G.

9. compound as claimed in claim 7, it is characterised in that substituted pyrazolyls of the HAr selected from Fig. 2A to 2Z, 2AA into 2HH and Fig. 3.

10. compound as claimed in claim 8, it is characterised in that the R³One of group is selected from-Y and-X³- Y, Y therein is selected from phenyl, thienyl, furyl, pyridine radicals, pyrimidine radicals, pyrazinyl, pyridizinyl, pyrazolyl, imidazole radicals, thiazolyl, _ oxazolyl, different _ oxazolyl, isothiazolyl, triazolyl, tetrazole radical and _ di azoly, and they are optionally independently selected from following substituent by 1-3 and replaced：Halogen ,-OR^f、-NR^fR^g、-COR^f、-CO₂R^f、-CONR^fR^g、-NO₂、-R^h、-CN、-X³-OR^f、-X³-NR^fR^gWith-X³-NR^fS(O)₂R^h, wherein R^fAnd R^gIt is each independently selected from H, C_1-8Alkyl, C_3-6Cycloalkyl and C_1-8Haloalkyl, each R^hIndependently selected from C_1-8Alkyl, C_3-3Cycloalkyl and C_1-8Haloalkyl.

11. compound as claimed in claim 10, it is characterised in that Y is selected from phenyl and thienyl, each of which is optionally replaced by 1-3 independently selected from following substituent：Halogen ,-OR^f、-NR^fR^g、-COR^f、-CO₂R^f、-CONR^fR^g、-NO₂、-R^h、-CN、-X³-OR^f、-X³-NR^fR^gWith-X³-NR^fS(O)₂R^h, wherein R^fAnd R^gIt is each independently selected from H, C_1-8Alkyl, C_3-6Cycloalkyl and C_1-8Haloalkyl, each R^hIndependently selected from C_1-8Alkyl, C_3-6Cycloalkyl and C_1-8Haloalkyl.

12. compound as claimed in claim 1, the compound has following formula, or its pharmaceutically acceptable salt or N- oxides：

In formula, R^1a、R^1b、R^1c、R^1d、R^1e、R^1f、R^1gAnd R^1hEach represent and be selected from following group：H、C_1-8Alkyl, C_1-8Haloalkyl, C_3-6Cycloalkyl, C_2-8Alkenyl, C_2-8Alkynyl ,-COR^a、-CO₂R^a、-CONR^aR^b、-NR^aCOR^b、-SO₂R^a、-X¹COR^a、-X¹CO₂R^a、-X¹CONR^aR^b、-X¹NR^aCOR^b、-X¹SO₂R^a、-X¹SO₂NR^aR^b、-X¹NR^aR^b、-X¹OR^a, wherein X¹It is to be selected from C_1-4Alkylidene, C_2-4Alkenylene and C_2-4Alkynylene, R^aAnd R^bIt is each independently selected from hydrogen, C_1-8Alkyl, C_1-8Haloalkyl, C_3-6Cycloalkyl and aryl-C_1-4Alkyl, or optionally work as R^aAnd R^bWhen being connected on same nitrogen-atoms, they are combined to form with 0-2 other hetero atoms as five yuan of annular atom or hexatomic ring with the nitrogen-atoms, each R¹The aliphatic part of substituent is optionally selected from following substituent group by 1-3：-OH、-OR^m、-OC(O)NHR^m、-OC(O)N(R^m)₂、-SH、-SR^m、-S(O)R^m、-S(O)₂R^m、-SO₂NH₂、-S(O)₂NHR^m、-S(O)₂N(R^m)₂、-NHS(O)₂R^m、-NR^mS(O)₂R^m、-C(O)NH₂、-C(O)NHR^m、-C(O)N(R^m)₂、-C(O)R^m、-NHC(O)R^m、-NR^mC(O)R^m、-NHC(O)NH₂、-NR^mC(O)NH₂、-NR^mC(O)NHR^m、-NHC(O)NHR^m、-NR^mC(O)N(R^m)₂、-NHC(O)N(R^m)₂、-CO₂H、-CO₂R^m、-NHCO₂R^m、-NR^mCO₂R^m、-CN、-NO₂、-NH₂、-NHR^m、-N(R^m)₂、-NR^mS(O)NH₂With-NR^mS(O)₂NHR^m, wherein each R^mIt is independently unsubstituted C_1-6Alkyl；Ar¹It is by 1-5 R²The phenyl of substituent group；HAr is by 1-3 R³The pyrazolyl of substituent group.

13. compound as claimed in claim 12, it is characterised in that L¹It is-CH₂-。

14. compound as claimed in claim 13, it is characterised in that substituted pyrazolyls of the HAr selected from Fig. 2A to 2Z, 2AA into 2HH and Fig. 3.

15. compound as claimed in claim 14, it is characterised in that Ar¹It is by the R of 1-3 independent selection²The phenyl of substituent substitution.

16. compound as claimed in claim 15, it is characterised in that the Ar¹Substituted phenyl moiety selected from Figure 1A into 1G.

17. compound as claimed in claim 16, it is characterised in that R^1aTo R^1hIt is not H no more than two.

18. compound as claimed in claim 1, the compound has following formula：

In formula, subscript m is 0-2 integer；

Each R¹0 is selected from-CO₂H、C_1-4Alkyl and C_1-4Haloalkyl, aliphatic part therein is optionally by following substituent group：-OH、-OR^m、-OC(O)NHR^m、-OC(O)N(R^m)₂、-SH、-SR^m、-S(O)R^m、-S(O)₂R^m、-SO₂NH₂、-S(O)₂NHR^m、-S(O)₂N(R^m)₂、-NHS(O)₂R^m、-NR^mS(O)₂R^m、-C(O)NH₂、-C(O)NHR^m、-C(O)N(R^m)₂、-C(O)R^m、-NHC(O)R^m、-NR^mC(O)R^m、-NHC(O)NH₂、-NR^mC(O)NH₂、-N^mC(O)NHR^m、-NHC(O)NHR^m、-NR^mC(O)N(R^m)₂、-NHC(O)N(R^m)₂、-CO₂H、-CO₂R^m、-NHCO₂R^m、-NR^mCO₂R^m、-CN、-NO₂、-NH₂、-NHR^m、-N(R^m)₂、-NR^mS(O)NH₂With-NR^mS(O)₂NHR^m, wherein each R^mIt is independently unsubstituted C_1-6Alkyl；

R^2a、R^2b、R^2c、R^2dAnd R^2eIt is each independently selected from：Hydrogen, halogen ,-OR^c、-OC(O)R^c、-NR^cR^d、-SR^c、-R^e、-CN、-NO₂、-CO₂R^c、-CONR^cR^d、-C(O)R^c、-OC(O)NR^cR^d、-NR^dC(O)R^c、-NR^dC(O)₂R^e、-NR^c-C(O)NR^cR^d、-NH-C(NH₂)=NH ,-NR^eC(NH₂)=NH ,-NH-C (NH₂)=NR^e、-NH-C(NHR^e)=NH ,-S (O) R^e、-S(O)₂R^e、-NR^cS(O)₂R^e、-S(O)₂NR^cR^d、-N₃、-C(NOR^c)R^d、-C(NR^cW)=NW ,-N (W) C (R^c)=NW ,-NR^cC(S)NR^cR^d、-X²C(NOR^c)R^d、-X²C(NR^cW)=NW ,-X²N(W)C(R^c)=NW ,-X²NR^cC(S)NR^cR^d、-X²OR^c、-O-X²OR^c、-X²OC(O)R^c、-X²NR^cR^d、-O-X²NR^cR^d、-X²SR^c、-X²CN、-X²NO₂、-X²CO₂R^c、-O-X²CO₂R^c、-X²CONR^cR^d、-O-X²CONR^cR^d、-X²C(O)R^c、-X²OC(O)NR^cR^d、-X²NR^dC(O)R^c、-X²NR^dC(O)₂R^e、-X²NR^cC(O)NR^cR^d、-X²NH-C(NH₂)=NH ,-X²NR^eC(NH₂)=NH ,-X²NH-C(NH₂)=NR^e、-X²NH-C(NHR^e)=NH ,-X²S(O)R^e、-X²S(O)₂R^e、-X²NR^cS(O)₂R^e、-X²S(O)₂NR^cR^d、-X²N₃、-NR^d-X²OR^c、-NR^d-X²NR^cR^d、-NR^d-X²CO₂R^cWith-NR^d-X²CONR^cR^d, wherein each W is selected from R^c、-CN、-CO₂R^eWith-NO₂, wherein each X²Selected from C_1-4Alkylidene, C_2-4Alkenylene and C_2-4Alkynylene, R^cAnd R^dIt is each independently selected from：Hydrogen, C_1-8Alkyl, C_1-8Haloalkyl, C_3-6Cycloalkyl, C_2-8Alkenyl, C_2-8Alkynyl, aryl, heteroaryl, aryl-C_1-4Alkyl and aryloxy group-C_1-4Alkyl, or optionally work as R^cAnd R^dWhen being connected on same nitrogen-atoms, they are combined to form with 0-2 other hetero atoms as five yuan of annular atom or hexatomic ring with the nitrogen-atoms；Each R^eIndependently selected from C_1-8Alkyl, C_1-8Haloalkyl, C_3-6Cycloalkyl, C_2-8Alkenyl, C_2-8Alkynyl, aryl, heteroaryl, aryl-C_1-4Alkyl and aryloxy group-C_1-4Alkyl, R^c、R^dAnd R^eFollowing substituent group is optionally also each selected from by 1-3：-OH、-ORⁿ、-OC(O)NHRⁿ、-OC(O)N(Rⁿ)₂、-SH、-SRⁿ、-S(O)Rⁿ、-S(O)₂Rⁿ、-SO₂NH₂、-S(O)₂NHRⁿ、-S(O)₂N(Rⁿ)₂、-NHS(O)₂Rⁿ、-NRⁿS(O)₂Rⁿ、-C(O)NH₂、-C(O)NHRⁿ、-C(O)N(Rⁿ)₂、-C(O)Rⁿ、-NHC(O)Rⁿ、-NRⁿC(O)Rⁿ、-NHC(O)NH₂、-NRⁿC(O)NH₂、-NRⁿC(O)NHRⁿ、-NHC(O)NHRⁿ、-NRⁿC(O)N(Rⁿ)₂、-NHC(O)N(Rⁿ)₂、-CO₂H、-CO₂Rⁿ、-NHCO₂Rⁿ、-NRⁿCO₂Rⁿ、-CN、-NO₂、-NH₂、-NHRⁿ、-N(Rⁿ)₂、-NRⁿS(O)NH₂With-NRⁿS(O)₂NHRⁿ, wherein each RⁿIt is independently unsubstituted C_1-6Alkyl, makes R^2a、R^2b、R^2c、R^2dAnd R^2eIn at least one be not H；

R^3a、R^3bAnd R^3cIt is each independently selected from：Hydrogen, halogen ,-OR^f、-OC(O)R^f、-NR^fR^g、-SR^f、-R^h、-CN、-NO₂、-CO₂R^f、-CONR^fR^g、-C(O)R^f、-OC(O)NR^fR^g、-NR^gC(O)R^f、-NR^gC(O)₂R^h、-NR^f-C(O)NR^fR^g、-NH-C(NH₂)=NH ,-NR^hC(NH₂)=NH ,-NH-C (NH₂)=NR^h、-NH-C(NHR^h)=NH ,-S (O) R^h、-S(O)₂R^h、-NR^fS(O)₂R^h、-S(O)₂NR^fR^g、-NR^fS(O)₂NR^fR^g、-N₃、-C(NOR^f)R^g、-C(NR^fW^a)=NW^a、-N(W^a)C(R^f)=NW^a、-X³C(NOR^f)R^g、-X³C(NR^fW^a)=NW^a、-X³N(W^a)C(R^f)=NW^a、-X³OR^f、-X³OC(O)R^f、-X³NR^fR^g、-X³SR^f、-X³CN、-X³NO₂、-X³CO₂R^f、-X³CONR^fR^g、-X³C(O)R^f、-X³OC(O)NR^fR^g、-X³NR^gC(O)R^f、-X³NR^gC(O)₂R^h、-X³NR^f-C(O)NR^fR^g、-X³NH-C(NH₂)=NH ,-X³NR^hC(NH₂)=NH ,-X³NH-C(NH₂)=NR^h、-X³NH-C(NHR^h)=NH ,-X³S(O)R^h、-X³S(O)₂R^h、-X³NR^fS(O)₂R^h、-X³S(O)₂NR^fR^g、-Y、-X³Y、-X³N₃、-O-X³OR^f、-O-X³NR^fR^g、-O-X³CO₂R^f、-O-X³CONR^fR^g、-NR^g-X³OR^f、-NR^g-X³NR^fR^g、-NR^g-X³CO₂R^fWith-NR^g-X³CONR^fR^g, wherein each W^aSelected from R^f、-CN、-CO₂R^hWith-NO₂, wherein Y is 5 yuan or 6 yuan of aryl, heteroaryl or heterocycle, and they optionally can be replaced by 1-3 selected from following substituent：Halogen ,-OR^f、-NR^fR^g、-R^h、-SR^f、-CN、-NO₂、-CO₂R^f、-CONR^fR^g、-C(O)R^f、-NR^gC(O)R^f、-S(O)R^h、-S(O)₂R^h、-NR^fS(O)₂R^h、-S(O)₂NR^fR^g、-C(NOR^f)R^g、-C(NR^fW^a)=NW^a、-N(W^a)C(R^f)=NW^a、-X³C(NOR^f)R^g、-X³C(NR^fW^a)=NW^a、-X³N(W^a)C(R^f)=NW^a、-X³OR^f、-X³NR^fR^g、-X³NR^fS(O)₂R^hWith-X³S(O)₂NR^fR^g, wherein each X³Independently selected from C_1-4Alkylidene, C_2-4Alkenylene and C_2-4Alkynylene, R^fAnd R^gIt is each independently selected from hydrogen, C_1-8Alkyl, C_1-8Haloalkyl, C_3-6Cycloalkyl, C_2-8Alkenyl, C_2-8Alkynyl, aryl, heteroaryl, aryl-C_1-4Alkyl and aryloxy group-C_1-4Alkyl, or when they are connected on same nitrogen-atoms, they are combined to form with 0-2 other hetero atoms as five yuan of annular atom or hexatomic ring, each R with the nitrogen-atoms^hIndependently selected from C_1-8Alkyl, C_1-8Haloalkyl, C_3-6Cycloalkyl, C_2-8Alkenyl, C_2-8Alkynyl, aryl, heteroaryl, aryl-C_1-4Alkyl and aryloxy group-C_1-4Alkyl, wherein R^f、R^gAnd R^hAliphatic part also optionally replaced by 1-3 selected from following substituent：-OH、-OR^o、-OC(O)NHR^o、-OC(O)N(R^o)₂、-SH、-SR^o、-S(O)R^o、-S(O)₂R^o、-SO₂NH₂、-S(O)₂NHR^o、-S(O)₂N(R^o)₂、-NHS(O)₂R^o、-NR^oS(O)₂R^o、-C(O)NH₂、-C(O)NHR^o、-C(O)N(R^o)₂、-C(O)R^o、-NHC(O)R^o、-NR^oC(O)R^o、-NHC(O)NH₂、-NR^oC(O)NH₂、-NR^oC(O)NHR^o、-NHC(O)NHR^o、-NR^oC(O)N(R^o)₂、-NHC(O)N(R^o)₂、-CO₂H、-CO₂R^o、-NHCO₂R^o、-NR^oCO₂R^o、-CN、-NO₂、-NH₂、-NHR^o、-N(R^o)₂、-NR^oS(O)NH₂With-NR^oS(O)₂NHR^o, wherein each R^oIt is independently unsubstituted C_1-6Alkyl, makes R^3a、R^3bAnd R^3cIn at least one be not H.

19. compound as claimed in claim 18, it is characterised in that R^3a、R^3bAnd R^3cIn at least one be selected from-Y and-X³-Y。

20. compound as claimed in claim 18, it is characterised in that m is 0 or 1；R^2aAnd R^2eIn at least one be hydrogen.

21. compound as claimed in claim 18, it is characterised in that R^3bIt is hydrogen, halogen or cyano group.

22. compound as claimed in claim 21, it is characterised in that R¹In the presence of be selected from-CO₂H or C_1-4Alkyl, optionally by-OH ,-OR^m、-S(O)₂R^m、-CO₂H and-CO₂R^mSubstitution.

23. compound as claimed in claim 20, it is characterised in that R^3a、R^3bAnd R^3cIn at least one be selected from halogen, C_1-4Alkyl and C_1-4Haloalkyl, aliphatic part therein is optionally replaced by 1-3 selected from following substituent：-OH、-OR^o、-OC(O)NHR^o、-OC(O)N(R^o)₂、-SH、-SR^o、-S(O)R^o、-S(O)₂R^o、-SO₂NH₂、-S(O)₂NHR^o、-S(O)₂N(R^o)₂、-NHS(O)₂R^o、-NR^oS(O)₂R^o、-C(O)NH₂、-C(O)NHR^o、-C(O)N(R^o)₂、-C(O)R^o、-NHC(O)R^o、-NR^oC(O)R^o、-NHC(O)NH₂、-NR^oC(O)NH₂、-NR^oC(O)NHR^o、-NHC(O)NHR^o、-NR^oC(O)N(R^o)₂、-NHC(O)N(R^o)₂、-CO₂H、-CO₂R^o、-NHCO₂R^o、-NR^oCO₂R^o、-CN、-NO₂、-NH₂、-NHR^o、-N(R^o)₂、-NR^oS(O)NH₂With-NR^oS(O)₂NHR^o, wherein each R^oIt is independently unsubstituted C_1-6Alkyl.

24. compound as claimed in claim 23, it is characterised in that R^2dIt is hydrogen, R^3a、R^3bAnd R^3cIn at least two be selected from：Halogen, C_1-4Alkyl and C_1-4Haloalkyl, aliphatic part therein is optionally selected from following substituent group by 1-3：-OH、-OR^o、-OC(O)NHR^o、-OC(O)N(R^o)₂、-SH、-SR^o、-S(O)R^o、-S(O)₂R^o、-SO₂NH₂、-S(O)₂NHR^o、-S(O)₂N(R^o)₂、-NHS(O)₂R^o、-NR^oS(O)₂R^o、-C(O)NH₂、-C(O)NHR^o、-C(O)N(R^o)₂、-C(O)R^o、-NHC(O)R^o、-NR^oC(O)R^o、-NHC(O)NH₂、-NR^oC(O)NH₂、-NR^oC(O)NHR^o、-NHC(O)NHR^o、-NR^oC(O)N(R^o)₂、-NHC(O)N(R^o)₂、-CO₂H、-CO₂R^o、-NHCO₂R^o、-NR^oCO₂R^o、-CN、-NO₂、-NH₂、-NHR^o、-N(R^o)₂、-NR^oS(O)NH₂With-NR^oS(O)₂NHR^o, wherein each R^oIt is independently unsubstituted C_1-6Alkyl.

25. compound as claimed in claim 24, it is characterised in that R^2cSelected from F, Cl, Br, CN, NO₂、CO₂CH₃、C(O)CH₃With S (O)₂CH₃, R^3a、R^3bAnd R^3cIt is not hydrogen.

26. compound as claimed in claim 18, it is characterised in that m is 0 or 1；R^2aAnd R^2eAll it is hydrogen.

27. compound as claimed in claim 26, it is characterised in that R^3a、R^3bAnd R^3cIn at least-it is individual be selected from halogen, C_1-4Alkyl and C_1-4Haloalkyl, aliphatic part therein is optionally selected from following substituent group by 1-3：-OH、-OR^o、-OC(O)NHR^o、-OC(O)N(R^o)₂、-SH、-SR^o、-S(O)R^o、-S(O)₂R^o、-SO₂NH₂、-S(O)₂NHR^o、-S(O)₂N(R^o)₂、-NHS(O)₂R^o、-NR^oS(O)₂R^o、-C(O)NH₂、-C(O)NHR^o、-C(O)N(R^o)₂、-C(O)R^o、-NHC(O)R^o、-NR^oC(O)R^o、-NHC(O)NH₂、-NR^oC(O)NH₂、-NR^oC(O)NHR^o、-NHC(O)NHR^o、-NR^oC(O)N(R^o)₂、-NHC(O)N(R^o)₂、-CO₂H、-CO₂R^o、-NHCO₂R^o、-NR^oCO₂R^o、-CN、-NO₂、-NH₂、-NHR^o、-N(R^o)₂、-NR^oS(O)NH₂With-NR^oS(O)₂NHR^o, wherein each R^oIt is independently unsubstituted C_1-6Alkyl.

28. compound as claimed in claim 27, it is characterised in that R^3a、R^3bAnd R^3cIt is not hydrogen.

29. compound as claimed in claim 28, it is characterised in that R^2cSelected from F, Cl, Br, CN, NO₂、CO₂CH₃、C(O)CH₃With S (O)₂CH₃。

30. compound as claimed in claim 18, it is characterised in that m is 0 or 1；R^2bAnd R^2eAll it is hydrogen.

31. compound as claimed in claim 18, the compound, which has, is selected from following formula：

32. compound as claimed in claim 31, it is characterised in that R^3cAnd R^3aIt is each independently selected from C1-6 alkyl, C_1-6Haloalkyl and C_3-6Cycloalkyl；R^3bIt is hydrogen, halogen or cyano group.

33. compound as claimed in claim 31, it is characterised in that R^3cAnd R^3aIt is each independently selected from：Halogen ,-NR^fR^g、-SR^f、-CO₂R^f,-Y and-R^h, wherein R^hIt is C_1-6Alkyl, C_1-6Haloalkyl and C_3-6Cycloalkyl, aliphatic part therein is also optionally selected from following substituent group by 1-3：-OH、-OR^o、-OC(O)NHR^o、-OC(O)N(R^o)₂、-SH、-SR^o、-S(O)R^o、-S(O)₂R^o、-SO₂NH₂、-S(O)₂NHR^o、-S(O)₂N(R^o)₂、-NHS(O)₂R^o、-NR^oS(O)₂R^o、-C(O)NH₂、-C(O)NHR^o、-C(O)N(R^o)₂、-C(O)R^o、-NHC(O)R^o、-NR^oC(O)R^o、-NHC(O)NH₂、-NR^oC(O)NH₂、-NR^oC(O)NHR^o、-NHC(O)NHR^o、-NR^oC(O)N(R^o)₂、-NHC(O)N(R^o)₂、-CO₂H、-CO₂R^o、-NHCO₂R^o、-NR^oCO₂R^o、-CN、-NO₂、-NH₂、-NHR^o、-N(R^o)₂、-NR^oS(O)NH₂With-NR^oS(O)₂NHR^o。

34. compound as claimed in claim 33, it is characterised in that R^3bIt is halogen.

35. compound as claimed in claim 31, it is characterised in that m is 0.

36. compound as claimed in claim 31, it is characterised in that m is 1 or 2, each R¹Independently selected from-CO₂H and C_1-4Alkyl, its moieties is optionally by-OH ,-OR_m、-S(O)₂R^m、-CO₂H and-CO₂R^mSubstitution.

37. compound as claimed in claim 31, it is characterised in that R^2bSelected from-SR^c、-O-X²-OR^c、-X²-OR^c、-R^c、-OR^c、-NR^cR^dWith-NR^cSO₂R^d。

38. compound as claimed in claim 18, the compound has following formula：

In formula, R^2cIt is halogen, cyano group or nitro；R^2bSelected from-SR^c、-O-X²-OR^c、-X²-OR^c、-R^e、-OR^c、-NR^cR^d、-NR^cS(O)₂R^eWith-NR^dC(O)R^c；R^3aSelected from NH₂、CF₃、SCH₃And Y；R^3bIt is chlorine or bromine；R^3cSelected from C_1-6Alkyl, C_1-6Haloalkyl and C_3-6Cycloalkyl.

39. compound as claimed in claim 18, the compound has following formula：

In formula, R^2cIt is halogen, cyano group or nitro；R^2bSelected from-SR^c、-O-X²-OR^c、-X²-OR^c、-R^e、-OR^c、-NR^cR^d、-NR^cS(O)₂R^eWith-NR^dC(O)R^c；R^3aSelected from C_1-6Alkyl, C_1-6Haloalkyl and C_3-6Cycloalkyl；R^3cSelected from NH₂、CF₃、SCH₃And Y；R^3dIt is chlorine or bromine.

40. compound as claimed in claim 18, the compound has following formula：

In formula, R^2cIt is halogen, cyano group or nitro；R^2bSelected from-SR^c、-O-X²-OR^c、-X²-OR^c、-R^e、-OR^c、-NR^cR^d、-NR^cS(O)₂R^eWith-NR^dC(O)R^c；R^3aSelected from NH₂、CF₃、SCH₃And Y；R^3bIt is chlorine or bromine；R^3cSelected from C_1-6Alkyl, C_1-6Haloalkyl and C_3-6Cycloalkyl, wherein R^3cAliphatic part be optionally selected from following substituent group：-OH、-OR^o、-OC(O)NHR^o、-OC(O)N(R^o)₂、-SH、-SR^o、-S(O)R^o、-S(O)₂R^o、-SO₂NH₂、-S(O)₂NHR^o、-S(O)₂N(R^o)₂、-NHS(O)₂R^o、-NR^oS(O)₂R^o、-C(O)NH₂、-C(O)NHR^o、-C(O)N(R^o)₂、-C(O)R^o、-NHC(O)R^o、-NR^oC(O)R^o、-NHC(O)NH₂、-NR^oC(O)NH₂、-NR^oC(O)NHR^o、-NHC(O)NHR^o、-NR^oC(O)N(R^o)₂、-NHC(O)N(R^o)₂、-CO₂H、-CO₂R^o、-NHCO₂R^o、-NR^oCO₂R^o、-CN、-NO₂、-NH₂、-NHR^o、-N(R^o)₂、-NR^oS(O)NH₂With-NR^oS(O)₂NHR^o。

41. compound as claimed in claim 40, it is characterised in that R¹In the presence of each be selected from-CO₂H and C_1-4Alkyl, is optionally selected from following substituent group-OH ,-OR^m、-S(O)₂R^m、-CO₂H and-CO₂R^m。

42. compound as claimed in claim 18, the compound has following formula：

In formula, R^2cIt is halogen, cyano group or nitro；R^2bSelected from-SR^c、-O-X²-OR^c、-X²-OR^c、-R^e、-OR^c、-NR^cR^d、-NR^cS(O)₂R^eWith-NR^dC(O)R^c；R^3aSelected from C_1-6Alkyl, C_1-6Haloalkyl and C_3-6Cycloalkyl, wherein R^3aAliphatic part be optionally selected from following substituent group：-OH、-OR^o、-OC(O)NHR^o、-OC(O)N(R^o)₂、-SH、-SR^o、-S(O)R^o、-S(O)₂R^o、-SO₂NH₂、-S(O)₂NHR^o、-S(O)₂N(R^o)₂、-NHS(O)₂R^o、-NR^oS(O)₂R^o、-C(O)NH₂、-C(O)NHR^o、-C(O)N(R^o)₂、-C(O)R^o、-NHC(O)R^o、-NR^oC(O)R^o、-NHC(O)NH₂、-NR^oC(O)NH₂、-NR^oC(O)NHR^o、-NHC(O)NHR^o、-NR^oC(O)N(R^o)₂、-NHC(O)N(R^o)₂、-CO₂H、-CO₂R^o、-NHCO₂R^o、-NR^oCO₂R^o、-CN、-NO₂、-NH₂、-NHR^o、-N(R^o)₂、-NR^oS(O)NH₂With-NR^oS(O)₂NHR^o；R^3cSelected from NH₂、CF₃、SCH₃And Y；R^3bIt is chlorine or bromine.

43. compound as claimed in claim 42, it is characterised in that R¹In the presence of each be selected from-CO₂H and C_1-4Alkyl, is optionally selected from following substituent group：-OH、-OR^m、-S(O)₂R^m、-CO₂H and-CO₂R^m。

44. compound as claimed in claim 18, the compound has following formula：

In formula, R^2aIt is not hydrogen；R^2cIt is halogen, cyano group or nitro；R^2dSelected from-SR^c、-O-X²-OR^c、-X²-OR^c、-R^e、-OR^c、-NR^cR^d、-NR^cS(O)₂R^eWith-NR^dC(O)R^c；R^3aSelected from C_1-6Alkyl, C_1-6Haloalkyl and C_3-6Cycloalkyl, is optionally selected from following substituent group：-OH、-OR^o、-OC(O)NHR^o、-OC(O)N(R^o)₂、-SH、-SR^o、-S(O)R^o、-S(O)₂R^o、-SO₂NH₂、-S(O)₂NHR^o、-S(O)₂N(R^o)₂、-NHS(O)₂R^o、-NR^oS(O)₂R^o、-C(O)NH₂、-C(O)NHR^o、-C(O)N(R^o)₂、-C(O)R^o、-NHC(O)R^o、-NR^oC(O)R^o、-NHC(O)NH₂、-NR^oC(O)NH₂、-NR^oC(O)NHR^o、-NHC(O)NHR^o、-NR^oC(O)N(R^o)₂、-NHC(O)N(R^o)₂、-CO₂H、-CO₂R^o、-NHCOR^o、-NR^oCO₂R^o、-CN、-NO₂、-NH₂、-NHR^o、-N(R^o)₂、-NR^oS(O)NH₂With-NR^oS(O)₂NHR^o；R^3bIt is chlorine or bromine；R^3cSelected from NH₂、CF₃、SCH₃And Y.

45. compound as claimed in claim 44, it is characterised in that R¹In the presence of each be selected from-CO₂H and C_1-4Alkyl, is optionally selected from following substituent group：-OH、-OR^m、-S(O)₂R^m、-CO₂H and-CO₂R^m。

46. compound as claimed in claim 18, the compound has following formula：

In formula, R^2aIt is not hydrogen；R^2cIt is halogen, cyano group or nitro；R^2dIt is-SR^c、-O-X²-OR^c、-X²-OR^c、-R^e、-OR^c、-NR^cR^d、-NR^cS(O)₂R^eWith-NR^dC(O)R^c；R^3aSelected from-NR^fR^g、-SR^f、-SO₂R^h、-R^h、-C(O)R^f,-Y and-X³Y；R^3bIt is hydrogen, fluorine, chlorine, bromine or cyano group；R^3cSelected from C_1-6Alkyl, C_1-6Haloalkyl and C_3-6Cycloalkyl, is optionally selected from following substituent group：-OH、-OR^o、-OC(O)NHR^o、-OC(O)N(R^o)₂、-SH、-SR^o、-S(O)R^o、-S(O)₂R^o、-SO₂NH₂、-S(O)₂NHR^o、-S(O)₂N(R^o)₂、-NHS(O)₂R^o、-NR^oS(O)₂R^o、-C(O)NH₂、-C(O)NHR^o、-C(O)N(R^o)₂、-C(O)R^o、-NHC(O)R^o、-NR^oC(O)R^o、-NHC(O)NH₂、-NR^oC(O)NH₂、-NR^oC(O)NHR^o、-NHC(O)NHR^o、-NR^oC(O)N(R^o)₂、-NHC(O)N(R^o)₂、-CO₂H、-CO₂R^o、-NHCO₂R^o、-NR^oCO₂R^o、-CN、-NO₂、-NH₂、-NHR^o、-N(R^o)₂、-NR^oS(O)NH₂With-NR^oS(O)₂NHR^o。

47. compound as claimed in claim 46, it is characterised in that R¹In the presence of each be selected from-CO₂H and C_1-4Alkyl, is optionally selected from following substituent group：-OH、-OR^m、-S(O)₂R^m、-CO₂H and-CO₂R^m。

48. compound as claimed in claim 30, it is characterised in that R^3a、R^3bAnd R^3cIn at least one be selected from halogen and C_1-4Haloalkyl.

49. compound as claimed in claim 48, it is characterised in that R^3a、R^3bAnd R^3cIt is not hydrogen.

50. compound as claimed in claim 18, it is characterised in that m is 0 or 1；R¹In the presence of be C_1-2Alkyl, is optionally selected from following substituent group：-OH、-OR^m、-S(O)₂R^m、-CO₂H and-CO₂R^m；R^2aSelected from H, CH₃And halogen；R^2bIt is H；R^2cSelected from H, Cl and Br；R^2dSelected from OCH₃、OCH₂CH₃、NHCH₃、CH₂OCH₃And CH₃；R^2eIt is H, makes R^2aAnd R^2cIn at least one be not H；R^3bIt is Cl or Br；R^3aAnd R^3cIn one be cyclopropyl, CF₃Or methyl, optionally by NH₂, OH or OCH₃Substitution, R^3aAnd R^3cIn another be selected from CF₃、Br、CH₃、-CO₂CH₃、-CO₂Et、-N(CH₃)₂、-NH₂, ethyl, isopropyl, substitution phenyl and substituted or unsubstituted thienyl.

51. compound as claimed in claim 18, it is characterised in that with R^2aTo R^2eSubstituted phenyl of the phenyl ring selected from Figure 1A into 1G.

52. compound as claimed in claim 18, it is characterised in that with R^3aTo R^3cSubstituted pyrazolyl of the pyrazole ring selected from Fig. 2A to 2Z, 2AA into 2HH and Fig. 3.

53. compound as claimed in claim 18, the compound has the formula III e in Fig. 5 A.

54. compound as claimed in claim 18, the compound has the formula III g in Fig. 5 A.

55. compound as claimed in claim 18, the compound has the formula III i in Fig. 5 A.

56. compound as claimed in claim 18, the compound has the formula III k in Fig. 5 B.

57. compound as claimed in claim 18, the compound has the formula III q in Fig. 5 C.

58. compound as claimed in claim 18, the compound has the formula III aa in Fig. 5 D.

59. compound as claimed in claim 18, the compound has the formula III mm in Fig. 5 F.

60. compound as claimed in claim 18, the compound has the formula III s in Fig. 5 C.

61. compound as claimed in claim 18, the compound has the formula III ii in Fig. 5 E.

62. compound as claimed in claim 18, the compound has the formula III kk in Fig. 5 E.

63. compound as claimed in claim 18, the compound has the formula III yy in Fig. 5 G.

64. compound as claimed in claim 18, the compound has the formula III aaa in Fig. 5 H.

65. compound as claimed in claim 18, the compound has the formula III www in Fig. 5 K.

66. compound as claimed in claim 18, the compound has the formula III yyy in Fig. 5 K.

67. compound as claimed in claim 18, the compound has the formula III cccc in Fig. 5 K.

68. compound as claimed in claim 18, the compound has the formula III eeee in Fig. 5 L.

69. compound as claimed in claim 18, the compound has the formula III gggg in Fig. 5 L.

70. a kind of compound, the structural formula with 1.308 in table 5,1.372,1.262,1.163,1.349,1.353,1.362,1.340,1.402,1.379 and 1.356.

71. a kind of compound selected from following structural formula, or its pharmaceutically acceptable salt or N- oxides：

With

72. a kind of pharmaceutical composition, the composition contains pharmaceutically acceptable excipient and the compound described in claim 1.

73. a kind of method for the disease or symptom for treating CCR1- mediations, methods described includes the compound with following formula for giving subject in need's therapeutically effective amount, or its pharmaceutically acceptable salt or N- oxides：

In formula,

Subscript n is 1-2 integer；

Subscript m is 0-10 integer；

Each R¹It is to be selected from following substituent with manor：C_1-8Alkyl, C_1-8Haloalkyl, C_3-6Cycloalkyl, C_2-8Alkenyl and C_2-8Alkynyl ,-COR^a、-CO₂R^a、-CONR^aR^b、-NR^aCOR^b、-SO₂R^a、-X¹COR^a、-X¹CO₂R^a、-X¹CONR^aR^b、-X¹NR^aCOR^b、-X¹SO₂R^a、-X¹SO₂NR^aR^b、-X¹NR^aR^b、-X¹OR^a, wherein X¹Selected from C_1-4Alkylidene, C_2-4Alkenylene and C_2-4Alkynylene, R^aAnd R^bI is selected from independently of one another：Hydrogen, C_1-8Alkyl, C_1-8Haloalkyl, C_3-6Cycloalkyl and aryl-C_1-4Alkyl, or optionally work as R^aAnd R^bWhen being connected on same nitrogen-atoms, they are combined to form with 0-2 other hetero atoms as five yuan of annular atom or hexatomic ring with the nitrogen-atoms, wherein each R¹Aliphatic part following substituent group is optionally selected from by 1-3：-OH、-OR^m、-OC(O)NHR^m、-OC(O)N(R^m)₂、-SH、-SR^m、-S(O)R^m、-S(O)₂R^m、-SO₂NH₂、-S(O)₂NHR^m、-S(O)₂N(R^m)₂、-NHS(O)₂R^m、-NR^mS(O)₂R^m、-C(O)NH₂、-C(O)NHR^m、-C(O)N(R^m)₂、-C(O)R^m、-NHC(O)R^m、-NR^mC(O)R^m、-NHC(O)NH₂、-NR^mC(O)NH₂、-NR^mC(O)NHR^m、-NHC(O)NHR^m、-NR^mC(O)N(R^m)₂、-NHC(O)N(R^m)₂、-CO₂H、-CO₂R^m、-NHCO₂R^m、-NR^mCO₂R^m、-CN、-NO₂、-NH₂、-NHR^m、-N(R^m)₂、-NR^mS(O)NH₂With-NR^mS(O)₂NHR^m, wherein each R^mIt is independently unsubstituted C_1-6Alkyl；

Ar¹Selected from phenyl, naphthyl, pyridine radicals, pyrazinyl, pyridazinyl, pyrimidine radicals, triazine radical, quinolyl, quinoxalinyl and purine radicals, each of which is optionally by 1-5 R²Substituent replaces, the R²Substituent independently selected from：Halogen ,-OR^c、-OC(O)R^c、-NR^cR^d、-SR^c、-R^o、-CN、-NO₂、-CO₂R^c、-CONR^cR^d、-C(O)R^c、-OC(O)NR^cR^d、-NR^dC(O)R^c、-NR^dC(O)₂R^e、-NR^c-C(O)NR^cR^d、-NH-C(NH₂)=NH ,-NR^eC(NH₂)=NH ,-NH-C (NH₂)=NR^e、-NH-C(NHR^e)=NH ,-NR^eC(NHR^e)=NH ,-NR^eC(NH₂)=NR^e、-NH-C(NHR^e)=NR^e、-NH-C(NR^eR^e)=NH ,-S (O) R^e、-S(O)₂R^e、-NR^cS(O)₂R^e、-S(O)₂NR^cR^d、-N₃、-C(NOR^c)R^d、-C(NR^cW)=NW ,-N (W) C (R^c)=NW ,-NR^cC(S)NR^cR^d、-X²C(NOR^c)R^d、-X²C(NR^cW)=NW ,-X²N(W)C(R^c)=NW ,-X²NR^cC(S)NR^cR^d、-X²OR^c、-O-X²OR^c、-X²OC(O)R^c、-X²NR^cR^d、-O-X²NR^cR^d、-X²SR^c、-X²CN、-X²NO₂、-X²CO₂R^c、-O-X²CO₂R^c、-X²CONR^cR^d、-O-X²CONR^cR^d、-X²C(O)R^c、-X²OC(O)NR^cR^d、-X²NR^dC(O)R^c、-X²NR^dC(O)₂R^e、-X²NR^cC(O)NR^cR^d、-X²NH-C(NH₂)=NH ,-X²NR^eC(NH₂)=NH ,-X²NH-C(NH₂)=NR^e、-X²NH-C(NHR^e)=NH ,-X²S(O)R^e、-X²S(O)₂R^e、-X²NR^cS(O)₂R^e、-X²S(O)₂NR^cR^d、-X²N₃、-NR^d-X²OR^c、-NR^d-X²NR^cR^d、-NR^d-X²CO₂R^cAnd-NR^d-X²CONR^cR^d, wherein W is selected from R^c、-CN、-CO₂R^eWith-NO₂, wherein X²Selected from C_1-4Alkylidene, C_2-4Alkenylene and C_2-4Alkynylene, R^cAnd R^dIt is each independently selected from：Hydrogen, C_1-8Alkyl, C_1-8Haloalkyl, C_3-6Cycloalkyl, C_3-8Alkenyl, C_2-8Alkynyl, aryl, heteroaryl, aryl-C_1-4Alkyl and aryloxy group-C_1-4Alkyl, or optionally work as R^cAnd R^dWhen being connected on same nitrogen-atoms, they are combined to form with 0-2 other hetero atoms as five yuan of annular atom or hexatomic ring with the nitrogen-atoms；Each R^eIndependently selected from C_1-8Alkyl, C_1-8Haloalkyl, C_3-6Cycloalkyl, C_2-8Alkenyl, C_2-8Alkynyl, aryl, heteroaryl, aryl-C_1-4Alkyl and aryloxy group-C_1-4Alkyl, R^c、R^dAnd R^eEach also optionally it is selected from following substituent group by 1-3：-OH、-ORⁿ、-OC(O)NHRⁿ、-OC(O)N(Rⁿ)₂、-SH、-SRⁿ、-S(O)Rⁿ、-S(O)₂Rⁿ、-SO₂NH₂、-S(O)₂NHRⁿ、-S(O)₂N(Rⁿ)₂、-NHS(O)₂Rⁿ、-NRⁿS(O)₂Rⁿ、-C(O)NH₂、-C(O)NHRⁿ、-C(O)N(Rⁿ)₂、-C(O)Rⁿ、-NHC(O)Rⁿ、-NRⁿC(O)Rⁿ、-NHC(O)NH₂、-NRⁿC(O)NH₂、-NRⁿC(O)NHRⁿ、-NHC(O)NHRⁿ、-NRⁿC(O)N(Rⁿ)₂、-NHC(O)N(Rⁿ)₂、-CO₂H、-CO₂Rⁿ、-NHCO₂Rⁿ、-NRⁿCO₂Rⁿ、-CN、-NO₂、-NH₂、-NHRⁿ、-N(Rⁿ)₂、-NRⁿS(O)NH₂With-NRⁿS(O)₂NHRⁿ, wherein each RⁿIt is independently the C of hydrogen substitution_1-6Alkyl；

HAr is heteroaryl, selected from pyrazolyl, imidazole radicals, triazolyl, tetrazole radical, _ oxazolyl, different _ oxazolyl, _ di azoly, _ thiadiazolyl group, pyrrole radicals, thiazolyl, isothiazolyl, benzimidazolyl, benzopyrazoles base and BTA base, each of which is by 1-5 R³Substituent replaces, the R³Substituent independently selected from：Halogen ,-OR^f、-OC(O)R^f、-NR^fR^g、-SR^f、-R^h、-CN、-NO₂、-CO₂R^f、-CONR^fR^g、-C(O)R^f、-OC(O)NR^fR^g、-NR^gC(O)R^f、-NR^gC(O)₂R^h、-NR^f-C(O)NR^fR^g、-NH-C(NH₂)=NH ,-NR^hC(NH₂)=NH ,-NH-C (NH₂)=NR^h、-NH-C(NHR^h)=NH ,-NR^hC(NHR^h)=NH ,-NR^hC(NH₂)=NR^h、-NH-C(NHR^h)=NR^h、-NH-C(NR^hR^h)=NH ,-S (O) R^h、-S(O)₂R^h、-NR^fS(O)₂R^h、-S(O)₂NR^fR^g、-NR^fS(O)₂NR^fR^g、-N₃、-C(NOR^f)R^g、-C(NR^fW^a)=NW^a、-N(W^a)C(R^f)=NW^a、-X³C(NOR^f)R^g、-X³C(NR^fW^a)=NW^a、-X³N(W^a)C(R^f)=NW^a、-NR^fC(S)NR^fR^g、-X³NR^fC(S)NR^fR^g、-X³OR^f、-X³OC(O)R^f、-X³NR^fR^g、-X³SR^f、-X³CN、-X³NO₂、-X³CO₂R^f、-X³CONR^fR^g、-X³C(O)R^f、-X³OC(O)NR^fR^g、-X³NR^gC(O)R^f、-X³NR^gC(O)₂R^h、-X³NR^f-C(O)NR^fR^g、-X³NH-C(NH₂)=NH ,-X³NR^hC(NH₂)=NH ,-X³NH-C(NH₂)=NR^h、-X³NH-C(NHR^h)=NH ,-X³S(O)R^h、-X³S(O)₂R^h、-X³NR^fS(O)₂R^h、-X³S(O)₂NR^fR^g、-Y、-SO₂Y、-C(O)Y、-X³Y、-X³N₃、-O-X³OR^f、-O-X³NR^fR^g、-O-X³CO₂R^f、-O-X³CONR^fR^g、-NR^g-X³OR^f、-NR^g-X³NR^fR^g、-NR^g-X³CO₂R^fAnd-NR^g-X³CONR^fR^g, wherein W^aSelected from R^f、-CN、-CO₂R^hWith-NO₂, wherein Y is aryl, heteroaryl or the heterocycle of 5-10 members, is optionally replaced by 1-3 selected from following substituent：Halogen ,-OR^f、-NR^fR^g、-R^h、-SR^f、-CN、-NO₂、-CO₂R^f、-CONR^fR^g、-C(O)R^f、-NR^gC(O)R^f、-S(O)R^h、-S(O)₂R^h、-NR^fS(O)₂R^h、-S(O)₂NR^fR^g、-C(NOR^f)R^g、-C(NR^fW^a)=NW^a、-N(W^a)C(R^f)=NW^a、-X³C(NOR^f)R^g、-X³C(NR^fW^a)=NW^a、-X³N(W^a)C(R^f)=NW^a、-X³OR^f、-X³NR^fR^g、-X³NR^fS(O)₂R^hWith-X³S(O)₂NR^fR^g, wherein each X³Independently selected from C_1-4Alkylidene, C_2-4Alkenylene and C_2-4Alkynylene, R^fAnd R^gIt is each independently selected from hydrogen, C_1-8Alkyl, C_1-8Haloalkyl, C_3-6Cycloalkyl, C_2-8Alkenyl, C_2-8Alkynyl, aryl, heteroaryl, aryl-C_1-4Alkyl and aryloxy group-C_1-4Alkyl, or when they are connected on same nitrogen-atoms, they are combined to form with 0-2 other hetero atoms as five yuan of annular atom or hexatomic ring, each R with the nitrogen-atoms^hIndependently selected from C_1-8Alkyl, C_1-4Haloalkyl, C_3-6Cycloalkyl, C_2-8Alkenyl, C_2-8Alkynyl, aryl, heteroaryl, aryl-C_1-4Alkyl and aryloxy group-C_1-4Alkyl, wherein R^f、R^gAnd R^hAliphatic part following substituent group is optionally also selected from by 1-3：-OH、-OR^o、-OC(O)NHR^o、-OC(O)N(R^o)₂、-SH、-SR^o、-S(O)R^o、-S(O)₂R^o、-SO₂NH₂、-S(O)₂NHR^o、-S(O)₂N(R^o)₂、-NHS(O)₂R^o、-NR^oS(O)₂R^o、-C(O)NH₂、-C(O)NHR^o、-C(O)N(R^o)₂、-C(O)R^o、-NHC(O)R^o、-NR^oC(O)R^o、-NHC(O)NH₂、-NR^oC(O)NH₂、-NR^oC(O)NHR^o、-NHC(O)NHR^o、-NR^oC(O)N(R^o)₂、-NHC(O)N(R^o)₂、-CO₂H、-CO₂R^o、-NHCO₂R^o、-NR^oCO₂R^o、-CN、-NO²、-NH₂、-NHR^o、-N(R^o)₂、-NR^oS(O)NH₂With-NR^oS(O)₂NHR^o, wherein each R^oIt is independently unsubstituted C_1-6Alkyl；

L¹It is the linker containing the 1-3 backbone atoms selected from C, N, O and S, optionally can be replaced by 1-3 selected from following substituent：Halogen, phenyl ,-ORⁱ、-OC(O)Rⁱ、-NRⁱR^j、-SRⁱ、-R^k,-CN ,-NO₂、-CO₂Rⁱ、-CONRⁱR^j、-C(O)Rⁱ、-OC(O)NRⁱR^j、-NR^jC(O)Rⁱ、-NR^jC(O)₂R^k、-X⁴ORⁱ、-X⁴OC(O)Rⁱ、-X⁴NRⁱR^j、-X⁴SRⁱ、-X⁴CN、-X⁴NO₂,-X⁴CO₂Rⁱ、-X⁴CONRⁱR^j、-X⁴C(O)Rⁱ、-X⁴OC(O)NRⁱR^j、-X⁴NR^jC(O)RⁱWith-X⁴NR^jC(O)₂R^k, wherein X⁴Selected from C_1-4Alkylidene, C_2-4Alkenylene and C_2-4Alkynylene, RⁱAnd R^jIt is each independently selected from：Hydrogen, C_1-8Alkyl, C_1-8Haloalkyl, C_3-6Cycloalkyl, C_2-8Alkenyl, C_2-8Alkynyl, aryl, heteroaryl, aryl-C_1-4Alkyl and aryloxy group-C_1-4Alkyl, each R^kIndependently selected from C_1-8Alkyl, C_1-8Haloalkyl, C_3-6Cycloalkyl, C_2-8Alkenyl, C_2-8Alkynyl, aryl, heteroaryl, aryl-C_1-4Alkyl and aryloxy group-C_1-4Alkyl.

74. a kind of method as described in claim 73, it is characterised in that the disease or illness of the CCR1- mediations are inflammatory symptoms.

75. a kind of method as described in claim 73, it is characterised in that the disease or illness of the CCR1- mediations are immunoregulatory disorders.

76. the method as described in claim 73, characterized in that, the disease or illness of the CCR1- mediations are selected from rheumatoid arthritis, multiple sclerosis, graft rejection, dermatitis, eczema, nettle rash, vasculitis, inflammatory bowel disease, food hypersenstivity, asthma, Alzheimer's, Parkinson's disease, psoriasis, lupus erythematosus, osteoarthritis, apoplexy and encephalomyelitis.

77. the method as described in claim 73, it is characterised in that the administration is oral, parenterally, rectum is percutaneously, sublingual, intranasal or local administration.

78. a kind of method as described in claim 73, it is characterised in that the compound is to merge administration with antiphlogistic, anodyne, anti-proliferative agent, metabolic poison, leucocyte migration inhibitor or immunomodulator.

Images