SUBSTITUTED PYRROLIDINE AS ANTI-INFE C TIVE S

Inventors: Yat Sun Or, Lu Ying, Ce Wang, Jiang Long and Yao-Ling Qiu

RELATED APPLICATIONS

This application claims the benefit of US provisional application number 60/946,312 filed on June 26, 2007; US provisional application number 60/950,388 filed on July 18, 2007; US provisional application number 60/953,351 filed on August 1, 2007; US provisional application number 60/955,511 filed on August 13, 2007; US provisional application number 60/957,876 filed on August 24, 2007; US provisional application number 60/970,126 filed on September 5, 2007; US provisional application number 60/971,701 filed on September 12, 2007; US provisional application number 61/060,705 filed on June 11, 2008; US provisional application number 61/060,708 filed on June 11, 2008; and US provisional application number 61/060,943 filed on June 12, 2008. The contents of the above applications are incorporated herein by reference.

TECHNICAL FIELD

The present invention relates to novel anti-infective agents. Specifically, the present invention relates to compounds, compositions, a method for inhibiting hepatitis C virus (HCV) polymerase, a method for inhibiting HCV viral replication, and a method for treating or preventing HCV infection.

BACKGROUND OF THE INVENTION

Infection with HCV is a major cause of human liver disease throughout the world. In the US, an estimated 4.5 million Americans are chronically infected with HCV. Although only 30% of acute infections are symptomatic, greater than 85% of infected individuals develop chronic, persistent infection. Treatment costs for

HCV infection have been estimated at $5.46 billion for the US in 1997. Worldwide over 200 million people are estimated to be infected chronically. HCV infection is responsible for 40-60% of all chronic liver disease and 30% of all liver transplants. Chronic HCV infection accounts for 30% of all cirrhosis, end-stage liver disease, and liver cancer in the U.S. The CDC estimates that the number of deaths due to HCV will minimally increase to 38,000/year by the year 2010.

Due to the high degree of variability in the viral surface antigens, existence of multiple viral genotypes, and demonstrated specificity of immunity, the development of a successful vaccine in the near future is unlikely. Alpha-interferon (alone or in combination with ribavirin) has been widely used since its approval for treatment of chronic HCV infection. However, adverse side effects are commonly associated with this treatment: flu-like symptoms, leukopenia, thrombocytopenia, depression from interferon, as well as anemia induced by ribavirin (Lindsay, K. L. (1997) Hepatology 26 (suppl 1): 71S-77S). This therapy remains less effective against infections caused by HCV genotype 1 (which constitutes -75% of all HCV infections in the developed markets) compared to infections caused by the other 5 major HCV genotypes. Unfortunately, only -50-80% of the patients respond to this treatment (measured by a reduction in serum HCV RNA levels and normalization of liver enzymes) and, of responders, 50-70% relapse within 6 months of cessation of treatment. Recently, with the introduction of pegylated interferon (Peg-IFN), both initial and sustained response rates have improved substantially, and combination treatment of Peg-IFN with ribavirin constitutes the gold standard for therapy. However, the side effects associated with combination therapy and the impaired response in patients with genotype 1 present opportunities for improvement in the management of this disease. First identified by molecular cloning in 1989 (Choo, Q-L et al (1989)

Science 244:359-362), HCV is now widely accepted as the most common causative agent of post-transfusion non-A, non-B hepatitis (NANBH) (Kuo, G et al (1989) Science 244:362-364). Due to its genome structure and sequence homology, this virus was assigned as a new genus in the Flaviviridae family. Like the other members of the Flaviviridae, such as flaviviruses (e.g. yellow fever virus and Dengue virus types 1-4) and pestiviruses (e.g. bovine viral diarrhea virus, border disease virus, and classic swine fever virus) (Choo, Q-L et al (1989) Science 244:359-362; Miller, R.H. and R.H. Purcell (1990) Proc. Natl. Acad. Sci. USA 87:2057-2061), HCV is an enveloped virus containing a single strand RNA molecule of positive polarity. The HCV genome is approximately 9.6 kilobases (kb) with a long, highly conserved, noncapped 5' nontranslated region (NTR) of approximately 340 bases which functions as an internal ribosome entry site (IRES) (Wang CY et al 'An RNA pseudoknot is an essential structural element of the internal ribosome entry site located within the hepatitis C virus 5' noncoding

region' RNA - A Publication of the RNA Society. 1(5): 526-537, 1995 JuL). This element is followed by a region which encodes a single long open reading frame (ORF) encoding a polypeptide of -3000 amino acids comprising both the structural and nonstructural viral proteins. Upon entry into the cytoplasm of the cell, this RNA is directly translated into a polypeptide of -3000 amino acids comprising both the structural and nonstructural viral proteins. This large polypeptide is subsequently processed into the individual structural and nonstructural proteins by a combination of host and virally-encoded proteinases (Rice, CM. (1996) in B.N. Fields, D.M.Knipe and P.M. Howley (eds) Virology 2 ^nd Edition, p931-960; Raven Press, N. Y.). There are three structural proteins, C, El and E2. The P7 protein is of unknown function and is comprised of a highly variable sequence. There are six non-structural proteins. NS2 is a zinc-dependent metalloproteinase that functions in conjunction with a portion of the NS3 protein. NS3 incorporates two catalytic functions (separate from its association with NS2): a serine protease at the N-terminal end, which requires NS4A as a cofactor, and an ATP-ase-dependent helicase function at the carboxyl terminus. NS4A is a tightly associated but non-covalent cofactor of the serine protease.

Following the termination codon at the end of the long ORF, there is a 3' NTR which roughly consists of three regions: an -40 base region which is poorly conserved among various genotypes, a variable length poly(U)/polypyrimidine tract, and a highly conserved 98 base element also called the "3' X-tail" (Kolykhalov, A. et al (1996) J. Virology 70:3363-3371; Tanaka, T. et al (1995) Biochem Biophys. Res. Commun. 215744-749; Tanaka, T. et al (1996) J. Virology 70:3307-3312; Yamada, N. et al (1996) Virology 223:255-261). The 3' NTR is predicted to form a stable secondary structure which is essential for HCV growth in chimps and is believed to function in the initiation and regulation of viral RNA replication.

The NS5B protein (591 amino acids, 65 kDa) of HCV (Behrens, S.E. et al (1996) EMBO J. 151 2-22), encodes an RNA-dependent RNA polymerase (RdRp) activity and contains canonical motifs present in other RNA viral polymerases. The NS5B protein is fairly well conserved both intra-typically (-95-98% amino acid (aa) identity across Ib isolates) and inter-typically (-85% aa identity between genotype 1 a and 1 b isolates). The essentiality of the HCV NS5B RdRp activity for

the generation of infectious progeny virions has been formally proven in chimpanzees (A. A. Kolykhalov et al. (2000) Journal of Virology, 74(4): 2046- 2051). Thus, inhibition of NS5B RdRp activity (inhibition of RNA replication) is predicted to be useful to treat HCV infection. Based on the foregoing, there exists a significant need to identify compounds with the ability to inhibit HCV. A general strategy for the development of antiviral agents is to inactivate virally encoded enzymes, including NS5B, that are essential for the replication of the virus.

SUMMARY OF THE INVENTION The present invention relates to novel antiviral compounds represented herein below, pharmaceutical compositions comprising such compounds, and methods for the of treatment or prophylaxis of viral (particularly HCV) infection in a subject in need of such therapy with said compounds.

In one embodiment, the present invention provides a compound of formulae (A):

or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, prodrug, or combination thereof, wherein:

M at each occurrence is -ORi; -SRi; -NRiR ₂ ; or -R ₁ ; wherein Ri and R ₂ at each occurrence are each independently selected from the group consisting of: hydrogen; deuterium; and -R ₃ ;

Wherein R ₃ at each occurrence is selected from the group consisting of: -C ₁ -C ₈ alkyl, -C ₂ -Cs alkenyl, -C ₂ -Cs alkynyl or -C ₃ -Cs cycloalkyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; substituted -Ci-C ₈ alkyl, substituted -C ₂ -C ₈ alkenyl, substituted -C ₂ -C ₈ alkynyl or substituted -C ₃ -C ₈ cycloalkyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; heterocyclic; substituted heterocyclic; aryl; substituted aryl; heteroaryl; and substituted heteroaryl; or Ri and R ₂ taken together with the nitrogen atom to which they are attached form a substituted or unsubstituted heterocyclic or heteroaryl group;

Q at each occurrence is selected from the group consisting of: -R ₁ ; -C(O)Ri ₀ , wherein R ₁₀ is -Ri, -ORi, -SRi or -NR _x R ₂ ; -S(O) _n Ri, wherein n = 0, 1, or 2; -S(O) _1n NRiR ₂ , m = 1 or 2; -(C=NR ₄ )NRiR ₂ , wherein R ₄ is independently Ri; -P(O)RiR ₂ ; -P(O)(ORi)(OR ₂ ); -P(O)(NRiR ₂ )(NR ₂ R ₄ ); and

X' at each occurrence is selected from the group consisting of: halogen; -ORi; -NRiR ₂ ; -OC(O)R ₄ , wherein R ₄ is -R _h -ORi, -SRi, -NRiR ₂ , or -N(Ri)OR ₂ ; -N(Ri)C(O)R ₄ ; -N(Ri)S(O) _n R ₂ ; -(CO)-M; -S(O) _n -M; -NO ₂ ; -N ₃ ; - C(Rs)=N-O-Ri, wherein R ₅ is independently -R ₂ ; -C(Rs)=N-NRiR ₂ ; -M; -Q; -

X at each occurrence is -X'; -R ₁ ; or -CN;

Y at each occurrence is selected from the group consisting of: -X'; -R ₁ ; -C(O)- M; -NO ₂ ; -CN; halogen; -S(O) _n R ₃ ; -C(Rs)=N-O-R ₁ ; and -C(R ₅ )=N-

Optionally, provided that when either X or Y is -CN or saturated or unsaturated 5-membered heterocyclic ring, the other is not substituted or unsubstituted -Ci-C ₆ alkyl; or X and Y taken together with the carbon atom to which they attached form a group consisting of: carbonyl; C=C(Ri)R ₂ ; C=N-O-Ri; C=N-NRiR ₂ ; substituted or unsubstituted C ₃ -C8-cycloalkyl group; substituted or unsubstituted C ₃ -Cg-cycloalkenyl group; and substituted or unsubstituted heterocyclic group;

U and W at each occurrence are each independently X', X or Y; or U and W taken together with the carbon atom to which they are attached form a group consisting of: substituted or unsubstituted C ₃ -C8-cycloalkyl group; substituted or unsubstituted C ₃ -C ₈ -cycloalkenyl group; substituted or unsubstituted heterocyclic group; C=O; C=C(Ri)R ₂ ; C=N-ORi; and C=N-NRiR ₂ ;

X and W taken together can be selected from the group consisting of: -C(AiA ₂ )-, -C(AiA ₂ )C(BiB ₂ )-, or -W-C(AiA ₂ )C(BiB ₂ )-, wherein A _h A ₂ , Bi, B ₂ at each occurrence are each independently -M, halogen, and -Q; and W at each occurrence is O, S, or NRi;

G and X taken together with the carbon atoms to which they are attached form a group consisting of: substituted or unsubstituted C ₃ -C8-cycloalkyl group;

substituted or unsubstituted C ₃ -Cg-cycloalkenyl group; substituted or unsubstituted heterocyclic group;

G and Z taken together with the carbon atom to which they are attached form a group consisting of: substituted or unsubstituted C ₃ -C ₈ -cycloalkyl group; substituted or unsubstituted C ₃ -Cg-cycloalkenyl group; substituted or unsubstituted heterocyclic group;

Z and J at each occurrence are each independently: -R ₁ ;

U and J taken together with the two carbons to which they are attached form a ring selected from the group consisting of: -C ₃ -Cg cycloalkyl, -C ₃ -Cg cycloalkenyl or -C ₃ -Cg cycloalkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; substituted -C ₃ -Cg cycloalkyl, substituted -C ₃ -Cg cycloalkenyl or substituted -C ₃ -Cg cycloalkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N. The inventions described herein refer to specific principle embodiments originally described in the priority documents. With respect to each principle embodiment of the invention, the original formulae numbers from its respective priority document has been retained and corresponds to the subsection referenced above. As such, it will be seen that a plurality of formulae have the number (Ia), for example. However, it should be understood that where it appears with respect to a first, second, third, etc. principle embodiment, the formula refers to the specific subsection set forth below.

In its first principle embodiment, the present invention provides a compound of formulae (I), and (II)

or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, prodrug, or combination thereof, wherein:

M at each occurrence is selected from the group consisting of: -ORi; -SRi; -NRiR ₂ ; -R ₁ ; wherein Ri and R ₂ at each occurrence are each independently selected from the group consisting of: hydrogen; deuterium; and -R ₃ ;

Wherein R ₃ at each occurrence is selected from the group consisting of: -Ci-Cg alkyl, -C ₂ -Cg alkenyl, -C ₂ -Cg alkynyl or -C ₃ -Cg cycloalkyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; substituted -Ci-Cg alkyl, substituted -C ₂ -Cg alkenyl, substituted -C ₂ -Cg alkynyl or substituted -C ₃ -Cg cycloalkyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; aryl; substituted aryl; heteroaryl; and substituted heteroaryl; or Ri and R ₂ taken together with the nitrogen atom to which they are attached form a substituted or unsubstituted heterocyclic group;

Q at each occurrence is selected from the group consisting of: -C(O)RiO, wherein R _i0 is -R ₃ , -OR ₃ , or -NRiR ₂ ; -S(O) _n Ri, wherein n = 0, 1 , or 2; -S(O) _1n NRiR ₂ , m = 1 or 2; and -R ₃ ;

X' at each occurrence is selected from the group consisting of: halogen; -ORi; -NRiR ₂ ; -OC(O)R ₄ , wherein R ₄ is -R _h -OR ₃ , -NRiR ₂ , or -N(Ri)OR ₂ ; -N(Ri)C(O)R ₄ ; -NO ₂ ; -N ₃ ; -C(R ₅ )=N-0-Ri, wherein R ₅ is independently -R ₂ ;

X at each occurrence is -X'; -R ₃ ; or -CN;

Y at each occurrence is selected from the group consisting of: -R ₃ ; -C(O)- M; -NO ₂ ; -CN; halogen; -S(O) _n R ₃ ; -C(R ₅ )=N-0-Ri; and -C(Rs)=N-NRiR ₂ ; provided that when either X or Y is -CN or saturated or unsaturated 5-membered heterocyclic ring, the other is not substituted or unsubstituted -Ci-C ₆ alkyl; or X and Y taken together with the carbon atom to which they attached form a group consisting of: carbonyl; C=C(Ri)R ₂ ; C=N-O-Ri; and C=N-NRiR ₂ ;

Z and J at each occurrence are each independently -Ri;

In a second principle embodiment, the present invention also provides a compound of formula (2-1) :

or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, prodrug, or combination thereof, in combination with a pharmaceutically acceptable carrier or excipient, wherein:

M at each occurrence is selected from the group consisting of: -ORi; wherein Ri and R ₂ at each occurrence are each independently selected from the group consisting of: hydrogen; deuterium; and -R ₃ ; Wherein R3 at each occurrence is selected from the group consisting of:

-Ci-Cg alkyl, -C ₂ -Cg alkenyl, -C ₂ -Cg alkynyl or -C ₃ -Cg cycloalkyl containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; substituted -Ci-Cg alkyl, substituted -C ₂ -Cg alkenyl, substituted -C ₂ -Cg alkynyl or substituted -C ₃ -Cg cycloalkyl containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; heterocyclic; substituted heterocyclic; aryl; substituted aryl; heteroaryl; and substituted heteroaryl; or Ri and R ₂ taken together with the nitrogen atom to which they are attached form a substituted or unsubstituted heterocyclic group;

Q at each occurrence is selected from the group consisting of: -R ₁ ; -C(O)Ri; -C(O)ORi; -C(O)NRiR ₂ ; -S(O) _n Ri, wherein n = 0, 1, or 2;

-S(O) _1n NRiR ₂ , m = 1 or 2; -(C=NR ₄ )NRiR ₂ , wherein R ₄ is independently Ri; -P(O)RiR ₂ ; -P(O)(ORi)(OR ₂ ); -P(O)(NRiR ₂ )(NR ₂ R ₄ ); and -P(O)(NRiR ₂ )(OR ₄ );

X and Y taken together with the carbon atom to which they are attached form a group consisting of: substituted or unsubstituted C ₃ -C ₈ -cycloalkyl group; substituted or unsubstituted C ₃ -Cg-cycloalkenyl group; and substituted or unsubstituted heterocyclic group;

Z and J at each occurrence are each independently -R ₃ .

In a third principle embodiment, the present invention also provides a compound of formula (3-1):

or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, prodrug, or combination thereof, in combination with a pharmaceutically acceptable carrier or excipient, wherein:

M at each occurrence is selected from the group consisting of: -ORi; -NRiR ₂ ; -SRi; and -Ri;

wherein Ri and R ₂ at each occurrence are each independently selected from the group consisting of: hydrogen; deuterium; and -R ₃ ;

Wherein R3 at each occurrence is selected from the group consisting of: -Ci-Cg alkyl, -C ₂ -Cg alkenyl, -C ₂ -Cg alkynyl or -C ₃ -Cg cycloalkyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; substituted -Ci-Cg alkyl, substituted -C ₂ -Cg alkenyl, substituted -C ₂ -Cg alkynyl or substituted -C ₃ -Cg cycloalkyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; heterocyclic; substituted heterocyclic; aryl; substituted aryl; heteroaryl; and substituted heteroaryl; or Ri and R ₂ taken together with the nitrogen atom to which they are attached form a substituted or unsubstituted heterocyclic group;

Q at each occurrence is selected from the group consisting of: -R ₁ ; -C(O)Ri; -C(O)ORi; -C(O)NRiR ₂ ; -S(O) _n Ri, wherein n = 0, 1, or 2; -S(O) _1n NRiR ₂ , m = 1 or 2; -(C=NR ₄ )NRiR ₂ , wherein R ₄ is independently R ₁ ; -P(O)RiR _2; -P(O)(ORi)(OR ₂ ); -P(O)(NRiR ₂ )(NR ₂ R ₄ ); and -P(O)(NRiR ₂ )(OR ₄ );

X and Y at each occurrence are each independently selected from the group consisting of: halogen; -M; -Q; -NO ₂ ; -CN; -N ₃ ; -C(R ₄ )=N-0-R ₁ ; -C(R _t )=N- NRiR ₂ ; -0-Q; and -N(Ri)-Q; or X and Y taken together with the carbon atom to which they are attached form a group consisting of: substituted or unsubstituted C ₃ -Cg-cycloalkyl group; substituted or unsubstituted C ₃ -Cg-cycloalkenyl group; substituted or unsubstituted heterocyclic group; C=O; C=C(Ri)R ₂ ; C=N-ORi; and C=N-NR _x R ₂ ;

Z is independently selected from the groups in -R ₁ ;

J at each occurrence is selected from the group consisting of: -C(Rt)=N-O- R ₁ J aUd -C(Rt)=N-NR ₁ R ₂ .

In a fourth principle embodiment, the present invention provides a compound of formula (4-1):

or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, prodrug, or combination thereof, wherein:

M at each occurrence is selected from the group consisting of: -ORi; wherein Ri and R ₂ at each occurrence are each independently selected from the group consisting of: hydrogen; deuterium; and -R ₃ ; Wherein R3 at each occurrence is selected from the group consisting of:

-Ci-Cg alkyl, -C ₂ -Cg alkenyl, -C ₂ -Cg alkynyl or -C ₃ -Cg cycloalkyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; substituted -Ci-Cg alkyl, substituted -C ₂ -Cg alkenyl, substituted -C ₂ -Cg alkynyl or substituted -C ₃ -Cg cycloalkyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; heterocyclic; substituted heterocyclic; aryl; substituted aryl; heteroaryl; and substituted heteroaryl; or Ri and R ₂ taken together with the nitrogen atom to which they are attached form a substituted or unsubstituted heterocyclic group;

Q at each occurrence is selected from the group consisting of: -R ₁ ; -C(O)-M; -S(O) _n Ri, wherein n = 1 or 2; and -S(O) _n NRiR _2;

U and W at each occurrence are each independently selected from the group consisting of: halogen; -ORi; -SRi; -NRiR ₂ ; -R ₁ ; -OC(O)-M; -N(Ri)C(O)-M; -N(Ri)S(O) _n R ₂ ; -NO ₂ ; -CN; -C(O)-M; -S(O) _n -M; -N ₃ ; - C(Rs)=N-O-Ri, wherein R ₅ is independently -Ri; and -C(Rs)=N-NRiR ₂ ; or U and W taken together with the carbon atom to which they are attached form the group consisting of: C=O; C=C(Ri)R ₂ ; C=N-ORi; substituted or unsubstituted C ₃ -C ₈ -cycloalkyl group; substituted or unsubstituted C ₃ -Cg-cycloalkenyl group; and substituted or unsubstituted heterocyclic group;

X and Y at each occurrence is each independently selected from the group consisting of: -U; -W; Hydrogen; and Deuterium; provided when Y is -C(O)-Ri, -C(O)-NRiR ₂ , -CN, or saturated or unsaturated 5-membered heterocyclic ring, at least one of X, U and W is selected from the group consisting of: -ORi; -NRiR ₂ ; -SRi; halogen; -N(Ri)S(O) _n R ₂ ; -NO ₂ ; -CN; -C(O)-M; -S(O) _n -M; -N ₃ ; -C(Rs)=N-O-Ri; -C(Rs)=N-NRiR ₂ ; -OC(O)-M; and-N(Ri)C(0)-M;

Z at each occurrence is -R ₁ ;

J at each occurance is selected from the group consisting of: -R ₁ ; -CN;

In a fifth principle embodiment, the present invention provides a compound of formula (5-1):

or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, prodrug, or combination thereof, wherein:

M at each occurrence is selected from the group consisting of: -ORi; wherein Ri and R ₂ at each occurrence are each independently selected from the group consisting of: hydrogen; deuterium; and -R ₃ ;

Wherein R ₃ at each occurrence is selected from the group consisting of: -Ci-C ₈ alkyl, -C ₂ -C ₈ alkenyl, -C ₂ -C ₈ alkynyl or -C ₃ -C ₈ cycloalkyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; substituted -Ci-C ₈ alkyl, substituted -C ₂ -C ₈ alkenyl, substituted -C ₂ -C ₈ alkynyl or substituted -C ₃ -C ₈ cycloalkyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; heterocyclic; substituted heterocyclic; aryl; substituted aryl; heteroaryl; andsubstituted heteroaryl; or Ri and R ₂ taken together with the nitrogen atom to which they are attached form a substituted or unsubstituted heterocyclic group;

Q at each occurrence is selected from the group consisting of: -R ₁ ; -C(O)Ri; -C(O)ORi; -C(O)NRiR ₂ ; -S(O) _n Ri, wherein n = 0, 1, or 2; -S(O) _1n NRiR ₂ , m = 1 or 2; -(C=NR ₄ )NRiR ₂ , wherein R ₄ is independently Ri; -P(O)RiR ₂ ; -P(O)(ORi)(OR ₂ ); -P(O)(NRiR ₂ )(NR ₂ R ₄ ); and -P(O)(NRiR ₂ )(OR ₄ ); Y at each occurrence is independently selected from the group consisting of: halogen; -M; -Q; -NO ₂ ; -CN; -N ₃ ; -C(R-O=N-O-Ri; -C(RO=N-NRiR ₂ ; -O-

U and W at each occurrence are each independently Y; or U and W taken together with the carbon atom to which they are attached form a group consisting of: substituted or unsubstituted C ₃ -C ₈ -cycloalkyl group;

substituted or unsubstituted C3-Cg-cycloalkenyl group; substituted or unsubstituted heterocyclic group; C=O; C=C(Ri)R ₂ ; C=N-ORi; and C=N-NRiR ₂ ;

Z at each occurrence is independently -R ₁ ;

G and X taken together with the carbon atoms to which they are attached form a group consisting of: substituted or unsubstituted C3-Cg-cycloalkyl group; substituted or unsubstituted C3-Cg-cycloalkenyl group; substituted or unsubstituted heterocyclic group;

J at each occurrence is selected from the group consisting of: -C(TL _t )=N-O- R ₁ ; -C(R ₄ )=N-NR ₁ R ₂ ; and -R ₁ . In a sixth principle embodiment, the present invention provides a compound of formula (6-1):

or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, prodrug, or combination thereof, wherein: M at each occurrence is selected from the group consisting of: -ORi; wherein Ri and R ₂ at each occurrence are each independently selected from the group consisting of: hydrogen; deuterium; and -R ₃ ;

Wherein R3 at each occurrence is selected from the group consisting of: -Ci-Cg alkyl, -C ₂ -Cg alkenyl, -C ₂ -Cg alkynyl or -C3-Cg cycloalkyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; substituted -Ci-Cg alkyl, substituted -C ₂ -Cg alkenyl, substituted -C ₂ -Cg alkynyl or substituted -C ₃ -Cg cycloalkyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; heterocyclic; substituted heterocyclic; aryl; substituted aryl; heteroaryl; and substituted heteroaryl; or Ri and R ₂ taken together with the nitrogen atom to which they are attached form a substituted or unsubstituted heterocyclic group;

Q at each occurrence is selected from the group consisting of: -R ₁ ; -C(O)Ri; -C(O)ORi; -C(O)NRiR ₂ ; -S(O) _n Ri, wherein n = 0, 1, or 2;

-S(O) _1n NRiR ₂ , m = 1 or 2; -(C=NR ₄ )NRiR ₂ , wherein R ₄ is independently R ₁ ; -P(O)RiR ₂ ; -P(O)(ORi)(OR ₂ ); -P(O)(NRiR ₂ )(NR ₂ R ₄ ); and -P(O)(NRiR ₂ )(OR ₄ );

U and Y at each occurrence are each independently selected from the group consisting of: halogen; -M; -Q; -NO ₂ ; -CN; -N ₃ ; -C(R _t )=N-O-R ₁ ; -C(R _t )=N- NRiR ₂ ; -0-Q; and -N(Ri)-Q;

Z at each occurrence is independently -R ₁ ;

X is selected from the group consisting of: -C(AiA ₂ )-, -C(AiA ₂ )C(BiB ₂ )-, or -W-C(AiA ₂ )C(BiB ₂ )-, wherein A ₁ , A ₂ , B ₁ , B ₂ at each occurrence are each independently -M, halogen, and -Q; and W at each occurrence is O, S, or NRi;

J at each occurrence is selected from the group consisting of: -C(R ₄ )=N-0- R ₁ ; -C(Rt)=N-NR ₁ R ₂ ; and -R ₁ .

In a seventh principle embodiment, the present invention provides a compound of formula (7-1):

or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, prodrug, or combination thereof, wherein:

M at each occurrence is selected from the group consisting of: -ORi; wherein Ri and R ₂ at each occurrence are each independently selected from the group consisting of: hydrogen; deuterium; and -R ₃ ;

Wherein R ₃ at each occurrence is selected from the group consisting of: -Ci-C ₈ alkyl, -C ₂ -C ₈ alkenyl, -C ₂ -C ₈ alkynyl or -C ₃ -C ₈ cycloalkyl each containing O, 1, 2, or 3 heteroatoms selected from O, S or N; substituted -Ci-C ₈ alkyl, substituted -C ₂ -C ₈ alkenyl, substituted -C ₂ -C ₈ alkynyl or substituted -C ₃ -C ₈ cycloalkyl each containing O, 1, 2, or 3 heteroatoms selected from O, S or N; heterocyclic; substituted heterocyclic; aryl; substituted aryl; heteroaryl; and substituted heteroaryl; or Ri and R ₂ taken together with the nitrogen atom to which they are attached form a substituted or unsubstituted heterocyclic group;

Q at each occurrence is selected from the group consisting of: -R ₁ ; -C(O)-M; -S(O) _n Ri, wherein n = 1 or 2; and -S(O) _n NRiR _2;

X and Y at each occurrence are each independently selected from the group consisting of: halogen; -M; -OC(O)-M; -N(Ri)C(O)-M; -N(Ri)S(O) _n R ₂ ; -NO ₂ ; -CN; -C(O)-M; -S(O) _n -M; -N ₃ ; -C(R ₅ )=N-0-Ri, wherein R ₅ is independently -R ₁ ; and -C(Rs)=N-NRiR ₂ ; or X and Y taken together with the carbon atom to which they are attached form the group consisting of: C=O; C=C(Ri)R ₂ ; C=N-ORi; C=N-NR _x R ₂ ; substituted or unsubstituted C ₃ -Cg-cycloalkyl group; substituted or unsubstituted C ₃ -Cg-cycloalkenyl group; and substituted or unsubstituted heterocyclic group;

W at each occurrence is each independently selected from the group consisting of: halogen; -M -OC(O)-Mj-N(R ₁ )C(O)-M; -N(Ri)S(O) _n R ₂ ;

Z at each occurrence is -R ₁ ;

J at each occurance taken together with the two carbons to which it is attached form a ring selected from the group consisting of: -C ₃ -Cs cycloalkyl, -C ₃ - Cg cycloalkenyl or -C ₃ -Cg cycloalkynyl each containing O, 1, 2, or 3 heteroatoms selected from O, S or N; substituted -C ₃ -Cg cycloalkyl, substituted -C ₃ -Cg cycloalkenyl or substituted -C ₃ -Cg cycloalkynyl each containing O, 1, 2, or 3 heteroatoms selected from O, S or N. In another embodiment, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound or combination of compounds of the present invention, or a pharmaceutically acceptable salt form, prodrug, salt of a prodrug, stereoisomer, tautomer, solvate, or combination thereof, in combination with a pharmaceutically acceptable carrier or excipient.

In yet another embodiment, the present invention provides a method of inhibiting the replication of an RNAcontaining virus comprising contacting said virus with a therapeutically effective amount of a compound or a combination of compounds of the present invention, or a pharmaceutically acceptable salt, prodrug, salt of a pro drug, stereoisomer, tautomer, solvate, or combination thereof. Particularly, this invention is directed to methods of inhibiting the replication of hepatitis C virus.

In still another embodiment, the present invention provides a method of treating or preventing infection caused by an RNA-containing virus comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound or combination of compounds of the present invention, or a pharmaceutically acceptable salt form, prodrug, salt of a prodrug, stereoisomer, or tautomer, solvate, or combination thereof. Particularly, this invention is directed to methods of treating or preventing infection caused by hepatitis C virus.

Yet another embodiment of the present invention provides the use of a compound or combination of compounds of the present invention, or a therapeutically acceptable salt form, prodrug, salt of a prodrug, stereoisomer or tautomer, solvate, or combination thereof, as defined hereinafter, in the preparation of a medicament for the treatment or prevention of infection caused by RNA- containing virus, specifically hepatitis C virus (HCV).

DETAILED DESCRIPTION OF THE INVENTION

I. First Principle Embodiment

In a first embodiment of the present invention is a compound of Formulae (I) or (II) as illustrated above, or a pharmaceutically acceptable salt, ester or prodrug thereof. In a second embodiment of the present invention is the relative stereochemistry of a racemic compound of Formulae (I) or (II), is represented by Formulae (Ia), (Ib) or (Ha):

(Ia) (Ib) (Ma) relative stereochemistry relative s stereochemistry relative stereochemistry wherein M, Q, Z, X', X, Y and J are as previously defined. In a third embodiment of the present invention is the absolute stereochemistry of a chiral compound of Formulae (I) or (II), is represented by Formulae (Iaa), (Ibb) or (Haa):

(laa) (Ibb) (llaa) absolute stereochemistry absolute stereochemistry absolute stereochemistry wherein M, Q, Z, X', X, Y and J are as previously defined.

In a fourth embodiment of the present invention relates to compound of

Formula (Ilia), or a pharmaceutically acceptable salt, ester or prodrug thereof:

wherein M, Q, Z, Y and J are as previously defined and Ai is halogen.

In a fifth embodiment of the present invention relates to compound of Formula (HIb), or a pharmaceutically acceptable salt, ester or prodrug thereof:

wherein M, Q, Z, Y, R ₃ and J are as previously defined; provided that when Y is -CN or saturated or unsaturated 5-membered heterocyclic ring, R3 is not substituted or unsubstituted -Ci-C ₆ alkyl.

In a sixth embodiment of the present invention relates to compound of

Formula (HIc), or a pharmaceutically acceptable salt, ester or prodrug thereof:

wherein M, Q, Z, Y, Ri and J are as previously defined.

In a seventh embodiment of the present invention relates to compound of

Formula (HId), or a pharmaceutically acceptable salt, ester or prodrug thereof:

wherein M, Q, Z, Y, Ri, R ₂ , and J are as previously defined.

In an eighth embodiment of the present invention relates to compound of

Formula (HIe), or a pharmaceutically acceptable salt, ester or prodrug thereof:

wherein M, Q, Z, Y, R ₄ , and J are as previously defined.

In a ninth embodiment of the present invention relates to compound of

Formula (HIf), or a pharmaceutically acceptable salt, ester or prodrug thereof:

wherein M, Q, Z, Y, R ₁ , R ₄ , and J are as previously defined.

In a tenth embodiment of the present invention relates to compound of Formula (HIg), or a pharmaceutically acceptable salt, ester or prodrug thereof:

wherein M, Q, Z, X, R ₁ , R ₅ , and J are as previously defined.

In an eleventh embodiment of the present invention relates to compound of Formula (HIh), or a pharmaceutically acceptable salt, ester or prodrug thereof:

wherein M, Q, Z, X, R ₁ , R ₂ , R ₅ , and J are as previously defined.

In a twelfth embodiment of the present invention relates to compound of Formula (HIi), or a pharmaceutically acceptable salt, ester or prodrug thereof:

wherein M, Q, Z, X, and Y are as previously defined.

In a thirteen embodiment of the present invention relates to compound of Formula (IVa), or a pharmaceutically acceptable salt, ester or prodrug thereof:

wherein M, Q, Z, Ai and J are as previously defined.

In a fourteenth embodiment of the present invention relates to compound of Formula (IVb), or a pharmaceutically acceptable salt, ester or prodrug thereof:

wherein M, Q, Z, Ri and J are as previously defined.

In a fifteenth embodiment of the present invention relates to compound of Formula (IVc), or a pharmaceutically acceptable salt, ester or prodrug thereof:

wherein M, Q, Z, R ₁ , R ₂ , and J are as previously defined. In a sixteenth embodiment of the present invention relates to compound of

Formula (IVd), or a pharmaceutically acceptable salt, ester or prodrug thereof:

wherein M, Q, Z, R ₄ , and J are as previously defined.

In a seventeenth embodiment of the present invention relates to compound of Formula (IVe), or a pharmaceutically acceptable salt, ester or prodrug thereof:

wherein M, Q, Z, R ₁ , R ₄ , and J are as previously defined.

In an eighteenth embodiment of the present invention relates to compound of Formula (IVf), or a pharmaceutically acceptable salt, ester or prodrug thereof:

wherein M, Q, Z, R ₁ , R ₅ , and J are as previously defined.

In a nineteenth embodiment of the present invention relates to compound of Formula (IVg), or a pharmaceutically acceptable salt, ester or prodrug thereof:

wherein M, Q, Z, R ₁ , R ₂ , R ₅ , and J are as previously defined.

In a twentieth embodiment of the present invention relates to compound of Formula (IVh), or a pharmaceutically acceptable salt, ester or prodrug thereof:

wherein M, Q, Z, and X' are as previously defined. Representative compounds of the present invention are those selected from:

1. Compound of Formula (Ia), wherein M = tert-butoxyl, Q = 4-tert-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxycarbonyl, J = IH- pyrazol- 1 -ylmethyl.

2. Compound of Formula (Ia), wherein M = tert-butoxy, Q = 4-te/t-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = hydroxymethyl, J = IH- pyrazol- 1 -ylmethyl.

3. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = hydroxymethyl, J = IH- pyrazol- 1 -ylmethyl.

4. Compound of Formula (Ia), wherein M = tert-butoxy, Q = 4-tert-buty\-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, J = IH- pyrazol- 1 -ylmethyl.

5. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyi-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, J = IH- pyrazol- 1 -ylmethyl. 6. Compound of Formula (Ia), wherein M = tert-butyl, Q = 4-tert-buty\-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = carbamoyl, J = lH-pyrazol- 1 -ylmethyl.

7. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyi-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = carbamoyl, J = lH-pyrazol- 1 -ylmethyl.

8. Compound of Formula (Ia), wherein M = tert-butyi, Q = 4-tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = 2,2,2- trichloroacetylcarbamoyloxymethyl, J = lH-pyrazol-1 -ylmethyl.

9. Compound of Formula (Ia), wherein M = tert-butyl, Q = 4-te/t-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = carbamoyloxymethyl, J = 1 H-pyrazol- 1 -ylmethyl.

10. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = carbamoyloxymethyl, J = 1 H-pyrazol- 1 -ylmethyl. 11. Compound of Formula (Ia), wherein M = tert-butyi, Q = 4-te/t-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = Me, Y = methoxycarbonyl, J = IH- pyrazol- 1 -ylmethyl.

12. Compound of Formula (Ia), wherein M = tert-butyl, Q = 4-te/t-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = methoxycarbonylmethyl, Y = methoxycarbonyl, J = 1 H-pyrazol- 1 -ylmethyl.

13. Compound of Formula (Ia), wherein M = tert-butyi, Q = 4-te/t-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = 2 -hydroxy ethyl, Y = hydroxymethyl, J = 1 H-pyrazol- 1 -ylmethyl.

14. Compound of Formula (Ia), wherein M = tert-butyl, Q = 4-tert-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = chloro, Y = methoxycarbonyl, J = IH- pyrazol- 1 -ylmethyl.

15. Compound of Formula (Ia), wherein M = tert-butyl, Q = 4-tert-buty\-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = acetamido, Y = methoxycarbonyl, J = 1 H-pyrazol- 1 -ylmethyl.

16. Compound of Formula (Ia), wherein M = tert-butyl, Q = 4-tert-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = Me, Y = hydroxymethyl, J = IH- pyrazol- 1 -ylmethyl. 17. Compound of Formula (Ia), wherein M = tert-butyl, Q = 4-tert-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = Me, Y = formyl, J = 1 H-pyrazol- 1- ylmethyl.

18. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = Me, Y = formyl, J = 1 H-pyrazol- 1- ylmethyl.

19. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = Me, Y = methoxyimino-methyl, J = 1 H-pyrazol- 1 -ylmethyl.

20. Compound of Formula (Ia), wherein M = tert-butyl, Q = 4-te/t-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = Me, Y = methoxymethyl, J = IH- pyrazol- 1 -ylmethyl.

21. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = Me, Y = methoxymethyl, J = IH- pyrazol- 1 -ylmethyl. 22. Compound of Formula (Ia), wherein M = tert-butyl, Q = 4-tert-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = acetoxy, Y = cyano, J = lH-pyrazol-1- ylmethyl.

23. Compound of Formula (Ia), wherein M = tert-butyl, Q = 4-tert-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = trifluoromethyl, Y = methoxycarbonyl, J = I H-pyrazol- 1 -ylmethyl.

24. Compound of Formula (Ia), wherein M = hydroxy, Q = 3-bromo-4-te/t- butylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, J = IH- pyrazol- 1 -ylmethyl.

25. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- vinylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, J = IH- pyrazol- 1 -ylmethyl.

26. Compound of Formula (Ia), wherein M = hydroxy, Q = 2-fluoro-4-te/t-butyl-5- vinylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, J = IH- pyrazol- 1 -ylmethyl.

27. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, J = 1,3- thiazol-4-ylmethyl. 28. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, J = 1,3- thiazol-2-ylmethyl.

29. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, J = 1,2- thiazol-3-ylmethyl.

30. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxylbenzoyl, Z = 5-methylisoxazol-3-yl, X = fluoro, Y = methoxymethyl, J = 1 H-pyrazol- 1 -ylmethyl.

31. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-te/t-butyl-3- methoxylbenzoyl, Z = thiophen-2-yl, X = fluoro, Y = methoxymethyl, J = IH- pyrazol- 1 -ylmethyl.

32. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxylbenzoyl, Z = thiophen-3-yl, X = fluoro, Y = methoxymethyl, J = IH- pyrazol- 1 -ylmethyl. 33. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxylbenzoyl, Z = furan-2-yl, X = fluoro, Y = methoxymethyl, J = lH-pyrazol- 1 -ylmethyl.

34. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxylbenzoyl, Z = furan-3-yl, X = fluoro, Y = methoxymethyl, J = lH-pyrazol- 1 -ylmethyl.

35. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-te/t-butyl-3- methoxylbenzoyl, Z = l,3-oxazol-2-yl, X = fluoro, Y = methoxymethyl, J = IH- pyrazol- 1 -ylmethyl.

36. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxylbenzoyl, Z = phenyl, X = fluoro, Y = methoxymethyl, J = lH-pyrazol-1- ylmethyl.

37. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxylbenzoyl, Z = pyridin-2-yl, X = fluoro, Y = methoxymethyl, J = IH- pyrazol- 1 -ylmethyl.

38. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxylbenzoyl, Z = pyridin-3-yl, X = fluoro, Y = methoxymethyl, J = IH- pyrazol- 1 -ylmethyl. 39. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxylbenzoyl, Z = pyridin-4-yl, X = fluoro, Y = methoxymethyl, J = IH- pyrazol- 1 -ylmethyl.

40. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxyl benzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, J = thiophen-2-yl.

41. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxylbenzoyl, Z = l,3-thiazol-2-yl-methyl, X = fluoro, Y = methoxymethyl, J = lH-pyrazol-1 -ylmethyl.

42. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-te/t-butyl-3- methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = -CHO, J = lH-pyrazol-1- ylmethyl.

43. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = -CH=NOMe, J = IH- pyrazol- 1 -ylmethyl. 44. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = -CH=NOEt, J = IH- pyrazol- 1 -ylmethyl.

45. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = -CH=NO"Pr, J = IH- pyrazol-1 -ylmethyl.

46. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-te/t-butyl-3- methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = -CH=NO-allyl, J = IH- pyrazol- 1 -ylmethyl.

47. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = -CH=NOCH ₂ CO ₂ Me, J = 1 H-pyrazol- 1 -ylmethyl.

48. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxylbenzoyl, Z = 1 ,3-thiazol-2-yl, X = fluoro, Y = -CH=NOPh, J = IH- pyrazol- 1 -ylmethyl.

49. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = -CH=NO-Bn, J = IH- pyrazol- 1 -ylmethyl. 50. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = -CH=NO-(2- chlorophenyl), J = 1 H-pyrazol- 1 -ylmethyl.

51. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = -CH=NO-(3- chlorophenyl), J = 1 H-pyrazol- 1 -ylmethyl.

52. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = -CH=NO-(4- chlorophenyl), J = 1 H-pyrazol- 1 -ylmethyl.

53. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-te/t-butyl-3- methoxylbenzoyl, Z = 1 ,3-thiazol-2-yl, X = fluoro, Y = -CH=NO-(2- fluorophenyl), J = 1 H-pyrazol- 1 -ylmethyl.

54. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = -CH=NO-(3- fluorophenyl), J = 1 H-pyrazol- 1 -ylmethyl. 55. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = -CH=NO-(4- fluorophenyl), J = 1 H-pyrazol- 1 -ylmethyl.

56. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = -CH=NO-(2- cyanophenyl), J = 1 H-pyrazol- 1 -ylmethyl.

57. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-te/t-butyl-3- methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = -CH=NO-(3- cyanophenyl), J = 1 H-pyrazol- 1 -ylmethyl.

58. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = -CH=NO-(4- cyanophenyl), J = lH-pyrazol-1-ylmethyl.

59. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxylbenzoyl, Z = 1 ,3-thiazol-2-yl, X = fluoro, Y = -CH=NO-(4- methylphenyl), J = lH-pyrazol-1-ylmethyl.

60. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = -CH=NO-(4- trifluoromethylphenyl), J = lH-pyrazol-1-ylmethyl. 61. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = -CH=NO-(4- acetamidophenyl), J = lH-pyrazol-1-ylmethyl.

62. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = -CH=NO-(4- methoxycarbonylaminophenyl), J = lH-pyrazol-1-ylmethyl.

63. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = -CH=NO-(4- methanesulfonylaminophenyl), J = lH-pyrazol-1-ylmethyl.

64. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-te/t-butyl-3- methoxylbenzoyl, Z = 1 ,3-thiazol-2-yl, X = fluoro, Y = -CH=NO-(2,4- difluorophenyl), J = lH-pyrazol-1-ylmethyl.

65. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = -CH=NO-(3,4- difluorophenyl), J = lH-pyrazol-1-ylmethyl. 66. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = -CH=NO-(2-chloro-4- fluorophenyl), J = lH-pyrazol-1-ylmethyl.

67. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{- benzenesulfonyl, Z = l,3-thiazol-2-yl, X is cyano, Y is acetoxy, J = lH-pyrazol-1- ylmethyl.

68. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\- phenylcarbamoyl, Z = l,3-thiazol-2-yl, X is cyano, Y is acetoxy, J = lH-pyrazol-1- ylmethyl.

69. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\- benzenesulfonyl, Z = l,3-thiazol-2-yl, X is fluoro, Y = -CH=NOMe, J = IH- pyrazol- 1 -ylmethyl.

70. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\- phenylcarbamoyl, Z = 1 ,3-thiazol-2-yl, X = fluoro, Y = -CH=NOMe, J = IH- pyrazol- 1 -ylmethyl.

71. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\- benzenesulfonyl, Z = l,3-thiazol-2-yl, X is fluoro, Y is methoxymethyl, J = IH- pyrazol- 1 -ylmethyl. 72. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{- phenylcarbamoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y is methoxymethyl, J = IH- pyrazol- 1 -ylmethyl.

73. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = Y = methoxymethyl, J = hydrogen. 74. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxylbenzoyl, Z = l,3-thiazol-2-yl, X is methoxymethyl, Y = benzyloxymethyl, J = hydrogen.

75. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = lH-pyrazol-1 -ylmethyl, Y = benzyloxymethyl, J = hydrogen.

76. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = -CH ₂ OC(O)NMe ₂ , Y = benzyloxymethyl, J = hydrogen.

77. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-te/t-butyl-3- methoxylbenzoyl, Z = 1 ,3-thiazol-2-yl, X = -CH ₂ NSO ₂ Me, Y = benzyloxymethyl, J = hydrogen.

78. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = -CH ₂ ON=CMe ₂ , Y = benzyloxymethyl, J = hydrogen. 79. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxylbenzoyl, Z = l,3-thiazol-2-yl, X is fluoro, Y is -C(Me)=NOPh, J = IH- pyrazol- 1 -ylmethyl.

80. Compound of Formula (Ha), wherein M = hydroxy, Q = 4-tert-butyl-3- methoxylbenzoyl, Z = l,3-thiazol-2-yl, X' = -CH=NOPh, J = lH-pyrazol-1- ylmethyl.

81. Compound of Formula (Ha), wherein M = hydroxy, Q = 4-tert-butyl-3- methoxylbenzoyl, Z = l,3-thiazol-2-yl, X' = -C(Me)=NOPh, J = lH-pyrazol-1- ylmethyl.

82. Compound of Formula (Ha), wherein M = hydroxy, Q = 4-tert-butyl-3- methoxylbenzoyl, Z = l,3-thiazol-2-yl, X' = -O-allyl, J = lH-pyrazol-1-ylmethyl.

83. Compound of Formula (Ha), wherein M = hydroxy, Q = 4-tert-butyl-3- methoxylbenzoyl, Z = l,3-thiazol-2-yl, X' = -0-CH ₂ CH ₂ Ph, J = lH-pyrazol-1- ylmethyl.

84. Compound of Formula (Ha), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxylbenzoyl, Z = l,3-thiazol-2-yl, X' = -N(allyl) ₂ , J = lH-pyrazol-1- ylmethyl. 85. Compound of Formula (Ha), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxylbenzoyl, Z = l,3-thiazol-2-yl, X' = -NHC(O)CH ₂ Ph, J = lH-pyrazol-1- ylmethyl.

86. Compound of Formula (Ha), wherein M = hydroxy, Q = 4-tert-butyl-3- methoxylbenzoyl, Z = l,3-thiazol-2-yl, X' = 4-morpholinyl, J = lH-pyrazol-1- ylmethyl.

87. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl-3- methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = lH-pyrazol-1 -ylmethyl, Y = methoxymethyl, J = hydrogen.

88. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-te/t-butyl-3- methoxylbenzoyl, Z = 1 ,3-thiazol-2-yl, X = -CH ₂ OC(O)NMe ₂ , Y = methoxymethyl, J = hydrogen.

89. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = -CH ₂ NSO ₂ Me, Y = methoxymethyl, J = hydrogen. 90. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-te/t-butyl-3- methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = -CH=NO-^-Bu, J = IH- pyrazol- 1 -ylmethyl.

91. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = -CH ₂ OCH ₂ Ph, J = IH- pyrazol- 1 -ylmethyl.

92. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = -Ac, J = lH-pyrazol-1- ylmethyl.

93. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = -C(Me)=NO-(4- fluorophenyl), J = lH-pyrazol-1 -ylmethyl. 94. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = -CH=NO-Z-Pr, J = IH- pyrazol- 1 -ylmethyl.

95. Compound of Formula (Ha), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = -CH=NO-(4-fiuorophenyl), J = IH- pyrazol- 1 -ylmethyl.

96. Compound of Formula (Ha), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = -CH=NO-phenyl, J = lH-pyrazol-1- ylmethyl.

97. Compound of Formula (Ia), wherein M = tert-butoxy, Q = 4-te/t-butyl-3- methoxylbenzoyl, Z = 1 ,3-thiazol-2-yl, X = fluoro, Y = -CH ₂ OMe, J = hydroxymethyl.

98. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = -NHAc, Y = -CO ₂ Me, J = IH- pyrazol- 1 -ylmethyl. 99. Compound of Formula (Ia), wherein M = tert-butoxy, Q = 4-tert-buty{-3- methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = -C(O)N(Me)OMe, J = IH- pyrazol- 1 -ylmethyl.

100. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = -NHAc, Y = -CH ₂ OH, J = IH- pyrazol- 1 -ylmethyl.

101. Compound of Formula (Ia), wherein M = tert-butoxy, Q = 4-te/t-butyl-3- methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = -CH(OH)Me, J = IH- pyrazol- 1 -ylmethyl.

102. Compound of Formula (Ia), wherein M = tert-butoxy, Q = 4-tert-butyl-3- methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = -CH ₂ OH, Y = -CH ₂ OMe, J = -CH ₂ OH.

103. Compound of Formula (Ia), wherein M = tert-butoxy, Q = 4-tert-butyl-3- methoxylbenzoyl, Z = 1 ,3-thiazol-2-yl, X = -CH ₂ Br, Y = -CO ₂ Et, J = lH-pyrazol- 1-ylmethyl.

104. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl-3- methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = -CH=N-OH, J = IH- pyrazol- 1 -ylmethyl. 105. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl-3- methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = -CN, J = lH-pyrazol-1- ylmethyl.

106. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = -C(O)NHMe, J = IH- pyrazol- 1 -ylmethyl.

107. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = -C(O)NHEt, J = IH- pyrazol- 1 -ylmethyl.

108. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-te/t-butyl-3- methoxylbenzoyl, Z = 1 ,3-thiazol-2-yl, X = fluoro, Y = -C(O)NHOH, J = IH- pyrazol- 1 -ylmethyl.

109. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl-3- methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = -C(O)NHBn, J = IH- pyrazol- 1 -ylmethyl. 110. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl-3- methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = -CH ₂ OBz, J = lH-pyrazol- 1 -ylmethyl.

111. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = -CH ₂ OMs, J = IH- pyrazol- 1 -ylmethyl.

112. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-te/t-butyl-3- methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = -(/^)-CH=CHCN, J = IH- pyrazol- 1 -ylmethyl.

113. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = -(^)-CH=CHCN, J = IH- pyrazol- 1 -ylmethyl.

114. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxylbenzoyl, Z = 1 ,3-thiazol-2-yl, X = fluoro, Y = -CH ₂ CH ₂ CN, J = IH- pyrazol- 1 -ylmethyl.

115. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = -CH ₂ O-propargyl, J = IH- pyrazol- 1 -ylmethyl. 116. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = -CH ₂ O-allyl, J = IH- pyrazol- 1 -ylmethyl.

117. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = 3-(pyridin-2-yl)-prop-2- ynyloxymethyl, J = lH-pyrazol-1 -ylmethyl.

118. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = -CH ₂ ON=CMe ₂ , J = IH- pyrazol- 1 -ylmethyl.

119. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-te/t-butyl-3- methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = -CH ₂ N ₃ , J = lH-pyrazol-1- ylmethyl.

120. Compound of Formula (Ia), wherein M = hydroxy, Q = benzoyl, Z = 1,3- thiazol-2-yl, X = fluoro, Y = -CH ₂ N ₃ , J = lH-pyrazol-1 -ylmethyl.

121. Compound of Formula (Ia), wherein M = hydroxy, Q = 3 -methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = -CH ₂ N ₃ , J = lH-pyrazol-1 -ylmethyl.

122. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-te/t-butyl-benzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = -CH ₂ N ₃ , J = lH-pyrazol-1 -ylmethyl.

123. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = -CH ₂ NHBz, J = IH- pyrazol-1 -ylmethyl.

124. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-te/t-butyl-3- methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = -CH ₂ NHSO ₂ Ph, J = IH- pyrazol- 1 -ylmethyl.

125. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = -CH ₂ NHAc, J = IH- pyrazol- 1 -ylmethyl.

126. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = -CH ₂ NHMs, J = IH- pyrazol- 1 -ylmethyl.

127. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = -CH ₂ NHCO ₂ Me, J = IH- pyrazol- 1 -ylmethyl. 128. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = -CH ₂ NMe ₂ , J = IH- pyrazol- 1 -ylmethyl. 129. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3-

methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = -CH ₂ ' ^N " ^N ^-/ J = _1H _ pyrazol- 1 -ylmethyl.

Example 130. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-

butyl-3-methoxylbenzoyl, Z = 1 ,3-thiazol-2-yl, X = fluoro, Y = -CH ₂ ^ ^N Y- ^/ J = lH-pyrazol-1 -ylmethyl.

131. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-te/t-butyl-3- methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = l,3-oxazol-2-yl, J = IH- pyrazol- 1 -ylmethyl.

132. Compound of Formula (Ia), wherein M = tert-butoxy, Q = 4-tert-buty\-3-

methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = J = IH- pyrazol- 1 -ylmethyl. 133. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-te/t-butyl-3-

methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = J = IH- pyrazol- 1 -ylmethyl.

134. Compound of Formula (Ia), wherein M = tert-butoxy, Q = 4-tert-buty\-3- methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = -COOH, J = lH-pyrazol- 1-ylmethyl.

135. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3-

methoxylbenzoyl, Z = 1 ,3-thiazol-2-yl, X = fluoro, Y = -CH ₂ ' ^N ^' ^- ^γ , J = IH- pyrazol- 1 -ylmethyl.

136. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = -C(O)NH-cyclopropyl, J = 1 H-pyrazol- 1 -ylmethyl. 137. Compound of Formula (Ia), wherein M = tert-butoxy, Q = 4-tert-buty\-3- methoxylbenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon atom to which they attached form C=CH ₂ , J = 1 H-pyrazol- 1 -ylmethyl.

138. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxylbenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon atom to which they attached form C=CH ₂ , J = 1 H-pyrazol- 1 -ylmethyl.

139. Compound of Formula (Ia), wherein M = tert-butoxy, Q = 4-tert-buty{-3- methoxylbenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon atom to which they attached form a carbonyl, J = 1 H-pyrazol- 1 -ylmethyl.

140. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-te/t-butyl-3- methoxylbenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon atom to which they attached form a carbonyl, J = 1 H-pyrazol- 1 -ylmethyl.

141. Compound of Formula (Ia), wherein M = tert-butoxy, Q = 4-tert-buty\-3- methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = -CH ₂ N ₃ , J = lH-pyrazol-1- ylmethyl. 142. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = -CH ₂ ON=CMe ₂ , J = IH- pyrazol- 1 -ylmethyl.

143. Compound of Formula (Ia), wherein M = tert-butoxy, Q = 4-tert-buty{-3- methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = -CH ₂ NH ₂ , J = lH-pyrazol- 1 -ylmethyl.

144. Compound of Formula (Ia), wherein M = tert-butoxy, Q = 4-tert-buty\-3- methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = -CH ₂ NHBz, J = IH- pyrazol- 1 -ylmethyl.

145. Compound of Formula (Ia), wherein M = tert-butoxy, Q = 4-tert-buty\-3- methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = -CH ₂ NMe ₂ , J = IH- pyrazol- 1 -ylmethyl.

146. Compound of Formula (Ia), wherein M = tert-butoxy, Q = 4-tert-buty\-3-

methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = -CH ₂ ' ^NV ^~^-^, J = IH- pyrazol- 1 -ylmethyl. 147. Compound of Formula (Ia), wherein M = tert-butoxy, Q = 4-tert-buty\-3- methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = -C(O)NHCH ₂ CH ₂ OH, J = 1 H-pyrazol- 1 -ylmethyl.

148. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = l,3-oxazol-2-yl, J = IH- pyrazol- 1 -ylmethyl.

149. Compound of Formula (Iaa), wherein M = tert-butoxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = hydroxymethyl, J = IH- pyrazol- 1 -ylmethyl.

II. Second Principle Embodiment

In a first embodiment of the present invention is a compound of Formulae (2-1) as illustrated above, or a pharmaceutically acceptable salt, ester or prodrug thereof.

In a second embodiment of the present invention is the relative stereochemistry of a racemic compound of Formula (2-1), is represented by formulae (2-Ia) or (2-Ib) (each referred to in this section as (I), (Ia) and (Ib)):

(Ia) (Ib) relative stereochemistry relative stereochemistry wherein M, Q, Z, X, Y and J are as previously defined.

In a third embodiment of the present invention is the absolute stereochemistry of a chiral compound of Formula (2-1), is represented by formulae (2-Iaa) or (2-Ibb) (each referred to in this section as (I), (Iaa) and (Ibb)):

(Iaa) (Ibb) absolute stereochemistry absolute stereochemistry wherein M, Q, Z, X, Y and J are as previously defined.

In a fourth embodiment of the present invention relates to compound of Formula (2-IIa, Ua herein), or a pharmaceutically acceptable salt, ester or prodrug thereof:

wherein M, Q, Z and J are as previously defined and Xi and Yi taken together with the carbon atom to which they are attached form a substituted or unsubstituted C3- Cg-cycloalkyl group.

In a fifth embodiment of the present invention relates to compound of Formula (2-IIb or Hb herein), or a pharmaceutically acceptable salt, ester or prodrug thereof:

wherein M, Q, Z and J are as previously defined and X ₂ and Y ₂ taken together with the carbon atom to which they are attached form a substituted or unsubstituted C3- Cg-cycloalkenyl group. In a sixth embodiment of the present invention relates to compound of

Formula (2-IIc, Hc herein), or a pharmaceutically acceptable salt, ester or prodrug thereof:

wherein M, Q, Z and J are as previously defined and X ₃ and Y ₃ taken together with the carbon atom to which they are attached form a substituted or unsubstituted heterocyclic group.

Representative compounds of the present invention (referring to the formulae within this section) are those selected from: 1. Compound of Formula (Ia), wherein M = tert-butoxy, Q = 4-tert-buty\-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

atom to which they are attached is X ''^ ⁰ , J = lH-pyrazol-1-ylmethyl. 2. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

atom to which they are attached is > '--- ⁰ , J = lH-pyrazol-1-ylmethyl.

3. Compound of Formula (Ia), wherein M = tert-butoxy, Q = 4-tert-buty\-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

atom to which they are attached is ^ ^** --o^ ⁰ , J = lH-pyrazol-1-ylmethyl.

4. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

atom to which they are attached is = lH-pyrazol-1-ylmethyl.

5. Compound of Formula (Ia), wherein M = tert-butoxy, Q = 4-te/t-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

Ac n atom to which they are attached is X ''" ⁰ , J = lH-pyrazol-1-ylmethyl.

6. Compound of Formula (Ia), wherein M = tert-butoxy, Q = 4-tert-buty\-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

atom to which they are attached is N ''"° , J = lH-pyrazol-1-ylmethyl. 7. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

atom to which they are attached is J = lH-pyrazol-1-ylmethyl.

8. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

atom to which they are attached is >• "*-"° , J = lH-pyrazol-1-ylmethyl.

9. Compound of Formula (Ia), wherein M = tert-butoxy, Q = 4-tert-butyl-3- methoxybenzoyl, Z = I ,3-thiazol-2-yl, X and Y taken together with the carbon

X ^NAc atom to which they are attached is ^"1 ^ , J = lH-pyrazol-1-ylmethyl.

10. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

X ^NAc atom to which they are attached is ^ ^' ' , J = lH-pyrazol-1-ylmethyl. 11. Compound of Formula (Ia), wherein M = tert-butoxy, Q = 4-tert-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

& atom to which they are attached is o , J = lH-pyrazol-1-ylmethyl.

12. Compound of Formula (Ia), wherein M = tert-butoxy, Q = 4-tert-butyl-3- methoxybenzoyl, Z = I ,3-thiazol-2-yl, X and Y taken together with the carbon

atom to which they are attached is ^- , J = lH-pyrazol-1-ylmethyl.

13. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon κ atom to which they are attached is ^"* "* ' ^y , J = lH-pyrazol-1-ylmethyl. 14. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

atom to which they are attached is 6 >■T ''—V o o , J = lH-pyrazol-1-ylmethyl. 15. Compound of Formula (Ia), wherein M = tert-butoxy, Q = 4-te/t-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

atom to which they are attached is 6 ^" ^c ^* '—° o) , J = lH-pyrazol-1-ylmethyl.

16. Compound of Formula (Ia), wherein M = tert-butoxy, Q = 4-tert-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

atom to which they are attached is X ^** '-~ ^NH , J = lH-pyrazol-1-ylmethyl. 17. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

atom to which they are attached is X ^* ''-- ^NH , J = lH-pyrazol-1-ylmethyl.

18. Compound of Formula (Ia), wherein M = tert-butoxy, Q = 4-tert-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

atom to which they are attached is ^% °" ^" %, J = lH-pyrazol-1-ylmethyl. 19. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

atom to which they are attached iiss ^ ^{% 'Ό} °-V o, JJ = lH-pyrazol-1-ylmethyl.

20. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\- benzenesulfonyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

atom to which they are attached is X ''^ ⁰ , J = lH-pyrazol-1-ylmethyl.

21. Compound of Formula (Ia), wherein M = tert-butoxy, Q = 4-tert-butyl- benzenesulfonyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

atom to which they are attached is X ''- ^* ° , J = lH-pyrazol-1-ylmethyl.

22. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl- benzenesulfonyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

atom to which they are attached is J = lH-pyrazol-1-ylmethyl.

23. Compound of Formula (Ia), wherein M = tert-butoxy, Q = 4-tert-buty\- phenylcarbamoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

atom to which they are attached is X '""° ', J = lH-pyrazol-1-ylmethyl.

24. Compound of Formula (Ia), wherein M = tert-butoxy, Q = 4-tert-buty\- phenylcarbamoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

atom to which they are attached is >> ^* '-- ⁰ , J = lH-pyrazol-1-ylmethyl.

25. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\- phenylcarbamoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

atom to which they are attached is V ^* '-*° , J = lH-pyrazol-1-ylmethyl.

26. Compound of Formula (Ia), wherein M = hydroxy, Q = 3-bromo-4-tert- butylbenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon atom to

which they are attached is 6 NO ''-*°, J = lH-pyrazol-1-ylmethyl. 27. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- vinylbenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon atom to

which they are attached J = lH-pyrazol-1-ylmethyl.

28. Compound of Formula (Ia), wherein M = hydroxy, Q = 2-fluoro-4-te/t-butyl-5- vinylbenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon atom to

which they are attached J = lH-pyrazol-1-ylmethyl.

29. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxylbenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

atom to which they are attached is > '--- ⁰ , J = l,3-thiazol-4-ylmethyl.

30. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-te/t-butyl-3- methoxylbenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

atom to which they are attached is >> ''-^ ⁰ , J = l,3-thiazol-2-ylmethyl.

31. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-te/t-butyl-3- methoxylbenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

atom to which they are attached is > ^* '-*"°, J = l,2-thiazol-3-ylmethyl.

32. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxylbenzoyl, Z = 5-methylisoxazol-3-yl, X and Y taken together with the

carbon atom to which they are attached is V ^* '-*° , J = lH-pyrazol-1-ylmethyl.

33. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxylbenzoyl, Z = thiophen-2-yl, X and Y taken together with the carbon atom

to which they are attached is X ^* '"" ⁰ , J = lH-pyrazol-1-ylmethyl.

34. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxylbenzoyl, Z = thiophen-3-yl, X and Y taken together with the carbon atom

to which they are attached is J = lH-pyrazol-1-ylmethyl. 35. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl-3- methoxylbenzoyl, Z = furan-2-yl, X and Y taken together with the carbon atom to

which they are attached is N ''-- ⁰ , J = lH-pyrazol-1-ylmethyl.

36. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl-3- methoxylbenzoyl, Z = furan-3-yl, X and Y taken together with the carbon atom to which they are attached is X ''-^ ⁰ , J = lH-pyrazol-1-ylmethyl.

37. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl-3- methoxylbenzoyl, Z = l,3-oxazol-2-yl, X and Y taken together with the carbon

atom to which they are attached is > ''^ ⁰ , J = lH-pyrazol-1-ylmethyl.

38. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxylbenzoyl, Z = phenyl, X and Y taken together with the carbon atom to

which they are attached J = lH-pyrazol-1-ylmethyl.

39. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-te/t-butyl-3- methoxylbenzoyl, Z = pyridin-2-yl, X and Y taken together with the carbon atom

to which they are attached is > ^* '-*"°, J = lH-pyrazol-1-ylmethyl.

40. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxylbenzoyl, Z = pyridin-3-yl, X and Y taken together with the carbon atom

to which they are attached is >> '-^ ^-0 , J = lH-pyrazol-1-ylmethyl.

41. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxylbenzoyl, Z = pyridin-4-yl, X and Y taken together with the carbon atom

to which they are attached is ***> ^* '"" ⁰ , J = lH-pyrazol-1-ylmethyl.

42. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxylbenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

atom to which they are attached is J = thiophen-2-yl. 43. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl-3- methoxylbenzoyl, Z = l,3-thiazol-2-yl-methyl, X and Y taken together with the

carbon atom to which they are attached is X ''^ ⁰ , J = lH-pyrazol-1-ylmethyl.

44. Compound of Formula (Ia), wherein M = tert-bvXoxy , Q = 4-tert-bvXy\-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

atom to which they are attached is > ^, '--- ⁰ , J = lH-pyrazol-1-ylmethyl.

45. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-bvXy\-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

atom to which they are attached is > ''-~° , J = lH-pyrazol-1-ylmethyl.

46. Compound of Formula (Ia), wherein M = tert-bvXoxy , Q = 4-te/t-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

atom to which they are attached is o , J = lH-pyrazol-1-ylmethyl.

47. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-te/t-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon κ atom to which they are attached iiss N >T■ W ^* '— o ,, JJ == lH-pyrazol-1-ylmethyl.

48. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon atom to which they are attached is o , J = lH-pyrazol-1-ylmethyl.

III. A Third Principle Embodiment

In a first embodiment of the present invention is a compound of Formulae (3-1) as illustrated above, or a pharmaceutically acceptable salt, ester or prodrug thereof.

A second embodiment of the present invention is the relative stereochemistry of a racemic compound of Formula (3-1), is represented by formulae (3-Ia) or (3-Ib) (also referred to in this section as (I), (Ia) and (Ib)):

(Ia) (Ib) relative stereochemistry relative stereochemistry wherein M, Q, Z, X, Y and J are as previously defined.

In a third embodiment of the present invention is the absolute stereochemistry of a chiral compound of Formula (3-1), is represented by formulae (3-Iaa) or (3-Ibb):

(laa) (Ibb) absolute stereochemistry absolute stereochemistry wherein M, Q, Z, X, Y and J are as previously defined.

In a fourth embodiment of the present invention relates to compound of Formula (3-IIa), or a pharmaceutically acceptable salt, ester or prodrug thereof:

wherein M, Q, Z, Y and J are as previously defined and Ai is halogen.

In a fifth embodiment of the present invention relates to compound of Formula (3-IIb), or a pharmaceutically acceptable salt, ester or prodrug thereof:

wherein M, Q, Z, Y, Ri and J are as previously defined. In a sixth embodiment of the present invention relates to compound of

Formula (3-IIc), or a pharmaceutically acceptable salt, ester or prodrug thereof:

wherein M, Q, Z, Y, Ri and J are as previously defined.

In a seventh embodiment of the present invention relates to compound of Formula (3-IId), or a pharmaceutically acceptable salt, ester or prodrug thereof:

wherein M, Q, Z, Y, R ₁ , R ₂ , and J are as previously defined.

In a eighth embodiment of the present invention relates to compound of Formula (3-IIe), or a pharmaceutically acceptable salt, ester or prodrug thereof:

wherein M, Q, Z, Y, R ₁ , and J are as previously defined.

In a ninth embodiment of the present invention relates to compound of

Formula (3-IIf), or a pharmaceutically acceptable salt, ester or prodrug thereof:

wherein M, Q, Z, Y, R ₁ , R ₂ , and J are as previously defined.

In a tenth embodiment of the present invention relates to compound of Formula (3-IIg), or a pharmaceutically acceptable salt, ester or prodrug thereof:

wherein M, Q, Z, Y, R ₁ , R ₂ , and J are as previously defined.

In a eleventh embodiment of the present invention relates to compound of Formula (3-IIh), or a pharmaceutically acceptable salt, ester or prodrug thereof:

wherein M, Q, Z, Y, R ₁ , R ₂ , R ₄ , and J are as previously defined. In a twelfth embodiment of the present invention relates to compound of

Formula (3-IIIa), or a pharmaceutically acceptable salt, ester or prodrug thereof:

wherein M, Q, Z and J are as previously defined and Xi and Yi taken together with the carbon atom to which they are attached form a substituted or unsubstituted C ₃ - C8-cycloalkyl group.

In a thirteenth embodiment of the present invention relates to compound of

Formula (3-IIIb), or a pharmaceutically acceptable salt, ester or prodrug thereof:

wherein M, Q, Z and J are as previously defined and X ₂ and Y ₂ taken together with the carbon atom to which they are attached form a substituted or unsubstituted C3- Cg-cycloalkenyl group.

In a fourteenth embodiment of the present invention relates to compound of Formula (3-IIIc), or a pharmaceutically acceptable salt, ester or prodrug thereof:

wherein M, Q, Z and J are as previously defined and X ₃ and Y ₃ taken together with the carbon atom to which they are attached form a substituted or unsubstituted heterocyclic group.

In a fifteenth embodiment of the present invention relates to compound of Formula (3-IVa), or a pharmaceutically acceptable salt, ester or prodrug thereof:

wherein M, Q, Z, X, Y, Ri and R ₂ are as previously defined.

In a sixteenth embodiment of the present invention relates to compound of Formula (3-IVb), or a pharmaceutically acceptable salt, ester or prodrug thereof:

wherein M, Q, Z, X, Y, R ₁ , R ₂ and R ₄ are as previously defined.

Representative compounds of the present invention are those selected from (referringt othe formulae within this section):

1. Compound of Formula (Ia), wherein M = tert-butoxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, J = -CH=NOMe.

2. Compound of Formula (Ia), wherein M = methoxy, Q = 4-tert-buty\-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxycarbonyl, J = -CH=NOMe.

3. Compound of Formula (Ia), wherein M = tert-butoxy, Q = 4-tert-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, J = -CH=NOMe.

4. Compound of Formula (Ia), wherein M = tert-butoxy, Q = 4-tert-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = methoxycarbonyl-methyl, Y = methoxycarbonyl, J = -CH=NOMe.

5. Compound of Formula (Ia), wherein M = tert-butoxy, Q = 4-tert-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = acetamido, Y = methoxycarbonyl, J = -CH=NOMe. 6. Compound of Formula (Ia), wherein M = tert-butoxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = acetoxy, Y = cyano, J = -CH=NOMe. 7. Compound of Formula (Ia), wherein M = tert-butoxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = -CH=NOMe, Y = methoxycarbonyl, J = -CH=NOMe. 8. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, J = -CH=NOMe.

9. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = -COOH, J = -CH=NOMe.

10. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, J = -CH=NOMe.

11. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-te/t-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = methoxycarbonyl-methyl, Y = methoxycarbonyl, J = -CH=NOMe.

12. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = acetamido, Y = methoxycarbonyl, J = -CH=NOMe. 13. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl-3 - methoxybenzoyl, Z = l,3-thiazol-2-yl, X = acetoxy, Y = cyano, J = -CH=NOMe.

14. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = -CH=NOMe, Y = methoxycarbonyl, J = -CH=NOMe.

15. Compound of Formula (Ia), wherein M = tert-butoxy, Q = 4-tert-buty\-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

atom to which they are attached is ^. ''-" ⁰ , J = -CH=N-OMe.

16. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

atom to which they are attached is ^ ''"°, J = -CH=N-OMe. 17. Compound of Formula (Ia), wherein M = tert-butoxy, Q = 4-tert-buty\-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

atom to which they are attached = -CH=N-OMe.

18. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

atom to which they are attached = -CH=N-OMe.

19. Compound of Formula (Ia), wherein M = tert-butoxy, Q = 4-tert-buty\-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

atom to which they are attached is J = -CH=N-OMe.

20. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-te/t-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

atom to which they are attached is J = -CH=N-OMe.

21. Compound of Formula (Ia), wherein M = tert-butoxy, Q = 4-tert-buty\-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

atom to which they are attached is V ''-^ ⁰ , J = -CH=N-OMe. 22. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-te/t-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

Ac atom to which they are attached I iSs υ Q N< ^' ',' ^N -r" ⁰ , J = -CH=N-OMe.

23. Compound of Formula (Ia), wherein M = tert-butoxy, Q = 4-tert-buty\-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

atom to which they are attached is J = -CH=N-OMe.

24. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

atom to which they are attached is ^"1 ^ , J = -CH=N-OMe.

25. Compound of Formula (Ia), wherein M = tert-butoxy, Q = 4-tert-buty\-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

atom to which they are attached is X ''-" ⁰ , J = -CH=N-OMe. 26. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon κ atom to which they are attached is X '"' , J = -CH=N-OMe.

27. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

atom to which they are attached iiss X Xλ ^* '-—< of °,, JJ == --CCHH==NN--(OMe.

28. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

atom to which they are attached is 6 >c ^* '—° o) , J = -CH=N-OMe.

29. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-te/t-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

30. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-te/t-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X is cyano, Y is acetoxy, J = -CH=N-OMe.

31. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-te/t-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

atom to which they are attached is ^ ⁰ ^o, J = -CH=N-OMe.

32. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\- benzenesulfonyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

atom to which they are attached is X ^* '-~°, J = -CH=N-OMe.

33. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{- phenylcarbamoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

atom to which they are attached is X ''^ ^*0 , J = -CH=N-OMe.

34. Compound of Formula (Ia), wherein M = hydroxy, Q = 3-bromo-4-tert- butylbenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon atom to

which they are attached is " XST ^' ''^ ⁰ i, J = -CH=N-OMe. 35. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- vinylbenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon atom to

which they are attached is V ''- ^* °, J = -CH=N-OMe.

36. Compound of Formula (Ia), wherein M = hydroxy, Q = 2-fluoro-4-ter£-butyl- 5-vinylbenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon atom

to which they are attached is X ^' ''^ ⁰ , J = -CH=N-OMe.

37. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxylbenzoyl, Z = 5-methylisoxazol-3-yl, X and Y taken together with the

carbon atom to which they are attached is X ''^ ⁰ , J = -CH=N-OMe.

38. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-te/t-butyl-3- methoxylbenzoyl, Z = thiophen-2-yl, X and Y taken together with the carbon atom

to which they are attached is % ^' ''-°, J = -CH=N-OMe.

39. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxylbenzoyl, Z = thiophen-3-yl, X and Y taken together with the carbon atom

to which they are attached is X ^' ''-°, J = -CH=N-OMe. 40. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-te/t-butyl-3- methoxylbenzoyl, Z = furan-2-yl, X and Y taken together with the carbon atom to

which they are attached is X ^' ''^ ⁰ , J = -CH=N-OMe.

41. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxylbenzoyl, Z = furan-3-yl, X and Y taken together with the carbon atom to

which they are attached is V ^* ''-- ⁰ , J = -CH=N-OMe.

42. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxylbenzoyl, Z = l,3-oxazol-2-yl, X and Y taken together with the carbon

atom to which they are attached is X ''^ ^*0 , J = -CH=N-OMe.

43. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxylbenzoyl, Z = phenyl, X and Y taken together with the carbon atom to

which they are attached is " XST ^' ''^ ⁰ i, J = -CH=N-OMe. 44. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxylbenzoyl, Z = pyridin-2-yl, X and Y taken together with the carbon atom

to which they are attached is X ^' ''^ ⁰ , J = -CH=N-OMe.

45. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxylbenzoyl, Z = pyridin-3-yl, X and Y taken together with the carbon atom

to which they are attached is X ^' ''^ ⁰ , J = -CH=N-OMe.

46. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxylbenzoyl, Z = pyridin-4-yl, X and Y taken together with the carbon atom

to which they are attached is X ''^ ⁰ , J = -CH=N-OMe.

47. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-te/t-butyl-3- methoxylbenzoyl, Z = l,3-thiazol-2-yl-methyl, X and Y taken together with the

carbon atom to which they are attached is X ''-" ⁰ , J = -CH=N-OMe.

48. Compound of Formula (Ia), wherein M = tert-butoxy, Q = 4-tert-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon 49. Compound of Formula (Ia), wherein M = tert-butoxy, Q = 4-te/t-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X is H, Y is -CH ₂ OMe, J = -CH=NNMe ₂ . 50. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-te/t-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X is H, Y is -CH ₂ OMe, J = -CH=NNMe ₂ .

51. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, J = -CH=NOEt.

52. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, J = -CH=NO-"Pr.

53. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, J = -CH=NO-allyl. 54. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, J = -CH=NO- ² Pr.

55. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, J = -CH=NO-CH ₂ CO ₂ H.

56. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, J = -CH=NOPh.

57. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-te/t-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, J =

-CH=NOCH ₂ Ph.

58. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, J = -CH=NO-2-pyridine. 59. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, J = -CH=NO-3-pyridine.

60. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, J = -CH=NO-4-pyridine.

61. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, J = -CH=NOCH ₂ -2-pyridine.

62. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, J = -CH=NOCH ₂ -3-pyridine.

63. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, J = -CH=NOCH ₂ -4-pyridine.

64. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, J = -CH=NO-2-pyrimidine. 65. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, J = -CH=NO-4-pyrimidine.

66. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, J = -CH=NO-5-pyrimidine.

67. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, J = -CH=NOCH ₂ -2-pyrimidine.

68. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-te/t-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, J =

-CH=NOCH ₂ -4-pyrimidine.

69. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, J = -CH=NOCH ₂ -5-pyrimidine. 70. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, J = -CH=NO-2-pyrazine.

71. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, J = -CH=NOCH ₂ -2-pyrazine.

72. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, J = -CH=NO-2-(l ,3-thiazole).

73. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, J = -CH=NOCH ₂ -2-(l,3-thiazole).

74. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, J = -CH=NO-4-(l ,3-thiazole).

75. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, J = -CH=NOCH ₂ -4-(l,3-thiazole). 76. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, J = -CH=NO-5-(l ,3-thiazole).

77. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, J = -CH=NOCH ₂ -5-(l,3-thiazole).

78. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, J = -CH=NO-3-(l ,2-thiazole).

79. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-te/t-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, J =

-CH=NOCH ₂ -3-(l,2-thiazole).

80. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, J = -CH=NO-4-(l ,2-thiazole). 81. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, J = -CH=NOCH ₂ -4-(l ,2-thiazole).

82. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, J = -CH=NO-5-(l,2-thiazole).

83. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, J = -CH=NOCH ₂ -5-(l,2-thiazole).

84. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, J = -CH=NO-2-(l ,3-oxazole).

85. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, J = -CH=NOCH ₂ -2-(l,3-oxazole).

86. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, J = -CH=NO-4-(l,3-oxazole). 87. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, J = -CH=NOCH ₂ -4-(l,3-oxazole).

88. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, J = -CH=NO-5-(l,3-oxazole).

89. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, J = -CH=NOCH ₂ -5-(l,3-oxazole).

90. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-te/t-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, J =

-CH=NO-3 -(5 -methyl- 1,2-oxazole).

91. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, J = -CH=NOCH ₂ -3-(5-methyl- 1,2-oxazole). 92. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, J = -CH=NO-4-(5-methyl-l,2-oxazole).

93. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, J = -CH=NOCH ₂ -4-(5-methyl- 1,2-oxazole).

94. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, J = -CH=NO-5-(l ,2-oxazole).

95. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, J = -CH=NOCH ₂ -5-(l,2-oxazole).

96. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, J =

-CH=NOEt.

97. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, J = -CH=NO-"Pr. 98. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, J = -CH=NO-allyl.

99. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, J = -CH=NO- ² Pr.

100. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, J = -CH=NO-CH ₂ CO ₂ H.

101. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-te/t-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, J =

-CH=NOPh.

102. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, J = -CH=NOCH ₂ Ph. 103. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, J = -CH=NO-2-pyridine.

104. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, J = -CH=NO-3-pyridine.

105. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, J = -CH=NO-4-pyridine.

106. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, J = -CH=NOCH ₂ -2-pyridine.

107. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, J =

-CH=NOCH ₂ -3-pyridine.

108. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, J = -CH=NOCH ₂ -4-pyridine. 109. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, J = -CH=NO-2-pyrimidine.

110. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, J = -CH=NO-4-pyrimidine.

111. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, J = -CH=NO-5-pyrimidine.

112. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-te/t-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, J =

-CH=NOCH ₂ -2-pyrimidine.

113. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, J = -CH=NOCH ₂ -4-pyrimidine. 114. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, J = -CH=NOCH ₂ -5-pyrimidine.

115. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, J = -CH=NO-2-pyrazine.

116. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, J = -CH=NOCH ₂ -2-pyrazine.

117. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, J = -CH=NO-2-(l ,3-thiazole).

118. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, J =

-CH=NOCH ₂ -2-(l,3-thiazole).

119. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, J = -CH=NO-4-(l ,3-thiazole). 120. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, J = -CH=NOCH ₂ -4-(l,3-thiazole).

121. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, J = -CH=NO-5-(l,3-thiazole).

122. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, J = -CH=NOCH ₂ -5-(l,3-thiazole).

123. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-te/t-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, J =

-CH=NO-3-(l ,2-thiazole).

124. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, J = -CH=NOCH ₂ -3-(l,2-thiazole). 125. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, J = -CH=NO-4-(l ,2-thiazole).

126. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, J = -CH=NOCH ₂ -4-(l,2-thiazole).

127. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, J = -CH=NO-5-(l ,2-thiazole).

128. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, J = -CH=NOCH ₂ -5-(l,2-thiazole).

129. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, J =

-CH=NO-2-(l ,3-oxazole).

130. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, J = -CH=NOCH ₂ -2-(l,3-oxazole). 131. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, J = -CH=NO-4-(l,3-oxazole).

132. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, J = -CH=NOCH ₂ -4-(l,3-oxazole).

133. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, J = -CH=NO-5-(l ,3-oxazole).

134. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-te/t-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, J =

-CH=NOCH ₂ -5-(l,3-oxazole).

135. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, J = -CH=NO-3 -(5 -methyl- 1,2-oxazole). 136. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, J = -CH=NOCH ₂ -3-(5-methyl- 1,2-oxazole).

137. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, J = -CH=NO-4-(5 -methyl- 1 ,2-oxazole).

138. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, J = -CH=NOCH ₂ -4-(5-methyl- 1,2-oxazole).

139. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, J = -CH=NO-5-(l ,2-oxazole).

140. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, J =

-CH=NOCH ₂ -5-(l,2-oxazole).

141. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

atom to which they are attached is X ^' '"-°, J = -CH=NOEt. 142. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

atom to which they are attached is X ^' '"-°, J = -CH=NO-"Pr.

143. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

atom to which they are attached is X ''^ ⁰ , J = -CH=NO-allyl.

144. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

atom to which they are attached is X ''"°, J = -CH=NO- ² Pr.

145. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-te/t-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

atom to which they are attached is X ^' '-- ⁰ , J = -CH=NO-CH ₂ CO ₂ H.

146. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

atom to which they are attached is X ^' '"-°, J = -CH=NOPh. 147. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

atom to which they are attached is X ^' ''-- ⁰ , J = -CH=NOCH ₂ Ph.

148. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

atom to which they are attached is ^ ''^ ⁰ , J = -CH=NO-2-pyridine.

149. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

atom to which they are attached is 6 ^O ''^ ⁰ , J = -CH=NO-3-pyridine.

150. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

atom to which they are attached is > ^, '--- ⁰ , J = -CH=NO-4-pyridine. 151. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

atom to which they are attached is > ^, '--- ⁰ , J = -CH=NOCH ₂ -2-pyridine.

152. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

atom to which they are attached is >• ''-"°, J = -CH=NOCH2-3-pyridine.

153. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-te/t-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

atom to which they are attached is >• '"-- ⁰ , J = -CH=NOCH2-4-pyridine.

154. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-te/t-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

atom to which they are attached is > ''^ ⁰ , J = -CH=NO-2-pyrimidine.

155. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

atom to which they are attached is > ''^ ⁰ , J = -CH=NO-4-pyrimidine. 156. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-te/t-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

atom to which they are attached is ^ ''^ ⁰ , J = -CH=NO-5-pyrimidine.

157. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

atom to which they are attached is X ''^ ⁰ , J = -CH=NOCH2-2-pyrimidine.

158. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

atom to which they are attached is 6 XO ''^ ⁰ , J = -CH=NOCH2-4-pyrimidine.

159. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

atom to which they are attached is > ^, '--- ⁰ , J = -CH=NOCH ₂ -S -pyrimidine. 160. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

atom to which they are attached is > ^, '--- ⁰ , J = -CH=NO-2-pyrazine.

161. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

atom to which they are attached is V ^, ''-- ⁰ , J = -CH=NOCH ₂ -2-pyrazine.

162. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

atom to which they are attached is X ^' ''-- ⁰ , J = -CH=NO-2-(l,3-thiazole).

163. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-te/t-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

atom to which they are attached is x ^' ''^ ⁰ , J = -CH=NOCH ₂ -2-(l,3-thiazole).

164. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

atom to which they are attached is > ''^ ⁰ , J = -CH=NO-4-(l,3-thiazole). 165. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-te/t-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

atom to which they are attached is X ^' ''^ ⁰ , J = -CH=NOCH ₂ -4-(l,3-thiazole).

166. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

atom to which they are attached is X ^' '"*°, J = -CH=NO-5-(l,3-thiazole).

167. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-te/t-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

atom to which they are attached is X ^' ''^ ⁰ , J = -CH=NOCH ₂ -5-(l,3-thiazole).

168. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-te/t-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

atom to which they are attached is X '--- ⁰ , J = -CH=NO-3-(l,2-thiazole). 169. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

atom to which they are attached is X ^' '"-°, J = -CH=NOCH ₂ -3-(l,2-thiazole).

170. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

atom to which they are attached is X ^' ''-- ⁰ , J = -CH=NO-4-(l ,2-thiazole).

171. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

atom to which they are attached is X ^' ''-- ⁰ , J = -CH=NOCH ₂ -4-(l,2-thiazole).

172. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-te/t-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

atom to which they are attached is X ^' ''^ ⁰ , J = -CH=NO-5-(l,2-thiazole).

173. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

atom to which they are attached is X ^' ''^ ⁰ , J = -CH=NOCH ₂ -5-(l,2-thiazole). 174. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-te/t-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

atom to which they are attached is X ''^ ⁰ , J = -CH=NO-2-(l,3-oxazole).

175. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

atom to which they are attached is X ^' '"*°, J = -CH=NOCH ₂ -2-(l,3-oxazole).

176. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-te/t-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

atom to which they are attached is ^ ''^ ^*0 , J = -CH=NO-4-(l,3-oxazole).

177. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-te/t-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

atom to which they are attached is X ^' '"-°, J = -CH=NOCH ₂ -4-(l,3-oxazole). 178. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-te/t-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

atom to which they are attached is > ^, '--- ⁰ , J = -CH=NO-5-(l,3-oxazole).

179. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

atom to which they are attached is N ^' ''-- ⁰ , J = -CH=NOCH ₂ -5-(l ,3-oxazole).

180. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

atom to which they are attached is >> ''-*' ⁰ , J = -CH=NO-3-(5-methyl-l,2-oxazole).

181. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-te/t-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, J =

-CH=NOCH ₂ -3-(5-methyl-l,2-oxazole).

182. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

atom to which they are attached is ^ ''^ ^*0 , J = -CH=NO-4-(5-methyl-l,2-oxazole). 183. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-te/t-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

atom to which they are attached is X ^' '"-°, J = -CH=NOCH ₂ -4-(5 -methyl- 1,2- oxazole).

184. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

atom to which they are attached is ^ ''^ ⁰ , J = -CH=NO-5-(l,2-oxazole).

185. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

atom to which they are attached is X ^' ''^ ⁰ , J = -CH=NOCH ₂ -5-(l,2-oxazole).

IV. Fourth Principle Embodiment

In a first embodiment of the present invention is a compound of Formula (4-1) as illustrated above, or a pharmaceutically acceptable salt, ester or prodrug thereof.

In a second embodiment of the present invention is the relative stereochemistry of a racemic compound of Formula (4-1), is represented by Formulae (4-Ia) or (4-Ib) (also referred to in this section as (I), (Ia) and (Ib) and the like):

(Ia) (Ib) relative stereochemistry relative stereochemistry wherein M, Q, Z, X, Y, U, W and J are as previously defined.

In a third embodiment of the present invention is the absolute stereochemistry of a chiral compound of Formula (4-1), is represented by Formulae (4-Iaa) or (4-Ibb):

(laa) (Ibb) absolute stereochemistry absolute stereochemistry wherein M, Q, Z, X, Y, U, W and J are as previously defined.

In a fourth embodiment of the present invention relates to compound of Formula (4-IIa), or a pharmaceutically acceptable salt, ester or prodrug thereof:

wherein M, Q, Z, X, Y, U and J are as previously defined and Ai is halogen, -ORi, -NR1R2, wherein Ri and R ₂ are as previously defined.

In a fifth embodiment of the present invention relates to compound of

Formula (4-IIb), or a pharmaceutically acceptable salt, ester or prodrug thereof:

wherein M, Q, Z, Y, W, U, Ai and J are as previously defined.

In a sixth embodiment of the present invention relates to compound of Formula (4-IIc), or a pharmaceutically acceptable salt, ester or prodrug thereof:

wherein M, Q, Z, X, Y, U, R ₃ , and J are as previously defined.

In a seventh embodiment of the present invention relates to compound of Formula (4-IId), or a pharmaceutically acceptable salt, ester or prodrug thereof:

wherein M, Q, Z, X, Y, U, and J are as previously defined, R ₄ is independent -M. In an eighth embodiment of the present invention relates to compound of

Formula (4-IIe), or a pharmaceutically acceptable salt, ester or prodrug thereof:

wherein M, Q, Z, X, Y, U, R ₁ , R ₄ , and J are as previously defined.

In a ninth embodiment of the present invention relates to compound of Formula (4-IIf), or a pharmaceutically acceptable salt, ester or prodrug thereof:

wherein M, Q, Z, X, Y, Ri and J are as previously defined. In a tenth embodiment of the present invention relates to compound of

Formula (4-IIg), or a pharmaceutically acceptable salt, ester or prodrug thereof:

wherein M, Q, Z, X, Y, Ri, R ₂ and J are as previously defined.

In an eleventh embodiment of the present invention relates to compound of Formula (4-IIh), or a pharmaceutically acceptable salt, ester or prodrug thereof:

^{0 Q} (Mh) wherein M, Q, Z, X, Y and J are as previously defined.

In a twelveth embodiment of the present invention relates to compound of Formula (4-IIi), or a pharmaceutically acceptable salt, ester or prodrug thereof:

wherein M, Q, Z, X, Y, Ri, R ₂ and J are as previously defined.

In a thirteenth embodiment of the present invention relates to compound of Formula (4-IIj), or a pharmaceutically acceptable salt, ester or prodrug thereof:

wherein M, Q, Z, X, Y, Ri, R ₂ and J are as previously defined.

In a fourteenth embodiment of the present invention relates to compound of

Formula (4-IIk), or a pharmaceutically acceptable salt, ester or prodrug thereof:

wherein M, Q, Z, X, Y, U, Ri, R ₂ , R ₄ and J are as previously defined.

In a fifteenth embodiment of the present invention relates to compound of Formula (4-II1), or a pharmaceutically acceptable salt, ester or prodrug thereof:

wherein M, Q, Z, X, Y, n and J are as previously defined.

In a sixteenth embodiment of the present invention relates to compound of Formula (4-IIm), or a pharmaceutically acceptable salt, ester or prodrug thereof:

wherein M, Q, Z, X, Y and J are as previously defined.

In a seventeenth embodiment of the present invention relates to compound of Formula (4-IIn), or a pharmaceutically acceptable salt, ester or prodrug thereof:

wherein M, Q, Z, U, W and J are as previously defined and Xi and Yi are taken together with the carbon atom to which they are attached form a substituted or unsubstituted Cs-Cg-cycloalkyl group.

In an eighteenth embodiment of the present invention relates to compound of Formula (4-IIo), or a pharmaceutically acceptable salt, ester or prodrug thereof:

wherein M, Q, Z, X, Y, U, R ₁ , R ₄ , and J are as previously defined.

Representative compounds of the present invention are those selected from: 1. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, W = fluoro, U = hydrogen, J = methyl.

2. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, W = methoxy, U = hydrogen, J = methyl.

3. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, W = acetoxy, U = hydrogen, J = methyl.

4. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = I ,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, W = acetylamino, U = hydrogen, J = methyl.

5. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, W = dimethylamino, U = hydrogen, J = methyl. 6. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, W = methylsulfanyl, U = methylsulfanyl, J = methyl.

7. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, W = carbamoyloxy, U = hydrogen, J = methyl.

8. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, W = ureido, U = hydrogen, J = methyl.

9. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, W = methoxycarbonylamino, U = hydrogen, J = methyl.

10. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, W = fluoro, U = fluoro, J = lH-pyrazol-1-ylmethyl.

11. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, W = hydrogen, U = bromo, J = lH-pyrazol-1-ylmethyl. 12. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, W and

U taken together with the carbon atom to which they are attached is \ , J = IH- pyrazol- 1 -ylmethyl.

13. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, W and U taken together with the carbon atom to which they are attached is C=CH ₂ , J = 1 H-pyrazol- 1 -ylmethyl.

14. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, W and U taken together with the carbon atom to which they are attached is C=O, J = IH- pyrazol- 1 -ylmethyl.

15. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, W and U taken together with the carbon atom to which they are attached is C=NOMe, J = 1 H-pyrazol- 1 -ylmethyl.

16. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, W and U taken together with the carbon atom to which they are attached is C=NNMe ₂ , J = 1 H-pyrazol- 1 -ylmethyl. 17. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, W = hydrogen, U = hydroxy, J = 1 H-pyrazol- 1 -ylmethyl.

18. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, W = hydroxy, U = hydrogen, J = lH-pyrazol-1-ylmethyl.

19. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, W and

U taken together with the carbon atom to which they are attached is J = IH- pyrazol- 1 -ylmethyl.

20. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = trifluoromethyl, Y = methoxymethyl, W = fluoro, U = fluoro, J = lH-pyrazol-1 -ylmethyl.

21. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = methyl, Y = methoxymethyl, W = bromo, U = hydrogen, J = lH-pyrazol-1 -ylmethyl.

22. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxybenzoyl, Z = I ,3-thiazol-2-yl, X = methoxy, Y = methoxymethyl, W = fluoro, U = fluoro, J = lH-pyrazol-1 -ylmethyl.

23. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

atom to which they are attached is W = fluoro, U = fluoro, J = IH- pyrazol-1 -ylmethyl.

24. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = acetylamino, Y = methoxymethyl, W = fluoro, U = benzyl, J = lH-pyrazol-1 -ylmethyl.

25. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-te/t-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = cyano, Y = methoxymethyl, W and U

taken together with the carbon atom to which they are attached is ^"1 ^ ° , J = hydrogen.

26. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = -CH=NOMe, W = fluoro, U = hydrogen, J = lH-pyrazol-1 -ylmethyl.

27. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fiuoro, Y = -CH=NOPh, W = fluoro, U = hydrogen, J = lH-pyrazol-1-ylmethyl.

28. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, W = fluoro, U = hydrogen, J = lH-pyrazol-1-ylmethyl.

29. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fiuoro, Y = -C(O)NHMe, W = fluoro, U = hydrogen, J = lH-pyrazol-1-ylmethyl. 30. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, W = methoxy, U = hydrogen, J = methyl.

31. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl-3- methoxybenzoyl, Z = thiophen-2-yl, X = hydrogen, Y = methoxymethyl, W = methoxy, U = hydrogen, J = methyl.

32. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxybenzoyl, Z = thiophen-3-yl, X = hydrogen, Y = methoxymethyl, W = methoxy, U = hydrogen, J = methyl.

33. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-te/t-butyl-3- methoxybenzoyl, Z = isopropyl, X = hydrogen, Y = methoxymethyl, W = methoxy, U = hydrogen, J = methyl.

34. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl-3- methoxybenzoyl, Z = oxazol-2-yl, X = hydrogen, Y = methoxymethyl, W = methoxy, U = hydrogen, J = methyl. 35. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxybenzoyl, Z = 5-methyl-isoxazol-3-yl, X = hydrogen, Y = methoxymethyl, W = methoxy, U = hydrogen, J = methyl.

36. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxybenzoyl, Z = furan-2-yl, X = hydrogen, Y = methoxymethyl, W = methoxy, U = hydrogen, J = methyl.

37. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl-3- methoxybenzoyl, Z = furan-3-yl, X = hydrogen, Y = methoxymethyl, W = methoxy, U = hydrogen, J = methyl.

38. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxybenzoyl, Z = pyridin-2-yl, X = hydrogen, Y = methoxymethyl, W = methoxy, U = hydrogen, J = methyl.

39. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxybenzoyl, Z = pyridin-3-yl, X = hydrogen, Y = methoxymethyl, W = methoxy, U = hydrogen, J = methyl.

40. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = pyridin-4-yl, X = hydrogen, Y = methoxymethyl, W = methoxy, U = hydrogen, J = methyl. 41. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3 - methoxybenzoyl, Z = phenyl, X = hydrogen, Y = methoxymethyl, W = methoxy, U = hydrogen, J = methyl.

42. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = thiazol-2-ylmethyl, X = hydrogen, Y = methoxymethyl, W = methoxy, U = hydrogen, J = methyl.

43. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, W = fluoro, U = hydrogen, J = lH-pyrazol-1-ylmethyl.

44. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-te/t-butylbenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, W = fluoro, U = hydrogen,

J = lH-pyrazol-1-ylmethyl.

45. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- vinylbenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, W = fluoro, U = hydrogen, J = lH-pyrazol-1-ylmethyl. 46. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-te/t-butyl-2-fluoro-5- vinylbenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, W = fluoro, U = hydrogen, J = lH-pyrazol-1-ylmethyl.

47. Compound of Formula (Ia), wherein M = hydroxy, Q = 3-bromo-4-tert- butylbenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, W = fluoro, U = hydrogen, J = lH-pyrazol-1-ylmethyl.

48. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl- benzenesulfonyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, W = fluoro, U = hydrogen, J = lH-pyrazol-1-ylmethyl.

49. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-Butyl- phenylcarbamoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, W = fluoro, U = hydrogen, J = lH-pyrazol-1-ylmethyl.

50. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, W = fluoro, U = hydrogen, J = -CH=NOMe.

51. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, W = fluoro, U = hydrogen, J = -CH=NOPh. 52. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, W = fluoro, U = hydrogen, J = -CH=NNMe ₂ .

53. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, W = fluoro, U = hydrogen, J = hydrogen.

54. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, W = fluoro, U = hydrogen, J = isobutyl.

55. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-te/t-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, W = fluoro, U = hydrogen, J = thiazol-2-ylmethyl.

56. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, W = fluoro, U = hydrogen, J = isothiazol-3-ylmethyl. 57. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, W = fluoro, U = hydrogen, J = thiazol-4-ylmethyl.

58. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, W = 3- tetrazol-1-ylmethyl, U = hydrogen, J = hydrogen.

59. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, W = 3- tetrazol-1-ylmethyl, U = hydrogen, J = methyl.

60. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, W = IH- pyrazol-1-ylmethyl, U = hydrogen, J = hydrogen.

61. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, W = IH- pyrazol-1-ylmethyl, U = hydrogen, J = methyl.

62. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = -CH=NOPh, W = -NHMs, U = hydrogen, J = methyl. 63. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = -CH=NOPh, W = methoxymethyl, U = hydrogen, J = methyl.

64. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = -CH ₂ OBn, W = -CH ₂ NHMs, U = hydrogen, J = methyl.

65. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = -CH ₂ OBn, W = methoxymethyl, U = hydrogen, J = methyl.

V. Fifth Principle Embodiment

In a first embodiment of the present invention is a compound of Formulae (5-1) as illustrated above, or a pharmaceutically acceptable salt, ester or prodrug thereof.

In a second embodiment of this principle embodiment of the present invention is the relative stereochemistry of a racemic compound of Formula (5-1), is represented by formulae (5-Ia) ~ (5-Id) (referred to within this section as (I), (IaHId) and the like):

(Ia) (Ib) relative stereochemistry relative stereochemistry

(Ic) (Id) relative stereochemistry relative stereochemistry wherein M, Q, G, Z, X, Y, U, W and J are as previously defined.

In a third embodiment of the present invention is the absolute stereochemistry of a chiral compound of Formula (5-1), is represented by formulae (5-Iaa) ~ (5-Idd):

(laa) (Ibb) absolute stereochemistry absolute stereochemistry

(Ice) (Idd) absolute stereochemistry absolute stereochemistry wherein M, Q, G, Z, X, Y, U, W and J are as previously defined.

In a fourth embodiment of the present invention relates to compound of Formula (5-IIa), or a pharmaceutically acceptable salt, ester or prodrug thereof:

wherein M, Q, Z, Y, U, W and J are as previously defined.

In a fifth embodiment of the present invention relates to compound of Formula (5-IIb), or a pharmaceutically acceptable salt, ester or prodrug thereof:

wherein M, Q, Z, Y, U, W and J are as previously defined.

In a sixth embodiment of the present invention relates to compound of Formula (5-IIc), or a pharmaceutically acceptable salt, ester or prodrug thereof:

wherein M, Q, Z, Y, U, W and J are as previously defined.

In a seventh embodiment of the present invention relates to compound of Formula (5-IId), or a pharmaceutically acceptable salt, ester or prodrug thereof:

wherein M, Q, Z, Y, U, W and J are as previously defined.

In an eighth embodiment of the present invention relates to compound of Formula (5-IIe), or a pharmaceutically acceptable salt, ester or prodrug thereof:

wherein M, Q, Z, Y, U, W and J are as previously defined.

In a ninth embodiment of the present invention relates to compound of Formula (5-IIf), or a pharmaceutically acceptable salt, ester or prodrug thereof:

wherein M, Q, Z, Y, U, W and J are as previously defined.

In a tenth embodiment of the present invention relates to compound of Formula (5-IIIa), or a pharmaceutically acceptable salt, ester or prodrug thereof:

wherein M, Q, Z, Y, U, W and Ri are as previously defined.

In an eleventh embodiment of the present invention relates to compound of Formula (5-IIIb), or a pharmaceutically acceptable salt, ester or prodrug thereof:

wherein M, Q, Z, U, W, R ₁ , R ₂ and J are as previously defined.

In a twelfth embodiment of the present invention relates to compound of Formula (5-IIIc), or a pharmaceutically acceptable salt, ester or prodrug thereof:

wherein M, Q, Z, U, W, R ₃ and J are as previously defined.

In a thirteenth embodiment of the present invention relates to compound of Formula (5-IIId), or a pharmaceutically acceptable salt, ester or prodrug thereof:

wherein M, Q, Z, Y and J are as previously defined and Ui is halogen, -R ₁ , -ORi,

In a fourteenth embodiment of the present invention relates to compound of

Formula (5-IIIc), or a pharmaceutically acceptable salt, ester or prodrug thereof:

Wherein M, Q, Z, Y and J are as previously defined and U ₂ and W ₂ taken together with the carbon atom to which they are attached form a substituted or unsubstituted C3-Cg-cycloalkyl group, or a substituted or unsubstituted heterocyclic group.

In a fifteenth embodiment of the present invention relates to compound of Formula (5-IVa), or a pharmaceutically acceptable salt, ester or prodrug thereof:

wherein M, Q, Z, Y, U, W and J are as previously defined.

In a sixteenth embodiment of the present invention relates to compound of Formula (5-IVb), or a pharmaceutically acceptable salt, ester or prodrug thereof:

wherein M, Q, Z, Y, U, W, J and Ri are as previously defined.

Representative compounds of the present invention are those selected from (referring to Formula (5-Ia), above as (Ia)): 1. Compound of Formula (Ia), wherein M = tert-bvXoxy, Q = 4-te/t-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and G taken together with the carbon atom to which they are attached is cyclopropane, Y = -CO ₂ Et, U = W = hydrogen, J = lH-pyrazol-1-ylmethyl.

2. Compound of Formula (Ia), wherein M = te/t-butoxy, Q = 4-te/t-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and G taken together with the carbon atom to which they are attached is cyclopropane, Y = -CO ₂ H, U = W = hydrogen, J = lH-pyrazol-1-ylmethyl.

3. Compound of Formula (Ia), wherein M = tert-bvXoxy, Q = 4-te/t-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and G taken together with the carbon atom to which they are attached is cyclopropane, Y = hydroxymethyl, U = W = hydrogen, J = lH-pyrazol-1-ylmethyl.

4. Compound of Formula (Ia), wherein M = te/t-butoxy, Q = 4-te/t-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and G taken together with the carbon

atom to which they are attached is cyclopropane, Y = -CHO, U = W = hydrogen, J = lH-pyrazol-1-ylmethyl.

5. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and G taken together with the carbon atom to which they are attached is cyclopropane, Y = -CHO, U = W = hydrogen, J = lH-pyrazol-1-ylmethyl.

6. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and G taken together with the carbon atom to which they are attached is cyclopropane, Y = -CH=NOPh, U = W = hydrogen, J = lH-pyrazol-1-ylmethyl.

7. Compound of Formula (Ia), wherein M = tert-butoxy, Q = 4-tert-buty\-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and G taken together with the carbon atom to which they are attached is cyclopropane, Y = -CH ₂ OMe, U = W = hydrogen, J = lH-pyrazol-1-ylmethyl. 8. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and G taken together with the carbon atom to which they are attached is cyclopropane, Y = -CH ₂ OMe, U = W = hydrogen, J = lH-pyrazol-1-ylmethyl.

9. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and G taken together with the carbon atom to which they are attached is cyclopropane, Y = -CO ₂ H, U = W = hydrogen, J = lH-pyrazol-1-ylmethyl.

10. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and G taken together with the carbon atom to which they are attached is cyclopropane, Y = -CH ₂ OH, U = W = hydrogen, J = lH-pyrazol-1-ylmethyl.

11. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and G taken together with the carbon atom to which they are attached is cyclopropane, Y = -C(O)NH ₂ , U = W = hydrogen, J = lH-pyrazol-1-ylmethyl.

12. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and G taken together with the carbon

atom to which they are attached is cyclopropane, Y = -C(O)NHBn, U = W = hydrogen, J = lH-pyrazol-1-ylmethyl.

13. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and G taken together with the carbon atom to which they are attached is cyclopropane, Y = -C(O)NHPh, U = W = hydrogen, J = lH-pyrazol-1-ylmethyl.

14. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and G taken together with the carbon atom to which they are attached is cyclopropane, Y = -CH ₂ OBn, U = W = hydrogen, J = lH-pyrazol-1-ylmethyl.

15. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and G taken together with the carbon atom to which they are attached is cyclopropane, Y = -SO ₂ Ph, U = W = hydrogen, J = lH-pyrazol-1-ylmethyl. 16. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and G taken together with the carbon atom to which they are attached is cyclopropane, Y = -NHMs, U = W = hydrogen, J = lH-pyrazol-1-ylmethyl.

17. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-te/t-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and G taken together with the carbon atom to which they are attached is cyclopropane, Y = -CO ₂ Et, U = W = hydrogen, J = lH-pyrazol-1-ylmethyl.

18. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and G taken together with the carbon atom to which they are attached is cyclopropane, Y = -CH ₂ OC(O)NH ₂ , U = W = hydrogen, J = lH-pyrazol-1-ylmethyl.

19. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and G taken together with the carbon atom to which they are attached is cyclopropane, Y = -CH ₂ OMe, U = Me, W = hydrogen, J = lH-pyrazol-1-ylmethyl.

20. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and G taken together with the carbon

atom to which they are attached is cyclopropane, Y = -CH=NOMe, U = F, W = hydrogen, J = lH-pyrazol-1-ylmethyl.

21. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\- benzenesulfonyl, Z = l,3-thiazol-2-yl, X and G taken together with the carbon atom to which they are attached is cyclopropane, Y = -CH ₂ OMe, U = W = hydrogen, J = lH-pyrazol-1-ylmethyl.

22. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\- phenylcarbamoyl, Z = l,3-thiazol-2-yl, X and G taken together with the carbon atom to which they are attached is cyclopropane, Y = -CH ₂ OMe, U = W = hydrogen, J = lH-pyrazol-1-ylmethyl.

23. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- bromobenzoyl, Z = l,3-thiazol-2-yl, X and G taken together with the carbon atom to which they are attached is cyclopropane, Y = -CH ₂ OMe, U = W = hydrogen, J = lH-pyrazol-1-ylmethyl. 24. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- vinylbenzoyl, Z = l,3-thiazol-2-yl, X and G taken together with the carbon atom to which they are attached is cyclopropane, Y = -CH ₂ OMe, U = W = hydrogen, J = lH-pyrazol-1-ylmethyl.

25. Compound of Formula (Ia), wherein M = hydroxy, Q = 2-fluoro-4-te/t-butyl-5- vinylbenzoyl, Z = l,3-thiazol-2-yl, X and G taken together with the carbon atom to which they are attached is cyclopropane, Y = -CH ₂ OMe, U = W = hydrogen, J = lH-pyrazol-1-ylmethyl.

26. Compound of Formula (Ia), wherein M = hydroxy, Q = tert-buty\-3- methoxybenzoyl, Z = l,3,4-thiadiazol-2-yl, X and G taken together with the carbon atom to which they are attached is cyclopropane, Y = -CH ₂ OMe, U = W = hydrogen, J = lH-pyrazol-1-ylmethyl.

27. Compound of Formula (Ia), wherein M = hydroxy, Q = tert-buty\-3- methoxybenzoyl, Z = 5-methylisoxazol-3-yl, X and G taken together with the carbon atom to which they are attached is cyclopropane, Y = -CH ₂ OMe, U = W = hydrogen, J = lH-pyrazol-1-ylmethyl.

28. Compound of Formula (Ia), wherein M = hydroxy, Q = tert-buty{-3- methoxybenzoyl, Z = thiophen-2-yl, X and G taken together with the carbon atom

to which they are attached is cyclopropane, Y = -CH ₂ OMe, U = W = hydrogen, J = lH-pyrazol-1-ylmethyl.

29. Compound of Formula (Ia), wherein M = hydroxy, Q = tert-buty\-3- methoxybenzoyl, Z = thiophen-3-yl, X and G taken together with the carbon atom to which they are attached is cyclopropane, Y = -CH ₂ OMe, U = W = hydrogen, J = lH-pyrazol-1-ylmethyl.

30. Compound of Formula (Ia), wherein M = hydroxy, Q = tert-buty{-3- methoxybenzoyl, Z = furan-2-yl, X and G taken together with the carbon atom to which they are attached is cyclopropane, Y = -CH ₂ OMe, U = W = hydrogen, J = lH-pyrazol-1-ylmethyl.

31. Compound of Formula (Ia), wherein M = hydroxy, Q = tert-buty\-3- methoxybenzoyl, Z = furan-3-yl, X and G taken together with the carbon atom to which they are attached is cyclopropane, Y = -CH ₂ OMe, U = W = hydrogen, J = lH-pyrazol-1-ylmethyl. 32. Compound of Formula (Ia), wherein M = hydroxy, Q = tert-buty\-3- methoxybenzoyl, Z = l,3-oxazol-2-yl, X and G taken together with the carbon atom to which they are attached is cyclopropane, Y = -CH ₂ OMe, U = W = hydrogen, J = lH-pyrazol-1-ylmethyl.

33. Compound of Formula (Ia), wherein M = hydroxy, Q = tert-buty{-3- methoxybenzoyl, Z = phenyl, X and G taken together with the carbon atom to which they are attached is cyclopropane, Y = -CH ₂ OMe, U = W = hydrogen, J = lH-pyrazol-1-ylmethyl.

34. Compound of Formula (Ia), wherein M = hydroxy, Q = tert-buty\-3- methoxybenzoyl, Z = pyridin-2-yl, X and G taken together with the carbon atom to which they are attached is cyclopropane, Y = -CH ₂ OMe, U = W = hydrogen, J = lH-pyrazol-1-ylmethyl.

35. Compound of Formula (Ia), wherein M = hydroxy, Q = tert-buty{-3- methoxybenzoyl, Z = pyridin-3-yl, X and G taken together with the carbon atom to which they are attached is cyclopropane, Y = -CH ₂ OMe, U = W = hydrogen, J = lH-pyrazol-1-ylmethyl.

36. Compound of Formula (Ia), wherein M = hydroxy, Q = tert-buty{-3- methoxybenzoyl, Z = pyridin-4-yl, X and G taken together with the carbon atom to

which they are attached is cyclopropane, Y = -CH ₂ OMe, U = W = hydrogen, J = lH-pyrazol-1-ylmethyl.

37. Compound of Formula (Ia), wherein M = hydroxy, Q = tert-buty\-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and G taken together with the carbon atom to which they are attached is cyclopropane, Y = -CH ₂ OMe, U = W = hydrogen, J = -CH=NOMe.

38. Compound of Formula (Ia), wherein M = hydroxy, Q = tert-buty\-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and G taken together with the carbon atom to which they are attached is cyclopropane, Y = -CH ₂ OMe, U = W = hydrogen, J = -CH=NNMe ₂ .

39. Compound of Formula (Ia), wherein M = hydroxy, Q = tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and G taken together with the carbon atom to which they are attached is cyclopropane, Y = -CH ₂ OMe, U = W = hydrogen, J = l,3-thiazol-4-ylmethyl. 40. Compound of Formula (Ia), wherein M = hydroxy, Q = tert-buty\-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and G taken together with the carbon atom to which they are attached is cyclopropane, Y = -CH ₂ OMe, U = W = hydrogen, J = l,3-thiazol-2-ylmethyl.

41. Compound of Formula (Ia), wherein M = hydroxy, Q = tert-buty\-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and G taken together with the carbon atom to which they are attached is cyclopropane, Y = -CH ₂ OMe, U = W = hydrogen, J = l,2-thiazol-3-ylmethyl.

42. Compound of Formula (Ia), wherein M = hydroxy, Q = tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and G taken together with the carbon atom to which they are attached is cyclopropane, Y = -CH ₂ OMe, U = W = hydrogen, J = isoxazol-3-ylmethyl.

43. Compound of Formula (Ia), wherein M = hydroxy, Q = tert-buty\-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and G taken together with the carbon atom to which they are attached is cyclopropane, Y = -CH ₂ OMe, U = W = hydrogen, J = pyridin-2-ylmethyl.

44. Compound of Formula (Ia), wherein M = hydroxy, Q = tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and G taken together with the carbon

atom to which they are attached is cyclopropane, Y = -CH ₂ OMe, U = W = hydrogen, J = pyrimidin-2-ylmethyl.

45. Compound of Formula (Ia), wherein M = hydroxy, Q = tert-buty\-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and G taken together with the carbon atom to which they are attached is cyclopropane, Y = -CH ₂ OMe, U = W = hydrogen, J = l,2-thiazol-5-yl.

46. Compound of Formula (Ia), wherein M = hydroxy, Q = tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and G taken together with the carbon atom to which they are attached is cyclopropane, Y = J = -CH ₂ OMe, U = W = hydrogen.

47. Compound of Formula (Ia), wherein M = hydroxy, Q = tert-buty\-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and G taken together with the carbon atom to which they are attached is cyclopropane, Y = -CH ₂ OMe, U = W = hydrogen, J = -CH ₂ CH ₂ OMe. 48. Compound of Formula (Ia), wherein M = hydroxy, Q = tert-buty\-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and G taken together with the carbon atom to which they are attached is cyclopropane, Y = -CH ₂ OMe, U = W = hydrogen, J = -CH ₂ NMe ₂ .

49. Compound of Formula (Ia), wherein M = hydroxy, Q = tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and G taken together with the carbon atom to which they are attached is cyclopropane, Y = -CH ₂ OMe, U = W = hydrogen, J = -CH ₂ CH ₂ NMe ₂ .

50. Compound of Formula (Ia), wherein M = hydroxy, Q = tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and G taken together with the carbon atom to which they are attached is cyclopropane, Y = -CH ₂ OMe, U = W = hydrogen, J = -CH ₂ NHMs.

51. Compound of Formula (Ia), wherein M = hydroxy, Q = tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and G taken together with the carbon atom to which they are attached is cyclopropane, Y = -CH ₂ OMe, U = W = hydrogen, J = -CH ₂ CH ₂ NHMs.

52. Compound of Formula (Ia), wherein M = hydroxy, Q = tert-buty\-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and G taken together with the carbon

atom to which they are attached is cyclopropane, Y = W = -CH ₂ OMe, U = hydrogen, J = Me.

53. Compound of Formula (Ia), wherein M = hydroxy, Q = tert-buty\-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and G taken together with the carbon atom to which they are attached is cyclopropane, Y = W = -CH ₂ OMe, U = J = hydrogen.

54. Compound of Formula (Ia), wherein M = hydroxy, Q = tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and G taken together with the carbon atom to which they are attached is cyclopropane, Y = -CH ₂ OMe, U = hydrogen, W = -CH ₂ NHMs, J = Me.

55. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl-methyl, X and G taken together with the carbon atom to which they are attached is cyclopropane, Y = -CH ₂ OMe, U = W = hydrogen, J = lH-pyrazol-1-ylmethyl. 56. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxybenzoyl, Z = isopropyl, X and G taken together with the carbon atom to which they are attached is cyclopropane, Y = -CH ₂ OMe, U = W = hydrogen, J = 1 H-pyrazol- 1 -ylmethyl.

57. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-te/t-butyl-3- methoxybenzoyl, Z = isopropyl, X and G taken together with the carbon atom to which they are attached is 2-cyclopentene, Y = -CH ₂ OMe, U = W = hydrogen, J = 1 H-pyrazol- 1 -ylmethyl.

58. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = isopropyl, X and G taken together with the carbon atom to which they are attached is cyclopentane, Y = -CH ₂ OMe, U = W = hydrogen, J = 1 H-pyrazol- 1 -ylmethyl.

59. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxybenzoyl, Z = isopropyl, X and G taken together with the carbon atom to

which they are attached i iss W = hydrogen, J = 1 H-pyrazol- 1 -ylmethyl.

60. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxybenzoyl, Z = isopropyl, X and G taken together with the carbon atom to

which they are attached is , 2-cyclopentene, Y = -CN, U = W = hydrogen, J = lH-pyrazol-1-ylmethyl.

VI. Sixth Principle Embodiment In a first embodiment of the present invention is a compound of Formulae

(6-1) as illustrated above, or a pharmaceutically acceptable salt, ester or prodrug thereof.

In a second embodiment of fifth principle embodiment, the present invention is the relative stereochemistry of a racemic compound of Formula (6-1), is represented by formulae (6-Ia) ~ (6-Id) (also referred to herein as I, Ia-Id and the like):

(Ia) (Ib) relative stereochemistry relative stereochemistry

(Ic) (Id) relative stereochemistry relative stereochemistry wherein M, Q, Z, X, Y, U, and J are as previously defined.

In a third embodiment of the present invention is the absolute stereochemistry of a chiral compound of Formula (6-1), is represented by formulae (6-Iaa) ~ (6-Idd):

(laa) (Ibb) absolute stereochemistry absolute stereochemistry

(Ice) (Idd) absolute stereochemistry absolute stereochemistry wherein M, Q, Z, X, Y, U, and J are as previously defined.

In a fourth embodiment of the present invention relates to compound of

Formula (6- Ua), or a pharmaceutically acceptable salt, ester or prodrug thereof:

wherein M, Q, Z, Y, U, A ₁ , A ₂ , and J are as previously defined,

In a fifth embodiment of the present invention relates to compound of

Formula (6- lib), or a pharmaceutically acceptable salt, ester or prodrug thereof:

wherein M, Q, Z, Y, U, A ₁ , A ₂ , B ₁ , B ₂ , and J are as previously defined. In a sixth embodiment of the present invention relates to compound of

Formula (6- Uc), (6-IId), or a pharmaceutically acceptable salt, ester or prodrug thereof:

wherein M, Q, Z, Y, U, A ₁ , A ₂ , B ₁ , B ₂ , and J are as previously defined.

In a seventh embodiment of the present invention relates to compound of Formula (6-IIIa), (6-IIIb), or a pharmaceutically acceptable salt, ester or prodrug thereof:

wherein M, Q, Z, U, A ₁ , A ₂ , B ₁ , B ₂ , Y and J are as previously defined.

In an eighth embodiment of the present invention relates to compound of Formula (6-IIIc), (6-IIId), or a pharmaceutically acceptable salt, ester or prodrug thereof:

wherein M, Q, Z, U, A ₁ , A ₂ , B ₁ , B ₂ , R ₁ , Y and J are as previously defined.

Representative compounds of the present invention (referring to formula Ia of this section) are those selected from:

1. Compound of Formula (Ia), wherein M = tert-butoxy, Q = 4-tert-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = CH ₂ , Y = -CO ₂ Et, U = hydrogen, J = methyl.

2. Compound of Formula (Ia), wherein M = tert-butoxy, Q = 4-tert-buty\-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = CH ₂ , Y = -CH ₂ OH, U = hydrogen, J = methyl.

3. Compound of Formula (Ia), wherein M = tert-butoxy, Q = 4-tert-buty\-3- methoxybenzoyl, Z = 1 ,3-thiazol-2-yl, X = CH ₂ , Y = -CH ₂ OCH ₃ , U = hydrogen, J = methyl.

4. Compound of Formula (Ia), wherein M = hydroxyl, Q = 4-tert-buty\-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = CH ₂ , Y = -CH ₂ OCH ₃ , U = hydrogen, J = methyl. 5. Compound of Formula (Ia), wherein M = hydroxyl, Q = 4-tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = CH ₂ , Y = -CH ₂ OCOCF ₃ , U = hydrogen, J = methyl.

6. Compound of Formula (Ia), wherein M = hydroxyl, Q = 4-tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = CH ₂ , Y = -CH ₂ OH, U = hydrogen, J = methyl.

7. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = CH ₂ , Y = -CH ₂ OCH ₃ , U = hydrogen, J = lH-pyrazol-1-ylmethyl.

8. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxybenzoyl, Z = 1 ,3-thiazol-2-yl, X = CH ₂ , Y = -C(O)NH ₂ , U = hydrogen, J = lH-pyrazol-1-ylmethyl.

9. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = CH ₂ , Y = -C(O)NHBn, U = hydrogen, J = lH-pyrazol-1-ylmethyl. 10. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = CH ₂ , Y = -C(O)NHPh, U = hydrogen, J = lH-pyrazol-1-ylmethyl.

11. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = CH ₂ , Y = -CH ₂ OBn, U = hydrogen, J = 1/f-pyrazol-l-ylmethyl.

12. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-te/t-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = CH ₂ , Y = -SO ₂ Ph, U = hydrogen, J = lH-pyrazol- 1 -ylmethyl.

13. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = CH ₂ , Y = -NHMs, U = hydrogen, J = lH-pyrazol- 1 -ylmethyl.

14. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxybenzoyl, Z = 1 ,3-thiazol-2-yl, X = CH ₂ , Y = -CO ₂ Et, U = hydrogen, J = lH-pyrazol- 1 -ylmethyl.

15. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = CH ₂ , Y = -CH ₂ OC(O)NH ₂ , U = hydrogen, J = lH-pyrazol-1 -ylmethyl. 16. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-te/t-butyl- benzenesulfonyl, Z = l,3-thiazol-2-yl, X = CH ₂ , Y = -CH ₂ OCH ₃ , U = hydrogen, J = lH-pyrazol-1 -ylmethyl.

17. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-te/t-butyl- phenylcarbamoyl, Z = l,3-thiazol-2-yl, X = CH ₂ , Y = -CH ₂ OCH ₃ , U = hydrogen, J = lH-pyrazol-1 -ylmethyl.

18. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- bromobenzoyl, Z = l,3-thiazol-2-yl, X = CH ₂ , Y = -CH ₂ OCH ₃ , U = hydrogen, J = lH-pyrazol- 1 -ylmethyl.

19. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-te/t-butyl-3- vinylbenzoyl, Z = 1 ,3-thiazol-2-yl, X = CH ₂ , Y = -CH ₂ OCH ₃ , U = hydrogen, J = lH-pyrazol- 1 -ylmethyl.

20. Compound of Formula (Ia), wherein M = hydroxy, Q = 2-fluoro-4-ter£-butyl- 5 -vinylbenzoyl, Z = l,3-thiazol-2-yl, X = CH ₂ , Y = -CH ₂ OCH ₃ , U = hydrogen, J = lH-pyrazol- 1 -ylmethyl. 21. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = l,3,4-thiadiazol-2-yl, X = CH ₂ , Y = -CH ₂ OCH ₃ , U = hydrogen, J = lH-pyrazol-1 -ylmethyl.

22. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxybenzoyl, Z = 5-methylisoxazol-3-yl, X = CH ₂ , Y = -CH ₂ OCH ₃ , U = hydrogen, J = lH-pyrazol-1 -ylmethyl.

23. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxybenzoyl, Z = thiophen-2-yl, X = CH ₂ , Y = -CH ₂ OCH ₃ , U = hydrogen, J = lH-pyrazol- 1 -ylmethyl.

24. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxybenzoyl, Z = thiophen-3-yl, X = CH ₂ , Y = -CH ₂ OCH ₃ , U = hydrogen, J = lH-pyrazol- 1 -ylmethyl.

25. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxybenzoyl, Z = furan-2-yl, X = CH ₂ , Y = -CH ₂ OCH ₃ , U = hydrogen, J = lH-pyrazol- 1 -ylmethyl.

26. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = furan-3-yl, X = CH ₂ , Y = -CH ₂ OCH ₃ , U = hydrogen, J = lH-pyrazol- 1 -ylmethyl. 27. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = l,3-oxazol-2-yl, X = CH ₂ , Y = -CH ₂ OCH ₃ , U = hydrogen, J = lH-pyrazol-1 -ylmethyl.

28. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxybenzoyl, Z = phenyl, X = CH ₂ , Y = -CH ₂ OCH ₃ , U = hydrogen, J = IH- pyrazol- 1 -ylmethyl.

29. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxybenzoyl, Z = pyridin-2-yl, X = CH ₂ , Y = -CH ₂ OCH ₃ , U = hydrogen, J = lH-pyrazol- 1 -ylmethyl.

30. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-te/t-butyl-3- methoxybenzoyl, Z = pyridin-3-yl, X = CH ₂ , Y = -CH ₂ OCH ₃ , U = hydrogen, J = lH-pyrazol- 1 -ylmethyl.

31. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = pyridin-4-yl, X = CH ₂ , Y = -CH ₂ OCH ₃ , U = hydrogen, J = lH-pyrazol- 1 -ylmethyl. 32. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = CH ₂ , Y = -CH ₂ OCH ₃ , U = hydrogen, J = -CH=NOMe.

33. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = CH ₂ , Y = -CH ₂ OCH ₃ , U = hydrogen, J = -CH=NNMe ₂ .

34. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = CH ₂ , Y = -CH ₂ OCH ₃ , U = hydrogen, J = l,3-thiazol-4-ylmethyl.

35. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = CH ₂ , Y = -CH ₂ OCH ₃ , U = hydrogen, J = l,3-thiazol-2-ylmethyl.

36. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxybenzoyl, Z = 1 ,3-thiazol-2-yl, X = CH ₂ , Y = -CH ₂ OCH ₃ , U = hydrogen, J = isoxazol-3-ylmethyl.

37. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = CH ₂ , Y = -CH ₂ OCH ₃ , U = hydrogen, J = pyridin-2-ylmethyl. 38. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = CH ₂ , Y = -CH ₂ OCH ₃ , U = hydrogen, J = -CH ₂ NMe ₂ .

39. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = CH ₂ , Y = -CH ₂ OCH ₃ , U = hydrogen, J = -CH ₂ CH ₂ NMe ₂ .

40. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = CH ₂ , Y = -CH ₂ OCH ₃ , U = hydrogen, J = -CH ₂ NHMs.

41. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-te/t-butyl-3- methoxybenzoyl, Z = 1 ,3-thiazol-2-yl, X = CH ₂ , Y = -CH ₂ OCH ₃ , U = hydrogen, J = -CH ₂ CH ₂ NHMs.

42. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl-methyl, X = CH ₂ , Y = -CH ₂ OCH ₃ , U = hydrogen, J = lH-pyrazol-1-ylmethyl. 43. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxybenzoyl, Z = isopropyl, X = CH ₂ , Y = -CH ₂ OCH ₃ , U = hydrogen, J = \H- pyrazol- 1 -ylmethyl.

44. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-bvXy\-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = CF ₂ , Y = -CH ₂ OCH ₃ , U = hydrogen, J = 1/f-pyrazol-l -ylmethyl.

45. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-bvXy\-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = -CH ₂ CF ₂ -, Y = -CH ₂ OCH ₃ , U = hydrogen, J = lH-pyrazol-1 -ylmethyl.

46. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = -OCH ₂ CF ₂ -, Y = -CH ₂ OCH ₃ , U = hydrogen, J = lH-pyrazol-1-ylmethyl.

VII. Sixth Principle Embodiment

In a first embodiment of the present invention is a compound of Formulae (7-1) as illustrated above, or a pharmaceutically acceptable salt, ester or prodrug thereof.

In a second embodiment of the sixth principle embodiment of the present invention is the relative stereochemistry of a racemic compound of Formula (6-1), is represented by Formulae (7-Ia) or (7-Ib) (also referred to in this section as (I), (Ia) and Ib) and the like):

(Ia) (Ib) relative stereochemistry relative stereochemistry wherein M, Q, Z, X, Y, W and J are as previously defined. In a third embodiment of the present invention is the absolute stereochemistry of a chiral compound of Formula (7-1), is represented by Formulae (7-Iaa) or (7-Ibb):

(laa) (Ibb) absolute stereochemistry absolute stereochemistry wherein M, Q, Z, X, Y, W and J are as previously defined. In a fourth embodiment of the present invention relates to compound of

Formula (7-IIa), or a pharmaceutically acceptable salt, ester or prodrug thereof:

wherein M, Q, Z, X, Y and J are as previously defined and Ai is hydrogen, halogen, -ORi, -NRiR ₂ , wherein Ri and R ₂ are as previously defined.

In a fifth embodiment of the present invention relates to compound of

Formula (7-IIb), or a pharmaceutically acceptable salt, ester or prodrug thereof:

wherein M, Q, Z, Y, W, Ai and J are as previously defined. In a sixth embodiment of the present invention relates to compound of

Formula (7-IIc), or a pharmaceutically acceptable salt, ester or prodrug thereof:

wherein M, Q, Z, X, Y, R ₃ and J are as previously defined.

In a seventh embodiment of the present invention relates to compound of Formula (7-IId), or a pharmaceutically acceptable salt, ester or prodrug thereof:

wherein M, Q, Z, X, Y and J are as previously defined, R ₄ is independent -M.

In an eighth embodiment of the present invention relates to compound of Formula (7-IIe), or a pharmaceutically acceptable salt, ester or prodrug thereof:

wherein M, Q, Z, X, Y, Ri, R ₄ , and J are as previously defined.

In a ninth embodiment of the present invention relates to compound of Formula (7-IIf), or a pharmaceutically acceptable salt, ester or prodrug thereof:

wherein M, Q, Z, W and J are as previously defined and X ¹⁰ and Y ¹⁰ are taken together with the carbon atom to which they are attached form a substituted or unsubstituted Cs-Cg-cycloalkyl group each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N.

In a tenth embodiment of the present invention relates to compound of Formula (7-IIg), or a pharmaceutically acceptable salt, ester or prodrug thereof:

wherein M, Q, Z, X, Y, R ₁ , R ₄ , and J are as previously defined. In an eleventh embodiment of the present invention relates to compound of

Formula (7-IIh), or a pharmaceutically acceptable salt, ester or prodrug thereof:

wherein A ₄ is aryl or heteroaryl, M, Q, Z, X, and Y are as previously defined.

In a twelvth embodiment of the present invention relates to compound of Formula (7-IIi), or a pharmaceutically acceptable salt, ester or prodrug thereof:

wherein A ₄ , M, Q, Z, X, Y, and W are as previously defined.

Representative compounds of the present invention (referring to the formula within this section) are those selected from: 1. Compound of Formula (Ia), wherein M = tert-bvXoxy, Q = 4-te/t-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, W = hydrogen, J = methylene.

2. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, W = hydrogen, J = methylene.

3. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, W = ethoxy, J = methylene.

4. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, W = methyl, J = methylene. 5. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, W = hydrogen, J = difluoromethylene.

6. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, W = fluoro, J = tetrafluoroethylene.

7. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = cyano, Y = cyano, W = phenyl, J = methylene.

8. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl-3- methoxybenzoyl, Z = thiophen-2-yl, X = hydrogen, Y = methoxymethyl, W = hydrogen, J = methylene.

9. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxybenzoyl, Z = thiophen-3-yl, X = hydrogen, Y = methoxymethyl, W = hydrogen, J = methylene. 10. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl-3- methoxybenzoyl, Z = isopropyl, X = hydrogen, Y = methoxymethyl, W = hydrogen, J = methylene.

11. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl-3- methoxybenzoyl, Z = oxazol-2-yl, X = hydrogen, Y = methoxymethyl, W = hydrogen, J = methylene.

12. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxybenzoyl, Z = 5-methyl-isoxazol-3-yl, X = hydrogen, Y = methoxymethyl, W = hydrogen, J = methylene.

13. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxybenzoyl, Z = furan-2-yl, X = hydrogen, Y = methoxymethyl, W = hydrogen, J = methylene.

14. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxybenzoyl, Z = furan-3-yl, X = hydrogen, Y = methoxymethyl, W = hydrogen, J = methylene.

15. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = pyridin-2-yl, X = hydrogen, Y = methoxymethyl, W = hydrogen, J = methylene. 16. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxybenzoyl, Z = pyridin-3-yl, X = hydrogen, Y = methoxymethyl, W = hydrogen, J = methylene.

17. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = pyridin-4-yl, X = hydrogen, Y = methoxymethyl, W = hydrogen, J = methylene.

18. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = phenyl, X = hydrogen, Y = methoxymethyl, W = hydrogen, J = methylene.

19. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-te/t-butyl-3- methoxybenzoyl, Z = thiazol-2-ylmethyl, X = hydrogen, Y = methoxymethyl, W = hydrogen, J = methylene.

20. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-te/t-butylbenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, W = hydrogen, J = methylene. 21. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- vinylbenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, W = hydrogen, J = methylene.

22. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-te/t-butyl-2-fluoro-5- vinylbenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, W = hydrogen, J = methylene.

23. Compound of Formula (Ia), wherein M = hydroxy, Q = 3-bromo-4-tert- butylbenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, W = hydrogen, J = methylene.

24. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl- benzenesulfonyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, W = hydrogen, J = methylene.

25. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-Butyl- phenylcarbamoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, W = hydrogen, J = methylene.

26. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, W =

hydrogen, J = -* /?"S>. 27. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, W = o

hydrogen, J = ** ^•

28. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, W =

hydrogen,

29. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, W =

hydrogen u, -A

30. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-te/t-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoride, Y = methoxymethyl, W =

hydrogen, J = * /τS">.

31. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-te/t-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoride, Y = -CH=NOMe, W =

hydrogen, J = * /τN">. 32. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-te/t-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoride, Y = fluoromethyl, W =

/\ hydrogen, J = *τ ^"1 T ¹ ".

33. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoride, Y = azide, W = hydrogen, J =

A.

34. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

atom to which they are attached is ^"1 ^ , W = hydrogen, J = ^• * » " ¹ T ^1* .

35. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

atom to which they are attached is ^" ^ , W = hydrogen, J = *τ ^"1 T ¹ ". 36. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

atom to which they are attached is ^"1 ^ ^0Me , W = hydrogen, J = *τ "/*". 37. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

A atom to which they are attached is ^"1 ^ '^ ⁰ , W = hydrogen, J = *V ^"1 T ¹ ".

38. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

atom to which they are attached is ***< , W = hydrogen, J = *τ ^" "7"".

VIII. Pharmaceutical Compositions

A further embodiment of the present invention includes pharmaceutical compositions comprising any single compound delineated herein, or principle embodiment or embodiment described therein, or a pharmaceutically acceptable salt, ester, solvate, or prodrug thereof, with a pharmaceutically acceptable carrier or excipient.

Yet another embodiment of the present invention is a pharmaceutical composition comprising a combination of two or more compounds delineated herein, or a pharmaceutically acceptable salt, ester, solvate, or prodrug thereof, with a pharmaceutically acceptable carrier or excipient.

Yet a further embodiment of the present invention is a pharmaceutical composition comprising any single compound delineated herein in combination with one or more HCV compounds known in the art, or a pharmaceutically acceptable salt, ester, solvate, or prodrug thereof, with a pharmaceutically acceptable carrier or excipient.

It will be appreciated that reference herein to therapy and/or treatment includes, but is not limited to prevention, retardation, prophylaxis, therapy and cure of the disease. It will further be appreciated that references herein to treatment or prophylaxis of HCV infection includes treatment or prophylaxis of HCV- associated disease such as liver fibrosis, cirrhosis and hepatocellular carcinoma. It will be further appreciated that the compounds of the present invention may contain one or more asymmetric carbon atoms and may exist in racemic, diastereoisomeric, and optically active forms. It will still be appreciated that certain compounds of the present invention may exist in different tautomeric forms. All tautomers are contemplated to be within the scope of the present invention.

It will be further appreciated that the compounds of the invention, or their pharmaceutically acceptable salts, stereoisomers, tautomers, prodrugs or salt of a prodrug thereof, inhibit HCV polymerase, an RNA dependent RNA polymerase, an enzyme essential for HCV viral replication. Compounds of the present invention can be administered as the sole active pharmaceutical agent, or used in combination with one or more agents to treat or prevent hepatitis C infections or the symptoms associated with HCV infection. Other agents to be administered in combination with a compound or combination of compounds of the invention include therapies for disease caused by HCV infection that suppresses HCV viral replication by direct or indirect mechanisms. These include agents such as host immune modulators (for example, interferon-alpha, pegylated interferon-alpha, interferon-beta, interferon-gamma, CpG oligonucleotides and the like), or antiviral compounds that inhibit host cellular functions such as inosine monophosphate dehydrogenase (for example, ribavirin and the like). Also included are cytokines that modulate immune function. Also included are vaccines comprising HCV antigens or antigen adjuvant combinations directed against HCV Also included are agents that interact with host cellular components to block viral protein synthesis by inhibiting the internal ribosome entry site (IRES) initiated translation step of HCV viral replication or to block viral particle maturation and release with agents

targeted toward the viroporin family of membrane proteins such as, for example, HCV P7 and the like. Other agents to be administered in combination with a compound of the present invention include any agent or combination of agents that inhibit the replication of HCV by targeting proteins of the viral genome involved in the viral replication. These agents include but are not limited to other inhibitors of HCV RNA dependent RNA polymerase such as, for example, nucleoside type polymerase inhibitors described in WO0190121(A2), or US6348587B1 or WOO 160315 or WOO 132153 or non-nucleoside inhibitors such as, for example, benzimidazole polymerase inhibitors described in EPl 162196Al or WO0204425. Accordingly, one aspect of the invention is directed to a method for treating or preventing an infection caused by an RNA-containing virus comprising coadministering to a patient in need of such treatment one or more agents selected from the group consisting of a host immune modulator and a second antiviral agent, or a combination thereof, with a therapeutically effective amount of a compound or combination of compounds of the invention, or a pharmaceutically acceptable salt, stereoisomer, tautomer, prodrug, salt of a prodrug, or combination thereof. Examples of the host immune modulator are, but not limited to, interferon- alpha, pegylated-interferon-alpha, interferon-beta, interferon-gamrna, a cytokine, a vaccine, and a vaccine comprising an antigen and an adjuvant, and said second antiviral agent inhibits replication of HCV either by inhibiting host cellular functions associated with viral replication or by targeting proteins of the viral genome.

Further aspect of the invention is directed to a method of treating or preventing infection caused by an RNA-containing virus comprising co- administering to a patient in need of such treatment an agent or combination of agents that treat or alleviate symptoms of HCV infection including cirrhosis and inflammation of the liver, with a therapeutically effective amount of a compound or combination of compounds of the invention, or a pharmaceutically acceptable salt, stereoisomer, tautomer, prodrug, salt of a prodrug, or combination thereof. Yet another aspect of the invention provides a method of treating or preventing infection caused by an RNA-containing virus comprising co-administering to a patient in need of such treatment one or more agents that treat patients for disease caused by hepatitis B (HBV) infection, with a therapeutically effective amount of a compound or a combination of compounds of the invention, or a pharmaceutically

acceptable salt, stereoisomer, tautomer, prodrug, salt of a prodrug, or combination thereof. An agent that treats patients for disease caused by hepatitis B (HBV) infection may be for example, but not limited thereto, L- deoxythymidine, adefovir, lamivudine or tenfovir, or any combination thereof. Example of the RNA- containing virus includes, but not limited to, hepatitis C virus (HCV).

Another aspect of the invention provides a method of treating or preventing infection caused by an RNA-containing virus comprising co-administering to a patient in need of such treatment one or more agents that treat patients for disease caused by human immunodeficiency virus (HIV) infection, with a therapeutically effective amount of a compound or a combination of compounds of the invention, or a pharmaceutically acceptable salt, stereoisomer, tautomer, prodrug, salt of a prodrug, or combination thereof. The agent that treats patients for disease caused by human immunodeficiency virus (HIV) infection may include, but is not limited thereto, ritonavir, lopinavir, indinavir, nelfmavir, saquinavir, amprenavir, atazanavir, tipranavir, TMC-114, fosamprenavir, zidovudine, lamivudine, didanosine, stavudine, tenofovir, zalcitabine, abacavir, efavirenz, nevirapine, delavirdine, TMC-125, L-870812, S-1360, enfuvirtide (T-20) or T-1249, or any combination thereof. Example of the RNA-containing virus includes, but not limited to, hepatitis C virus (HCV). In addition, the present invention provides the use of a compound or a combination of compounds of the invention, or a therapeutically acceptable salt form, stereoisomer, or tautomer, prodrug, salt of a prodrug, or combination thereof, and one or more agents selected from the group consisting of a host immune modulator and a second antiviral agent, or a combination thereof, to prepare a medicament for the treatment of an infection caused by an RNA-containing virus in a patient, particularly hepatitis C virus.

Examples of the host immune modulator are, but not limited to, interferon-alpha, pegylated- interferon-alpha, interferon-beta, interferon-gamma, a cytokine, a vaccine, and a vaccine comprising an antigen and an adjuvant, and said second antiviral agent inhibits replication of HCV either by inhibiting host cellular functions associated with viral replication or by targeting proteins of the viral genome.

When used in the above or other treatments, combination of compound or compounds of the invention, together with one or more agents as defined herein above, can be employed in pure form or, where such forms exist, in

pharmaceutically acceptable salt form, prodrug, salt of a prodrug, or combination thereof. Alternatively, such combination of therapeutic agents can be administered as a pharmaceutical composition containing a therapeutically effective amount of the compound or combination of compounds of interest, or their pharmaceutically acceptable salt form, prodrugs, or salts of the prodrug, in combination with one or more agents as defined hereinabove, and a pharmaceutically acceptable carriers. Such pharmaceutical compositions can be used for inhibiting the replication of an RNA-containing virus, particularly Hepatitis C virus (HCV), by contacting said virus with said pharmaceutical composition. In addition, such compositions are useful for the treatment or prevention of an infection caused by an RNA-containing virus, particularly Hepatitis C virus (HCV).

Hence, further aspect of the invention is directed to a method of treating or preventing infection caused by an RNA-containing virus, particularly a hepatitis C virus (HCV), comprising administering to a patient in need of such treatment a pharmaceutical composition comprising a compound or combination of compounds of the invention or a pharmaceutically acceptable salt, stereoisomer, or tautomer, prodrug, salt of a prodrug, or combination thereof, one or more agents as defined hereinabove, and a pharmaceutically acceptable carrier.

When administered as a combination, the therapeutic agents can be formulated as separate compositions which are given at the same time or within a predetermined period of time, or the therapeutic agents can be given as a single unit dosage form.

Antiviral agents contemplated for use in such combination therapy include agents (compounds or biologicals) that are effective to inhibit the formation and/or replication of a virus in a mammal, including but not limited to agents that interfere with either host or viral mechanisms necessary for the formation and/or replication of a virus in a mammal. Such agents can be selected from another anti-HCV agent; an HIV inhibitor; an HAV inhibitor; and an HBV inhibitor.

Other anti-HCV agents include those agents that are effective for diminishing or preventing the progression of hepatitis C related symptoms or disease. Such agents include but are not limited to immunomodulatory agents, inhibitors of HCV NS3 protease, other inhibitors of HCV polymerase, inhibitors of another target in the HCV life cycle and other anti-HCV agents, including but not limited to ribavirin, amantadine, levovirin and viramidine.

Immunomodulatory agents include those agents (compounds or biologicals) that are effective to enhance or potentiate the immune system response in a mammal. Immunomodulatory agents include, but are not limited to, inosine monophosphate dehydrogenase inhibitors such as VX-497 (merimepodib, Vertex Pharmaceuticals), class I interferons, class II interferons, consensus interferons, asialo-interferons pegylated interferons and conjugated interferons, including but not limited to interferons conjugated with other proteins including but not limited to human albumin. Class I interferons are a group of interferons that all bind to receptor type I, including both naturally and synthetically produced class I interferons, while class II interferons all bind to receptor type II. Examples of class I interferons include, but are not limited to, [alpha]-, [beta]-, [delta]-, [omega]-, and [tau] -interferons, while examples of class II interferons include, but are not limited to, [gamma]-interferons.

Inhibitors of HCV NS3 protease include agents (compounds or biologicals) that are effective to inhibit the function of HCV NS3 protease in a mammal.

Inhibitors of HCV NS3 protease include, but are not limited to, those compounds described in WO 99/07733, WO 99/07734, WO 00/09558, WO 00/09543, WO 00/59929, WO 03/064416, WO 03/064455, WO 03/064456, WO 2004/030670, WO 2004/037855, WO 2004/039833, WO 2004/101602, WO 2004/101605, WO 2004/103996, WO 2005/028501 , WO 2005/070955, WO 2006/000085, WO 2006/007700 and WO 2006/007708 (all by Boehringer Ingelheim), WO 02/060926, WO 03/053349, WO03/099274, WO 03/099316, WO 2004/032827, WO 2004/043339, WO 2004/094452, WO 2005/046712, WO 2005/051410, WO 2005/054430 (all by BMS), WO 2004/072243, WO 2004/093798, WO 2004/113365, WO 2005/010029 (all by Enanta), WO 2005/037214 (Intermune) and WO 2005/051980 (Schering), and the candidates identified as VX-950, ITMN- 191 and SCH 503034.

Inhibitors of HCV polymerase include agents (compounds or biologicals) that are effective to inhibit the function of an HCV polymerase. Such inhibitors include, but are not limited to, non-nucleoside and nucleoside inhibitors of HCV NS5B polymerase. Examples of inhibitors of HCV polymerase include but are not limited to those compounds described in: WO 02/04425, WO 03/007945, WO 03/010140, WO 03/010141 , WO 2004/064925, WO 2004/065367, WO 2005/080388 and WO 2006/007693 (all by Boehringer Ingelheim), WO

2005/049622 (Japan Tobacco), WO 2005/014543 (Japan Tobacco), WO 2005/012288 (Genelabs), WO 2004/087714 (IRBM), WO 03/101993 (Neogenesis), WO 03/026587 (BMS), WO 03/000254 (Japan Tobacco), and WO 01/47883 (Japan Tobacco), and the clinical candidates XTL-2125, HCV 796, R- 1626 and NM 283.

Inhibitors of another target in the HCV life cycle include agents (compounds or biologicals) that are effective to inhibit the formation and/or replication of HCV other than by inhibiting the function of the HCV NS3 protease. Such agents may interfere with either host or HCV viral mechanisms necessary for the formation and/or replication of HCV. Inhibitors of another target in the HCV life cycle include, but are not limited to, entry inhibitors, agents that inhibit a target selected from a helicase, a NS2/3 protease and an internal ribosome entry site (IRES) and agents that interfere with the function of other viral targets including but not limited to an NS5A protein and an NS4B protein. It can occur that a patient may be co-infected with hepatitis C virus and one or more other viruses, including but not limited to human immunodeficiency virus (HIV), hepatitis A virus (HAV) and hepatitis B virus (HBV). Thus also contemplated is combination therapy to treat such co-infections by coadministering a compound according to the present invention with at least one of an HIV inhibitor, an HAV inhibitor and an HBV inhibitor.

Definitions

Listed below are definitions of various terms used to describe this invention. These definitions apply to the terms as they are used throughout this specification and claims, unless otherwise limited in specific instances, either individually or as part of a larger group.

The term "aryl," as used herein, refers to a mono- or polycyclic carbocyclic ring system including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, idenyl. The term "heteroaryl," as used herein, refers to a mono- or polycyclic aromatic radical having one or more ring atom selected from S, O and N; and the remaining ring atoms are carbon, wherein any N or S contained within the ring may be optionally oxidized. Heteroaryl includes, but is not limited to, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl,

isooxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzooxazolyl, quinoxalinyl.

In accordance with the invention, any of the aryls, substituted aryls, heteroaryls and substituted heteroaryls described herein, can be any aromatic group. Aromatic groups can be substituted or unsubstituted.

The terms "Ci-Cs alkyl," or "C ₁ -C ₁₂ alkyl," as used herein, refer to saturated, straight- or branched-chain hydrocarbon radicals containing between one and eight, or one and twelve carbon atoms, respectively. Examples of Ci-Cg alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl, n-hexyl, heptyl and octyl radicals; and examples of Ci -C 12 alkyl radicals include, but are not limited to, ethyl, propyl, isopropyl, n-hexyl, octyl, decyl, dodecyl radicals.

The term "C ₂ -Cs alkenyl," as used herein, refer to straight- or branched- chain hydrocarbon radicals containing from two to eight carbon atoms having at least one carbon-carbon double bond by the removal of a single hydrogen atom. Alkenyl groups include, but are not limited to, for example, ethenyl, propenyl, butenyl, l-methyl-2-buten-l-yl, heptenyl, octenyl, and the like.

The term "C ₂ -Cs alkynyl," as used herein, refer to straight- or branched- chain hydrocarbon radicals containing from two to eight carbon atoms having at least one carbon-carbon triple bond by the removal of a single hydrogen atom.

Representative alkynyl groups include, but are not limited to, for example, ethynyl, 1-propynyl, 1-butynyl, heptynyl, octynyl, and the like.

The term "C ₃ -Cs-cycloalkyl", or "C ₃ -Ci ₂ -cycloalkyl," as used herein, refers to a monocyclic or polycyclic saturated carbocyclic ring compound. Examples of C ₃ -Cs-cycloalkyl include, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentyl and cyclooctyl; and examples of C ₃ -Ci ₂ -cycloalkyl include, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo [2.2.1] heptyl, and bicyclo [2.2.2] octyl.

The term "C ₃ -C ₈ cycloalkenyl", or "C ₃ -Ci ₂ cycloalkenyl" as used herein, refers to monocyclic or polycyclic carbocyclic ring compound having at least one carbon-carbon double bond. Examples Of C ₃ -C ₈ cycloalkenyl include, but not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, and the like; and examples Of C ₃ -Ci ₂ cycloalkenyl

include, but not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, and the like.

It is understood that any alkyl, alkenyl, alkynyl and cycloalkyl moiety described herein can also be an aliphatic group, an alicyclic group or a heterocyclic group. An "aliphatic" group is a non-aromatic moiety that may contain any combination of carbon atoms, hydrogen atoms, halogen atoms, oxygen, nitrogen or other atoms, and optionally contain one or more units of unsaturation, e.g., double and/or triple bonds. An aliphatic group may be straight chained, branched or cyclic and preferably contains between about 1 and about 24 carbon atoms, more typically between about 1 and about 12 carbon atoms. In addition to aliphatic hydrocarbon groups, aliphatic groups include, for example, polyalkoxyalkyls, such as polyalkylene glycols, polyamines, and polyimines, for example. Such aliphatic groups may be further substituted.

The term "alicyclic," as used herein, denotes a monovalent group derived from a monocyclic or bicyclic saturated carbocyclic ring compound by the removal of a single hydrogen atom. Examples include, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo [2.2.1] heptyl, and bicyclo [2.2.2] octyl. Such alicyclic groups may be further substituted.

The terms "heterocyclic" or "heterocycloalkyl" can be used interchangeably and referred to a non-aromatic ring or a bi- or tri-cyclic group fused system, where (i) each ring system contains at least one heteroatom independently selected from oxygen, sulfur and nitrogen, (ii) each ring system can be saturated or unsaturated (iii) the nitrogen and sulfur heteroatoms may optionally be oxidized, (iv) the nitrogen heteroatom may optionally be quaternized, (iv) any of the above rings may be fused to an aromatic ring, and (v) the remaining ring atoms are carbon atoms which may be optionally oxo-substituted. Representative heterocycloalkyl groups include, but are not limited to, 1,3-dioxolane, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, quinoxalinyl, pyridazinonyl, and tetrahydrofuryl. Such heterocyclic groups may be further substituted.

The term "substituted" refers to substitution by independent replacement of one, two, or three or more of the hydrogen atoms thereon with substituents including, but not limited to, -F, -Cl, -Br, -I, -OH, protected hydroxy, -NO ₂ , -CN, -

NH ₂ , protected amino, oxo, thioxo, -NH-Ci-C ₁₂ -alkyl, -NH-C ₂ -Cg-alkenyl, -NH- C ₂ -C ₈ -alkynyl, -NH-Cs-C^-cycloalkyl, -NH-aryl, -NH-heteroaryl, -NH- heterocycloalkyl, -dialkylamino, -diarylamino, -diheteroarylamino, -0-C ₁ -C ₁₂ - alkyl, -O-C ₂ -C ₈ -alkenyl, -O-C ₂ -C ₈ -alkynyl, -O-Q-C^-cycloalkyl, -O-aryl, -O- heteroaryl, -O-heterocycloalkyl, -C(O)-Ci-Ci ₂ -alkyl, -C(O)-C ₂ -C ₈ -alkenyl, -C(O)- C ₂ -C ₈ -alkynyl, -C(O)-C ₃ -C i ₂ -cycloalkyl, -C(O)-aryl, -C(O)-heteroaryl, -C(O)- heterocycloalkyl, -CONH ₂ , -CONH-C ₂ -C ₈ -alkenyl, -CONH- C ₂ -C ₈ -alkynyl, -CONH-C ₃ -Ci ₂ -cycloalkyl, -CONH-aryl, -CONH-heteroaryl, - CONH-heterocycloalkyl, -OCO ₂ -Ci-Ci ₂ -alkyl, -OCO ₂ -C ₂ -C ₈ -alkenyl, -OCO ₂ -C ₂ - C ₈ -alkynyl, -OCO ₂ -C ₃ -Ci ₂ -cycloalkyl, -OCO ₂ -aryl, -OCO ₂ -heteroaryl, -OCO ₂ - heterocycloalkyl, -OCONH ₂ , -OCONH-Ci-Ciz-alkyl, -OCONH-Cz-Cs-alkenyl, - OCONH-C ₂ -C ₈ -alkynyl, -OCONH-C ₃ -C i ₂ -cycloalkyl, -OCONH-aryl, -OCONH- heteroaryl, -OCONH- heterocycloalkyl, -NHC(O)-Ci -C i ₂ -alkyl, -NHC(O)-C ₂ -C ₈ - alkenyl, -NHC(O)-C ₂ -C ₈ -alkynyl, -NHC(O)-C ₃ -Ci ₂ -cycloalkyl, -NHC(0)-aryl, - NHC(O)-heteroaryl, -NHC(O)-heterocycloalkyl, -NHCO ₂ -Ci -C i ₂ -alkyl, -NHCO ₂ - C ₂ -C ₈ -alkenyl, -NHCO ₂ - C ₂ -C ₈ -alkynyl, -NHCO ₂ -C ₃ -C i ₂ -cycloalkyl, -NHCO ₂ - aryl, -NHCO ₂ -heteroaryl, -NHCO ₂ - heterocycloalkyl, -NHC(O)NH ₂ , -NHC(O)NH- Ci-Ci ₂ -alkyl, -NHC(O)NH-C ₂ -C ₈ -alkenyl, -NHC(O)NH-C ₂ -C ₈ -alkynyl, - NHC(O)NH-C ₃ -Ci ₂ -cycloalkyl, -NHC(O)NH-aryl, -NHC(O)NH-heteroaryl, - NHC(O)NH-heterocycloalkyl, NHC(S)NH ₂ , -NHC(S)NH-Ci-Ci ₂ -alkyl, -

NHC(S)NH-C ₂ -C ₈ -alkenyl, -NHC(S)NH-C ₂ -C ₈ -alkynyl, -NHC(S)NH-C ₃ -C _I2 - cycloalkyl, -NHC(S)NH-aryl, -NHC(S)NH-heteroaryl, -NHC(S)NH- heterocycloalkyl, -NHC(NH)NH ₂ , -NHC(NH)NH-Ci-Ci ₂ -alkyl, -NHC(NH)NH- C ₂ -C ₈ -alkenyl, -NHC(NH)NH-C ₂ -C ₈ -alkynyl, -NHC(NH)NH-C ₃ -Ci ₂ -cycloalkyl, - NHC(NH)NH-aryl, -NHC(NH)NH-heteroaryl, -NHC(NH)NH-heterocycloalkyl, - NHC(NH)-Ci-Ci ₂ -alkyl, -NHC(NH)-C ₂ -C ₈ -alkenyl, -NHC(NH)-C ₂ -C ₈ -alkynyl, - NHC(NH)-C ₃ -C ₁₂ -cycloalkyl, -NHC(NH)-aryl, -NHC(NH)-heteroaryl, - NHC(NH)-heterocycloalkyl, -C(NH)NH-Ci-Ci ₂ -alkyl, -C(NH)NH-C ₂ -C ₈ -alkenyl, -C(NH)NH-C ₂ -C ₈ -alkynyl, -C(NH)NH-C ₃ -Ci ₂ -cycloalkyl, -C(NH)NH-aryl, - C(NH)NH-heteroaryl, -C(NH)NH-heterocycloalkyl, -S(O)-Ci-Ci ₂ -alkyl, - S(O)- C ₂ -C ₈ -alkenyl, - S(O)-C ₂ -C ₈ -alkynyl, - S(O)-C ₃ -Ci ₂ -cycloalkyl, - S(O)-aryl, - S(O)-heteroaryl, - S(O)-heterocycloalkyl -SO ₂ NH ₂ , -SO ₂ NH-Ci-Ci ₂ -alkyl, - SO ₂ NH-C ₂ -C ₈ -alkenyl, -SO ₂ NH- C ₂ -C ₈ -alkynyl, -SO ₂ NH-C ₃ -C i ₂ -cycloalkyl, - SO ₂ NH-aryl, -SO ₂ NH-heteroaryl, -SO ₂ NH- heterocycloalkyl, -NHSO ₂ -Ci-Ci ₂ -

alkyl, -NHSO ₂ -C ₂ -C ₈ -alkenyl, - NHSO ₂ -C ₂ -C ₈ -alkynyl, -NHSO ₂ -C ₃ -Ci ₂ - cycloalkyl, -NHSO ₂ -aryl, -NHSO ₂ -heteroaryl, -NHSO ₂ -heterocycloalkyl, - CH ₂ NH ₂ , -CH ₂ SO ₂ CH ₃ , -aryl, -arylalkyl, -heteroaryl, -heteroarylalkyl, - heterocycloalkyl, -C ₃ -Ci ₂ -cycloalkyl, polyalkoxyalkyl, polyalkoxy, - methoxymethoxy, -methoxyethoxy, -SH, -S-Ci-Ci ₂ -alkyl, -S-C ₂ -Cg-alkenyl, -S-C ₂ - C _δ -alkynyl, -S-C ₃ -Ci ₂ -cycloalkyl, -S-aryl, -S-heteroaryl, -S-heterocycloalkyl, or methylthiomethyl. It is understood that the aryls, heteroaryls, alkyls, and the like can be further substituted.

The term "halogen," as used herein, refers to an atom selected from fluorine, chlorine, bromine and iodine.

The term "hydroxy activating group", as used herein, refers to a labile chemical moiety which is known in the art to activate a hydroxyl group so that it will depart during synthetic procedures such as in a substitution or an elimination reactions. Examples of hydroxyl activating group include, but not limited to, mesylate, tosylate, triflate, /?-nitrobenzoate, phosphonate and the like.

The term "activated hydroxy", as used herein, refers to a hydroxy group activated with a hydroxyl activating group, as defined above, including mesylate, tosylate, triflate, p-nitrobenzoate, phosphonate groups, for example.

The term "hydroxy protecting group," as used herein, refers to a labile chemical moiety which is known in the art to protect a hydroxyl group against undesired reactions during synthetic procedures. After said synthetic procedure(s) the hydroxy protecting group as described herein may be selectively removed. Hydroxy protecting groups as known in the art are described generally in T. H. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, New York (1999). Examples of hydroxyl protecting groups include benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4- bromobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, methoxycarbonyl, tert- butoxycarbonyl, isopropoxycarbonyl, diphenylmethoxycarbonyl, 2,2,2- trichloroethoxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl, 2-furfuryloxycarbonyl, allyloxycarbonyl, acetyl, formyl, chloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, benzoyl, methyl, t-butyl, 2,2,2-trichloroethyl, 2-trimethylsilyl ethyl, l,l-dimethyl-2-propenyl, 3 -methyl- 3 -butenyl, allyl, benzyl, para- methoxybenzyldiphenylmethyl, triphenylmethyl (trityl), tetrahydrofuryl, methoxymethyl, methylthiomethyl, benzyloxymethyl, 2,2,2-triehloroethoxymethyl,

2-(trimethylsilyl)ethoxymethyl, methanesulfonyl, para-toluenesulfonyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, and the like. Preferred hydroxyl protecting groups for the present invention are acetyl (Ac or -C(O)CH ₃ ), benzoyl (Bz or -C(O)C ₆ H ₅ ), and trimethylsilyl (TMS or-Si(CH ₃ ) ₃ ). The term "protected hydroxy," as used herein, refers to a hydroxy group protected with a hydroxy protecting group, as defined above, including benzoyl, acetyl, trimethylsilyl, triethylsilyl, methoxymethyl groups, for example.

The term "hydroxy prodrug group", as used herein, refers to a promoiety group which is known in the art to change the physicochemical, and hence the biological properties of a parent drug in a transient manner by covering or masking the hydroxy group. After said synthetic procedure(s), the hydroxy prodrug group as described herein must be capable of reverting back to hydroxy group in vivo. Hydroxy prodrug groups as known in the art are described generally in Kenneth B. Sloan, Prodrugs, Topical and Ocular Drug Delivery, (Drugs and the Pharmaceutical Sciences; Volume 53), Marcel Dekker, Inc., New York (1992).

The term "amino protecting group," as used herein, refers to a labile chemical moiety which is known in the art to protect an amino group against undesired reactions during synthetic procedures. After said synthetic procedure(s) the amino protecting group as described herein may be selectively removed. Amino protecting groups as known in the art are described generally in T. H.

Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, New York (1999). Examples of amino protecting groups include, but are not limited to, t-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyloxycarbonyl, and the like. The term "leaving group" means a functional group or atom which can be displaced by another functional group or atom in a substitution reaction, such as a nucleophilic substitution reaction. By way of example, representative leaving groups include chloro, bromo and iodo groups; sulfonic ester groups, such as mesylate, tosylate, brosylate, nosylate and the like; and acyloxy groups, such as acetoxy, trifluoroacetoxy and the like.

The term "protected amino," as used herein, refers to an amino group protected with an amino protecting group as defined above.

The term "aprotic solvent," as used herein, refers to a solvent that is relatively inert to proton activity, i.e., not acting as a proton-donor. Examples

include, but are not limited to, hydrocarbons, such as hexane and toluene, for example, halogenated hydrocarbons, such as, for example, methylene chloride, ethylene chloride, chloroform, and the like, heterocyclic compounds, such as, for example, tetrahydrofuran and N-methylpyrrolidinone, and ethers such as diethyl ether, bis-methoxymethyl ether. Such compounds are well known to those skilled in the art, and it will be obvious to those skilled in the art that individual solvents or mixtures thereof may be preferred for specific compounds and reaction conditions, depending upon such factors as the solubility of reagents, reactivity of reagents and preferred temperature ranges, for example. Further discussions of aprotic solvents may be found in organic chemistry textbooks or in specialized monographs, for example: Organic Solvents Physical Properties and Methods of Purification, 4th ed., edited by John A. Riddick et ah, Vol. II, in the Techniques of Chemistry Series. John Wiley & Sons, NY, 1986.

The term "protic solvent' as used herein, refers to a solvent that tends to provide protons, such as an alcohol, for example, methanol, ethanol, propanol, isopropanol, butanol, t-butanol, and the like. Such solvents are well known to those skilled in the art, and it will be obvious to those skilled in the art that individual solvents or mixtures thereof may be preferred for specific compounds and reaction conditions, depending upon such factors as the solubility of reagents, reactivity of reagents and preferred temperature ranges, for example. Further discussions of protogenic solvents may be found in organic chemistry textbooks or in specialized monographs, for example: Organic Solvents Physical Properties and Methods of Purification, 4th ed., edited by John A. Riddick et ah, Vol. II, in the Techniques of Chemistry Series, John Wiley & Sons, NY, 1986. Combinations of substituents and variables envisioned by this invention are only those that result in the formation of stable compounds. The term "stable", as used herein, refers to compounds which possess stability sufficient to allow manufacture and which maintains the integrity of the compound for a sufficient period of time to be useful for the purposes detailed herein (e.g., therapeutic or prophylactic administration to a subject).

The synthesized compounds can be separated from a reaction mixture and further purified by a method such as column chromatography, high pressure liquid chromatography, or recrystallization. As can be appreciated by the skilled artisan, further methods of synthesizing the compounds of the Formula herein will be

evident to those of ordinary skill in the art. Additionally, the various synthetic steps may be performed in an alternate sequence or order to give the desired compounds. Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful in synthesizing the compounds described herein are known in the art and include, for example, those such as described in R. Larock, Comprehensive Organic Transformations, 2 ^nd Ed. Wiley- VCH (1999); T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley and Sons (1999); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995), and subsequent editions thereof.

The term "subject" as used herein refers to an animal. Preferably the animal is a mammal. More preferably the mammal is a human. A subject also refers to, for example, dogs, cats, horses, cows, pigs, guinea pigs, fish, birds and the like.

The compounds of this invention may be modified by appending appropriate functionalities to enhance selective biological properties. Such modifications are known in the art and may include those which increase biological penetration into a given biological system (e.g., blood, lymphatic system, central nervous system), increase oral availability, increase solubility to allow administration by injection, alter metabolism and alter rate of excretion.

The compounds described herein contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)-, or as (D)- or (L)- for amino acids. The present invention is meant to include all such possible isomers, as well as their racemic and optically pure forms. Optical isomers may be prepared from their respective optically active precursors by the procedures described above, or by resolving the racemic mixtures. The resolution can be carried out in the presence of a resolving agent, by chromatography or by repeated crystallization or by some combination of these techniques which are known to those skilled in the art. Further details regarding resolutions can be found in Jacques, et al., Enantiomers, Racemates, and Resolutions (John Wiley & Sons, 1981). When the compounds described herein contain olefmic double bonds, other unsaturation, or other centers of geometric asymmetry, and unless specified

otherwise, it is intended that the compounds include both E and Z geometric isomers or cis- and trans- isomers. Likewise, all tautomeric forms are also intended to be included. Tautomers may be in cyclic or acyclic. The configuration of any carbon-carbon double bond appearing herein is selected for convenience only and is not intended to designate a particular configuration unless the text so states; thus a carbon-carbon double bond or carbon-heteroatom double bond depicted arbitrarily herein as trans may be cis, trans, or a mixture of the two in any proportion.

As used herein, the term "pharmaceutically acceptable salt" refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977). The salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting the free base function with a suitable organic acid. Examples of pharmaceutically acceptable salts include, but are not limited to, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include, but are not limited to, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, /?-toluenesulfonate, undecanoate, valerate salts, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further

pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl having from 1 to 6 carbon atoms, sulfonate and aryl sulfonate. As used herein, the term "pharmaceutically acceptable ester" refers to esters which hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof. Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moiety advantageously has not more than 6 carbon atoms. Examples of particular esters include, but are not limited to, formates, acetates, propionates, butyrates, acrylates and ethylsuccinates.

The term "pharmaceutically acceptable prodrugs" as used herein refers to those prodrugs of the compounds of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals with undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the present invention. "Prodrug", as used herein means a compound which is convertible in vivo by metabolic means (e.g. by hydrolysis) to a compound of the invention. Various forms of prodrugs are known in the art, for example, as discussed in Bundgaard, (ed.), Design of Prodrugs, Elsevier (1985); Widder, et al. (ed.), Methods in Enzymology, vol. 4, Academic Press (1985); Krogsgaard-Larsen, et al., (ed). "Design and Application of Prodrugs, Textbook of Drug Design and Development, Chapter 5, 113-191 (1991); Bundgaard, et al., Journal of Drug

Deliver Reviews, 8:1-38(1992); Bundgaard, J. of Pharmaceutical Sciences, 77:285 et seq. (1988); Higuchi and Stella (eds.) Prodrugs as Novel Drug Delivery Systems, American Chemical Society (1975); and Bernard Testa & Joachim Mayer, "Hydrolysis In Drug And Prodrug Metabolism: Chemistry, Biochemistry And Enzymology," John Wiley and Sons, Ltd. (2002).

The present invention also relates to solvates of the compounds of Formulae (I) and (II), for example hydrates.

This invention also encompasses pharmaceutical compositions containing, and methods of treating viral infections through administering, pharmaceutically

acceptable prodrugs of compounds of the invention. For example, compounds of the invention having free amino, amido, hydroxy or carboxylic groups can be converted into prodrugs. Prodrugs include compounds wherein an amino acid residue, or a polypeptide chain of two or more (e.g., two, three or four) amino acid residues is covalently joined through an amide or ester bond to a free amino, hydroxy or carboxylic acid group of compounds of the invention. The amino acid residues include but are not limited to the 20 naturally occurring amino acids commonly designated by three letter symbols and also includes 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid, citrulline, homocysteine, homoserine, ornithine and methionine sulfone. Additional types of prodrugs are also encompassed. For instance, free carboxyl groups can be derivatized as amides or alkyl esters. Free hydroxy groups may be derivatized using groups including but not limited to hemisuccinates, phosphate esters, dimethylaminoacetates, and phosphoryloxymethyloxycarbonyls, as outlined in Advanced Drug Delivery

Reviews, 1996, 19, 115. Carbamate prodrugs of hydroxy and amino groups are also included, as are carbonate prodrugs, sulfonate esters and sulfate esters of hydroxy groups. Derivatization of hydroxy groups as (acyloxy)methyl and (acyloxy)ethyl ethers wherein the acyl group may be an alkyl ester, optionally substituted with groups including but not limited to ether, amine and carboxylic acid functionalities, or where the acyl group is an amino acid ester as described above, are also encompassed. Prodrugs of this type are described in J. Med. Chem. 1996, 39, 10. Free amines can also be derivatized as amides, sulfonamides or phosphonamides. All of these prodrug moieties may incorporate groups including but not limited to ether, amine and carboxylic acid functionalities.

PHARMACEUTICAL COMPOSITIONS.

The pharmaceutical compositions of the present invention comprise a therapeutically effective amount of a compound of the present invention formulated together with one or more pharmaceutically acceptable carriers or excipients.

As used herein, the term "pharmaceutically acceptable carrier or excipient" means a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type. Some examples of materials which

can serve as pharmaceutically acceptable carriers are sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminun hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator.

The pharmaceutical compositions of this invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir, preferably by oral administration or administration by injection. The pharmaceutical compositions of this invention may contain any conventional non-toxic pharmaceutically-acceptable carriers, adjuvants or vehicles. In some cases, the pH of the formulation may be adjusted with pharmaceutically acceptable acids, bases or buffers to enhance the stability of the formulated compound or its delivery form. The term parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifϊers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3- butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as

wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions, may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S. P. 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 can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

In order to prolong the effect of a drug, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissues.

Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene

glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or: a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, ear drops, eye ointments,

powders and solutions are also contemplated as being within the scope of this invention.

The ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

Powders and sprays can contain, in addition to the compounds of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants such as chlorofluorohydrocarbons.

Transdermal patches have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

For pulmonary delivery, a therapeutic composition of the invention is formulated and administered to the patient in solid or liquid particulate form by direct administration e.g., inhalation into the respiratory system. Solid or liquid particulate forms of the active compound prepared for practicing the present invention include particles of respirable size: that is, particles of a size sufficiently small to pass through the mouth and larynx upon inhalation and into the bronchi and alveoli of the lungs. Delivery of aerosolized therapeutics, particularly aerosolized antibiotics, is known in the art (see, for example U.S. Pat. No. 5,767,068 to VanDevanter et al, U.S. Pat. No. 5,508,269 to Smith et ah, and WO 98/43,650 by Montgomery, all of which are incorporated herein by reference). A discussion of pulmonary delivery of antibiotics is also found in U.S. Pat. No. 6,014,969, incorporated herein by reference.

ANTIVIRAL ACTIVITY

An inhibitory amount or dose of the compounds of the present invention may range from about 0.01 mg/Kg to about 500 mg/Kg, alternatively from about 1 to about 50 mg/Kg. Inhibitory amounts or doses will also vary depending on route of administration, as well as the possibility of co-usage with other agents.

According to the methods of treatment of the present invention, viral infections, conditions are treated or prevented in a patient such as a human or another animal by administering to the patient a therapeutically effective amount of a compound of the invention, in such amounts and for such time as is necessary to achieve the desired result.

By a "therapeutically effective amount" of a compound of the invention is meant an amount of the compound which confers a therapeutic effect on the treated subject, at a reasonable benefit/risk ratio applicable to any medical treatment.

The therapeutic effect may be objective (i.e., measurable by some test or marker) or subjective (i.e., subject gives an indication of or feels an effect). An effective amount of the compound described above may range from about 0.1 mg/Kg to about 500 mg/Kg, preferably from about 1 to about 50 mg/Kg. Effective doses will also vary depending on route of administration, as well as the possibility of co-usage with other agents. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or contemporaneously with the specific compound employed; and like factors well known in the medical arts. The total daily dose of the compounds of this invention administered to a human or other animal in single or in divided doses can be in amounts, for example, from 0.01 to 50 mg/kg body weight or more usually from 0.1 to 25 mg/kg body weight. Single dose compositions may contain such amounts or submultiples thereof to make up the daily dose. In general, treatment regimens according to the present invention comprise administration to a patient in need of such treatment from about 10 mg to about 1000 mg of the compound(s) of this invention per day in single or multiple doses.

The compounds of the present invention described herein can, for example, be administered by injection, intravenously, intraarterially, subdermally,

intraperitoneally, intramuscularly, or subcutaneously; or orally, buccally, nasally, transmucosally, topically, in an ophthalmic preparation, or by inhalation, with a dosage ranging from about 0.1 to about 500 mg/kg of body weight, alternatively dosages between 1 mg and 1000 mg/dose, every 4 to 120 hours, or according to the requirements of the particular drug. The methods herein contemplate administration of an effective amount of compound or compound composition to achieve the desired or stated effect. Typically, the pharmaceutical compositions of this invention will be administered from about 1 to about 6 times per day or alternatively, as a continuous infusion. Such administration can be used as a chronic or acute therapy. The amount of active ingredient that may be combined with pharmaceutically exipients or carriers to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. A typical preparation will contain from about 5% to about 95% active compound (w/w). Alternatively, such preparations may contain from about 20% to about 80% active compound.

Lower or higher doses than those recited above may be required. Specific dosage and treatment regimens for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health status, sex, diet, time of administration, rate of excretion, drug combination, the severity and course of the disease, condition or symptoms, the patient's disposition to the disease, condition or symptoms, and the judgment of the treating physician.

Upon improvement of a patient's condition, a maintenance dose of a compound, composition or combination of this invention may be administered, if necessary. Subsequently, the dosage or frequency of administration, or both, may be reduced, as a function of the symptoms, to a level at which the improved condition is retained when the symptoms have been alleviated to the desired level. Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of disease symptoms. When the compositions of this invention comprise a combination of a compound of the Formula described herein and one or more additional therapeutic or prophylactic agents, both the compound and the additional agent should be present at dosage levels of between about 1 to 100%, and more preferably between about 5 to 95% of the dosage normally administered in a monotherapy regimen.

The additional agents may be administered separately, as part of a multiple dose regimen, from the compounds of this invention. Alternatively, those agents may be part of a single dosage form, mixed together with the compounds of this invention in a single composition. The said "additional therapeutic or prophylactic agents" includes but not limited to, immune therapies (eg. interferon), therapeutic vaccines, antifibrotic agents, anti-inflammatory agents such as corticosteroids or NSAIDs, bronchodilators such as beta-2 adrenergic agonists and xanthines (e.g. theophylline), mucolytic agents, anti-muscarinics, anti-leukotrienes, inhibitors of cell adhesion (e.g. ICAM antagonists), anti-oxidants (eg N-acetylcysteine), cytokine agonists, cytokine antagonists, lung surfactants and/or antimicrobial and anti-viral agents (eg ribavirin and amantidine). The compositions according to the invention may also be used in combination with gene replacement therapy.

Unless otherwise defined, all technical and scientific terms used herein are accorded the meaning commonly known to one of ordinary skill in the art. All publications, patents, published patent applications, and other references mentioned herein are hereby incorporated by reference in their entirety.

ABBREVIATIONS

Abbreviations which may be used in the descriptions of the scheme and the examples that follow are: Ac for acetyl; AcOH for acetic acid; AIBN for azobisisobutyronitrile; BINAP for 2,2'-bis(diphenylphosphino)-l,l '-binaphthyl; BoC ₂ O for di-te/t-butyl-dicarbonate; Boc for t-butoxycarbonyl; Bpoc for 1-methyl- l-(4-biphenylyl)ethyl carbonyl; Bz for benzoyl; Bn for benzyl; BocNHOH for tert- butyl N-hydroxycarbamate; t-BuOK for potassium te/t-butoxide; Bu ₃ SnH for tributyltin hydride; BOP for (benzotriazol-1- yloxy)tris(dimethylamino)phosphonium; Hexafluorophosphate; Brine for sodium chloride solution in water; CDI for carbonyldiimidazole; CH ₂ Cl ₂ for dichloromethane; CH3 for methyl; CH ₃ CN for acetonitrile; Cs ₂ CO ₃ for cesium carbonate; CuCl for copper (I) chloride; CuI for copper (I) iodide; dba for dibenzylidene acetone; dppb for diphenylphosphino butane; DBU for 1,8- diazabicyclo[5.4.0]undec-7-ene; DCC for N,N'-dicyclohexylcarbodiimide; DEAD for diethylazodicarboxylate; DIAD for diisopropyl azodicarboxylate;

DIPEA or (1-Pr) ₂ EtN for N,N,-diisopropylethyl amine; Dess-Martin periodinane for l,l,l-tris(acetyloxy)-l,l-dihydro-l,2-benziodoxol-3-(lH)-one ; DMAP for 4- dimethylaminopyridine; DME for 1 ,2-dimethoxyethane; DMF for N ₅ N- dimethylformamide; DMSO for dimethyl sulfoxide; DPPA for diphenylphosphoryl azide; EDC for N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide; EDC HCl for N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride; EtOAc for ethyl acetate; EtOH for ethanol; Et ₂ O for diethyl ether; HATU for O-(7-azabenzotriazol- l-yl)-N,N,N',N',-tetramethyluronium Hexafluorophosphate; HCl for hydrogen chloride; HOBT for 1-hydroxybenzotriazole; K2CO3 for potassium carbonate; n- BuLi for n-butyl lithium; /-BuLi for /-butyl lithium; /-BuLi for /-butyl lithium; PhLi for phenyl lithium; LDA for lithium diisopropylamide; TMEDA for N,N,N',N'-tetramethylethylene diamine; LiTMP for lithium 2,2,6,6- tetramethylpiperidinate; MeOH for methanol; MOM for methoxymethyl; Ms for mesyl or -SO2-CH3; Ms ₂ O for methanesulfonic anhydride or mesyl-anhydride; NaN(TMS)2 for sodium bis(trimethylsilyl)amide; NMMO for N- methylmorpholine N-oxide; TEA or Et ₃ N for triethylamine;TFA for trifluoroacetic acid; THF for tetrahydrofuran; TPP or PPh ₃ for triphenylphosphine; Troc for 2,2,2- trichloroethyl carbonyl; Ts for tosyl or -SO ₂ -C ₆ H ₄ CH ₃ ; Ts ₂ O for tolylsulfonic anhydride or tosyl-anhydride; TsOH for p-tolylsulfonic acid; Pd for palladium; Ph for phenyl; POPd for dihydrogen dichlorobis(di-tert-butylphosphinito-

DP)palladate(II); Pd ₂ (dba) ₃ for tris(dibenzylideneacetone) dipalladium (0); Pd(PPh ₃ ) ₄ for tetrakis(triphenylphosphine)palladium (0); PdCl ₂ (Ph ₃ P) ₂ for for trans-dichlorobis(triphenylphosphine)palladium (II); TBS for /er/-butyl dimethylsilyl; or TMS for trimethylsilyl; and TMSCl for trimethylsilyl chloride With respect to each principle embodiment of the invention, the original formulae numbers from its respective priority document has been retained and corresponds to the subsection referenced above. As such, it will be seen that a plurality of formulae have the number (Ia), for example. However, it should be understood that where it appears with respect to a first, second, third, etc. principle embodiment, the formula refers to the specific subsection set forth above.

SYNTHETIC METHODS

With respect to each principle embodiment of the invention, the original formulae numbers from its respective priority document has been retained and corresponds to the subsection referenced above. As such, it will be seen that a plurality of formulae have the number (I), for example. However, it should be understood that where it appears with respect to a first, second, third, etc. principle embodiment, the formula refers to the specific subsection set forth above.

The compounds and processes of the present invention will be better understood in connection with the following synthetic schemes that illustrate the methods by which the compounds of the invention may be prepared.

The compounds of the present invention with respect to each principle embodiment may be prepared via several different synthetic routes using similar chemistry strategy. The most straightforward method, which is exemplified as shown in Scheme 1 , in which and following schemes 2-4 M, Q, Z, X, Y, and J are as previously defined in the first principle embodiment of the invention unless otherwise defined, includes a ring closure between an imine intermediate (1-2) and a suitable olefin (1-2.1) promoted by a Lewis acid such as but not limited to lithium bromide, titanium (IV) chloride, boron trifluoride etherate, or the like; or by a base such as but not limited to triethylamine, DBU, pyridine, potassium carbonate, sodium bicarbonate, lithium tert-butoxidc, or the like; or a combination of a Lewis acid and a suitable base such as but not limited to lithium bromide and triethylamine, in an aprotic solvent at a temperature typically between -2O ⁰ C and 100 ⁰ C. The preferred temperature is O ⁰ C to room temperature. (1-2.1) is a suitably substituted olefin, with one or more substituents as electron- withdrawing-group or electron-deficient heteroaryl, such as but not limited to methyl methacrylate, methyl 2-chloroacrylate, methyl 2-fluoroacrylate, 2-methylacrylonitrile, methyl 2- bromomethylacrylate, methyl 3-methoxycarbonyl-3-butenoate, methyl vinyl ketone, 2-vinylpyrazine, 2-vinylbenzothiazole, 2-vinyl benzoxazole, 3-bromo-5- vinyl- 1 ,2,4-thiadiazole, 5-methyl-3-vinyl-l,2,4-thiadiazole, or the like. Imine (1-2) can be obtained by condensation of a α-amino carbonyl species, typically an amino acid derivative such as t-butyl 2-amino-3-(l,3-thiazol-4-yl)-propanoate, t-butyl 3- (lH-pyrazol-l-yl)-propanoate, benzyl 2-amino-3-(£-butyldimethylsilyloxy)-

propanoate, 2-amino-4-methyl-pentanoate, or the like, with an aldehyde (1-1.1) promoted by a water-scavenger such as but not limited to magnesium sulfate, molecular sieves, methyl ortho formate, or the like; optionally in the presence of an acid such as but not limited to acetic acid, /?-toluenesulfonic acid, lithium bromide, or the like, or a base such as but not limited to triethylamine, pyridine, sodium bicarbonate, or the like, or a combination of a Lewis acid and a suitable base; in an aprotic solvent at a temperature typically between -2O ⁰ C and 100 ⁰ C, to give a pyrrolidine derivative (1-3). The preferred temperature is O ⁰ C to room temperature. Pyrrolidine (1-3) is converted to a compound of formula (I) by derivatizing the reactive secondary amine with reagent (1-3.1), wherein LG is a leaving group such as but not limited to chloride, Ms, benzotriazolyl, hydroxyl, or the like, in the presence of a base such as but not limited to triethylamine, pyridine, sodium bicarbonate, or the like, optionally in the presence of an condensation reagent which is known in the art such as EDC, HATU, or the like, in an aprotic solvent at a temperature typically between O ⁰ C and 100 ⁰ C, preferably at room temperature.

Scheme 1

1- ₄ 1-5

Alternatively as shown in Scheme 1, the compound of formula (I) may be prepared from intermediate (1-5) by extracting a proton with a strong base such as but not limited to LDA, t-BuLi, PhLi, LiTMP, or the like, optionally in the presence of a lithium chelating agent, which is known in the art, such as TMEDA or the like, in an aprotic solvent or a combination of aprotic solvents at a temperature typically between -78 ⁰ C and room temperature, followed by trapping the resulted carbanion with reagent (1-5.1) in an aprotic solvent or a combination of aprotic solvents at a temperature typically between -78 ⁰ C and 100 ⁰ C. The carbanion trapping reagent (1-5.1) is a reactive species, selected from a group such

as but not limited to methyl iodide, acetyl chloride, benzyl bromide, allyl bromide, benzoyl chloride, N-fluorobenzenesulfonimide, NCS, 2-formylpyridine, methoxymethyl chloride, or the like. The intermediate (1-5) may be prepared by a two steps procedure: 1) cyclization of an imine (1-2) and an olefin (1-2.2) to give a pyrrolidine intermediate (1-4); and 2) condensation of (1-4) with reagent (1-3.1); using the conditions described above.

It will be appreciated that compounds of Formula (I), (1-3), (1-4), and/or (1-5) which exist as diastereoisomers may optionally be separated by techniques well known in the art, for example by column chromatography. It will be appreciated that racemic compounds of Formula (I), (1-3), (1-4), and/or (1-5) may be optionally resolved into their individual enantiomers. Such resolutions may conveniently be accomplished by standard methods known in the art. For example, a racemic compound of Formula (I), (1-3), (1-4), and/or (1-5) may be resolved by chiral preparative HPLC. Alternatively, racemic compounds of Formula (I), (1-3), (1-4), and/or (1-5) which contain an appropriate acidic or basic group, such as a carboxylic acid group or amine group may be resolved by standard diastereoisomeric salt formation with a chiral base or acid reagent respectively as appropriate. Such techniques are well established in the art. For example, a racemic compound of Formula (1-3) or (1-4) may be resolved by treatment with a chiral acid such as (R)-(-)- 1,1 '- binaphthyl-2,2'-diyl-hydrogen phosphate, in a suitable solvent, for example dichloromethane, isopropanol or acetonitrile. The enantiomer of Formula (1-3) or (1-4) may then be obtained by treating the salt with a suitable base, for example triethylamine, in a suitable solvent, for example methyl tert-butyl ether. Individual enantiomers of Formula (1-3), (1-4) and/or (1-5) may then be progressed to an enantiomeric compound of Formula (I) by the chemistry described above in respect of racemic compounds.

It will also be appreciated that individual enantiomeric compounds of Formula (1-3) and/or (1-4) may be prepared by general methods of asymmetric synthesis using, where appropriate, chiral auxiliaries or chiral catalytic reagents and additionally performing any suitable functional group interconversion step as hereinbefore described, including the addition or removal of any such chiral auxiliary. Such general methods of asymmetric synthesis are well known in the art and include, but are not restricted to, those described in "Asymmetric Synthesis,"

Academic Press, 1984 and/or "Chiral Auxiliaries and Ligands in Asymmetric Synthesis", Wiley, 1995. For example, suitable general chiral auxiliaries include chiral alcohols such as menthol or 1-phenylethanol; chiral oxazolidinones such as 4-benzyloxazolidin-2-one or 4-isopropyloxazolidin-2-one; chiral sultams such as camphor sultam; or chiral amines such as 1-phenylethylamine or 2-amino-2- phenylethanol. Suitable general chiral catalytic reagents include chiral basic amines and chiral ligands such as N-methylephedrine, l-phenyl-2-(l-pyrrolidinyl)- 1 -propanol, 3-(dimethylamino)- 1 ,7,7-trimethylbicyclo[2.2.1 ]-heptan-2-ol, 3,4- bis(diphenylphosphanyl)-l-(phenylmethyl)-pyrrolidine, chinchonine, chinchonidine, sparteine, hydroquinine or quinine, BINAP or chiral bis(oxazoline) (BOX) ligands and derivatives, optionally in the presence of a metal salt, for example A _a B _b where A is silver, cobalt, zinc, titanium, magnesium, or manganese, and B is halide (for example chloride or bromide), acetate, trifluoroacetate, p- toluenesulfonate, trifluoromethylsulfonate, hexafluorophosphate or nitrate, and _a , and b, are 1 , 2, 3 or 4, and optionally in the presence of a base, for example triethylamine. All of these chiral auxiliaries or chiral catalytic reagents are well described in the art. General illustrative examples of the preparation of various chiral pyrrolidines by asymmetric synthesis using chiral auxiliaries or chiral catalytic reagents include, but are not limited to, those described in Angew. Chem. Int. Ed, (2002), 41, 4236; Chem. Rev., (1998), 98, 863; J. Am. Chem. Soc, (2002), 124, 13400; J. Am. Chem. Soc, (2003), 125, 10175; Org. Lett., (2003), 5, 5043; Tetrahedron, (1995), 51, 273; Tetrahedron: Asymm., (1995), 6, 2475; Tetrahedron: Asymm., (2001), 12, 1977; Tetrahedron: Asymm., (2002), 13, 2099 and Tet. Lett., (1991), 41, 5817. In a particular aspect, a chiral pyrrolidine compound of Formula (l-3a) in

Scheme 2

Scheme 2 in which W ¹ represents -CO ₂ L or -CO ₂ L ¹ wherein L represents hydrogen or alkyl, L ¹ represents a chiral auxiliary, and M, Z, X, and J are as defined above for

Formula (I), and * denotes an enantioenriched chiral centre can be prepared by

reaction of a compound of Formula (1-2), as hereinbefore defined, with a compound of Formula (1-2.Ia) in which W ¹ represents a chiral ester group -CO ₂ L ¹ wherein L ¹ represents a chiral auxiliary and thereafter optionally carrying out any conversion Of-CO ₂ L ¹ into -CO ₂ L by standard methods for removal of chiral auxiliaries. Such chiral ester -CO ₂ L ¹ may be derived from a chiral alcohol L ¹ OH, for example menthol, by standard esterification techniques. Preferably, the reaction of a compound of Formula (1-2) with a compound of Formula (1-2.Ia) is carried out in an aprotic solvent, for example THF or acetonitrile, optionally in the presence of a Lewis acid catalyst, such as lithium bromide or silver acetate, and a base, such as triethylamine, DBU or tetramethyl guanidine. Alternatively, the reaction is carried out in an aprotic solvent, for example THF or acetonitrile, in the presence of an acid, such as acetic acid, or the reaction may be carried out by heating compounds of Formula (1-2) and (1-2.Ia) in a suitable solvent, for example toluene, xylene or acetonitrile in the absence of a catalyst. The preparation of compounds analogous to those of Formula (1-2.1 a) and (l-3a) is described in Tetrahedron: Asymm., 20 (1995), 6, 2475.

In a further aspect, a chiral pyrrolidine compound of Formula (l-3b) in Scheme 3

Scheme 3 in which W represents -CO ₂ L wherein L represents hydrogen or alkyl, and M, Z, X, and J are as defined above for Formula (I), and * denotes an enantioenriched chiral centre can be prepared by reaction of a compound of Formula (1-2) with a compound of Formula (1-2.Ib) as herein before defined, under asymmetric reaction conditions. It will be appreciated by those skilled in the art that such asymmetric reaction conditions may be afforded by, for example, the inclusion in the reaction mixture of a chiral catalytic reagent as herein before defined.

In one aspect, the reaction is carried out in the presence of a suitable chiral catalytic reagent, for example (-)-N-methylephedrine, and a suitable metal salt, for example manganese (II) bromide, in a suitable solvent, for example acetonitrile.

Preferably the reaction is carried out at a temperature in the range -30 ⁰ C to room temperature, suitably at -20 ⁰ C.

In an alternative aspect, the reaction is carried out in the presence of a suitable chiral catalytic reagent, for example (5)-BINAP, and a suitable metal salt, for example silver acetate, in the presence of a suitable base, for example diisopropylethylamine, in a suitable solvent, for example acetonitrile optionally co- solvated with toluene. Preferably the reaction is carried out at a temperature in the range -15°C to room temperature, suitably at -5°C.

Optionally, the major chiral diastereoisomer of a compound of Formula (1- 3 a) or Formula (l-3b) arising from such an asymmetric reaction may be further enantio-enriched by conventional purification techniques well known in the art, for example by chromatography, or by fractional crystallization. A favourable crystallization method is the fractional crystallization of a salt of the major chiral diastereoisomer, for example the hydrochloride salt or the (R)-(-)-l,l '-binaphthyl- 2,2'-diyl-hydrogen phosphate salt. The hydrochloride salt of a compound of Formula (l-3a) or Formula (l-3b) may be prepared by treating a compound of Formula (l-3a) or Formula (l-3b) with anhydrous hydrogen chloride in a suitable solvent, for example diethyl ether. Preferably the reaction is carried out at a temperature in the range -10 to 10 ⁰ C. The (R)-(-)-l,l '-binaphthyl-2,2'-diyl- hydrogen phosphate salt of a compound of Formula (l-3a) or Formula (l-3b) may be prepared as herein before described for the resolution of a racemic compound of Formula (1-3).

Optional removal of a chiral auxiliary from a group in which W ¹ represents -CO ₂ L ¹ to afford a group in which W ¹ represents -CO ₂ L is readily accomplished by standard methods, for example treatment with a hydrolytic reagent such as sodium hydroxide or an alkoxide such as sodium methoxide as appropriate, in a suitable solvent such as methanol.

Optionally as shown in Scheme 4, a chiral compound of Formula (4-1) may be converted into a chiral compound of Formula (4-2) in which T represents W or W ¹ , and M, Z, X, and J are as defined above for Formula (I) by the conditions described above for Scheme 1. Compound (4-2) may be treated with a suitable reagent for accomplishing the functional group interconversion of the group Y. For example a compound of Formula (4-2) may be treated with a suitable reducing

agent, for example lithium aluminium hydride or sodium borohydride, in a suitable solvent, for example tetrahydrofuran or a combination of methanol and ethanol, to give the primary alcohol (4-3). The latter may be alkylated to give compound (4-4) in which R is Ci-Cg alkyl with a suitable alkylating reagent such as but no t limited to methyl iodide, cyclopropylmethyl bromide, propargyl bromide, benzyl chloride, crotonyl bromide, or the like, in the presence of a suitable base such as but not limited to sodium hydride, sodium hydroxide, triethylamine, 2,6-dimethylpyridine, potassium carbonate, lithium t-butoxide, or the like, in a suitable solvent, for example DMF, THF, CH ₂ Cl ₂ , acetonitrile, at -2O ⁰ C to 100 ⁰ C, optionally in the presence of water and a suitable phase transfer catalyst such as but not limited to tetrabutylammonium iodide, trimethylcetyl chloride, triethylbenzylammonium chloride, or the like. The alcohol (4-3) can also be oxidized to aldehyde (4-5) with a suitable reagent, for example Dess-Martin Periodinane. It is well known in the art that an aldehyde may be further derivatized in many ways. For example, compound (4-5) reacts with a hydroxylamine (Ri-O-NH ₂ ) to afford an oxime (4-6) in a variety of mild conditions.

4-6 4-5 4-4

Optionally, formation of a spirocyclic moiety can be achieved using known chemistry in the art. For instance as in Scheme 5 for synthesis of some of the compounds of the second principle embodiment, wherein M, Q, Z, and J are as previously defined in the second principle embodiment of the invention unless otherwise defined, when A and B are both hydroxy or when one of A or B is a hydroxy and the other is thiol or amino, spirocyclic ether, sulfide and amine can be formed using hydroxy activating agent such as p-toluenesulfonyl chloride or methylsufonyl chloride. Spirocyclic carbonate, carbamate and urea can be

prepared when A and B are independently selected from hydroxy or amine with reagents such as phosgene, CDI or palladium catalyzed reaction under sealed tube with carbon monoxide. Cyclic ester and amide formation can be achieved via Mitsunobu reaction or with a carboxylate activating reagent such as BOP, HATU, DCC, EDC, or HOBT in a presence of a suitable base when A or B is a hydroxy and the other is a carboxylate. Spirocyclic sulfmyl urea can be formed when A and B are both amino in the presence of thionyl chloride and the like. The sulfmyl urea can be further converted to sulfonyl urea via further oxidation. The spirocyclic alkene can be formed when A and B are alkene via olefin metathesis and the spirocyclic methylene dioxy can be made with paraformaldehyde in the presence of an acid such as p-toluenesulfonic acid.

Scheme 5

A and B are independently selected V is selected from O, S, NH, OC(O)O, from: OH, NH ₂ , NHCOR ₁ , COR ₁ , CO ₂ R ₁ , NHC(O)O, NHC(O)NH, NHS(O)NH, CH=CH ₂ , alkyne NHSO ₂₁ NH, OC(O), NHC(O), CH=CH, q is 0 to 4 alkyne, OCH ₂ O, OSO ₂ and OSO ₂ CH ₂ CO r is 1 to 5

J, M, Q and Z are as previously defined

Optionally as shown in Scheme 6, a chiral compound of Formula (6-1) may be converted into a chiral compound of Formula (6-2) in which Ui represents halogen, Wi represent hydrogen, and M, Z, X, Y, and J are as previously defined in the fourth principle embodiment of the invention unless otherwise defined. Compound (6-2) may be treated with a suitable reagent to accomplish the functional group interconversion of the group W. For example a compound of Formula (6-2) may be treated with a suitable nucleophile, for example water, in the presence of a base such as but not limited to K2CO3, CaCO ₃ , NaOH, KOH, or the like, or in the presence of an activating metal salt such as but not limited to AgCN, AgClO ₄ , AgBF ₄ , or the like, or in the presence of an acid such as but not limited to p-TsOH, TfOH, or the like, in a suitable solvent, for example tetrahydrofuran, DMSO, dioxane or DMF, to give alcohol (6-3). The latter may be oxidized to give ketone (6-4) with a suitable reagent, for example Dess-Martin Periodinane. It

is well known in the art that a ketone may be further derivatized in many ways. For example, compound (6-4) reacts with a hydroxylamine (Ri-O-NH ₂ ) to afford an oxime (6-5) in a variety of mild conditions; or compound (6-4) reacts with a substituted or unsubstituted hydrazine (H ₂ N-NRiR ₂ ) to generate a hydrazone (6- 6); or ketone (6-4) is converted to substituted or unsubstituted alkene (6-7) by the methods of Wittig olefination, Tebbe olefϊnatin, Lawrence olefmation, or the like. The alkene (6-7) reacts with carbene generating reagents to form the cyclopropane compound (6-8).

Optionally as shown in Scheme 7, wherein Xi is a halogen, carbon or heteroatom-centered group, LG and LG' are as defined in Scheme 1, M, Q, Z, X, Y, U, W and J are as previously defined in the fifth principle embodiment of the invention unless otherwise defined, the intermediate (7-4) may be prepared following similar procedures described in Scheme 1. It may be necessary to convert intermediate (7-4) to (7-5, wherein X ₂ is a carbon or heteroatom-centered group, such as but not limited to bromomethyl, methanesulfonylmethyl, hydroxy, methylamino, acetamino, 3-acetoxy-l-propen-l-yl, or the like) through one-step or steps of functional group manipulation, which are known in the art, including but not limited to oxidation, reduction, protection, deprotection, hydrogenation, alkylation, hydrolysis, activation, Wittig olefination, substitution, elimination, or the like. Intermediate (7-5) can then be converted to the compound of the

invention through an intramolecular cyclization of a moiety from C4-position to C5-position of the pyrrolidine ring, some examples are detailed in Scheme 8.

Scheme 7

Scheme 8 describes methods that can be used to promote the intramolecular cyclization from C4 to C5 of the pyrrolidine core. The C5-proton of intermediate (8-1, wherein E is a carbon or heteroatom centered moiety; q is an integer from 1 to 6, and LG is as defined previously) is extracted by a base which can be added externally or generated internally from the LG-group, and optionally in the presence of a transitional metal catalyst such as but not limited to Pd(PPtLs) ₄ , Pd ₂ (dba) ₃ , Pd(OAc) ₂ , or the like; and a ligand such as but not limited to dppb, AsPh ₃ , tris-(2-furyl)phosphine, trimethyl phosphite, or the like, in an aprotic solvent such as but not limited to THF, DMF, acetonitrile, toluene, or the like, at temperature typically from -2O ⁰ C to refluxing depending on the solvent used, for a period of time from 1 hour to 5 days. The externally added base includes but not limited to DBU, LDA, sodium hydride, potassium hydride, DMAP, or the like. The carbanion thus generated at C5 can attack a moiety at C4 in a nucleophilic fashion which is known in the art to form a carbon-carbon or carbon-heteroatom bond in (8-2) with departure of the LG group. Optionally this intramolecular cyclization process can happen with an expansion of forming ring size in the presence of an alkylating reagent (8-1.1, wherein LGi and LG ₂ are each independently LG, Ei is independently E and r is independently q) such as but not limited to 1,3- dichloroacetone, 3-chloro-2-chloromethyl-l-propene, 2-bromomethyl-oxirane, carbonic acid 2-t-butoxycarbonyloxymethyl-allyl ester t-butyl ester, carbonic acid 4-£-butoxycarbonyloxy-but-2-enyl ester t-butyl ester, or the like.

Scheme 8

8-1 8-2

E ₂ = E or E-E ₁

8-1 ,* 1 ** /

8-3

Optionally as shown in Scheme 9, a substituent of a chiral compound of Formula (9-1) may be converted into a chiral compound of Formula (9-2) in which X represents hydrogen, in which V is -CO ₂ L wherein L represents hydrogen or alkyl and V ¹ represents -CO ₂ L ¹ , M, Q, Z, W and J are as previously defined in the seventh principle embodiment of the invention unless otherwise defined. The primary alcohol (9-2) may be further manipulated to accomplish the functional group interconversions. For example a compound of Formula (9-2) may be treated with certain suitable selenium species to generate the corresponded organoselenium compound, which can be further converted into alkene (9-3) after oxadative elimination. Alkene (9-3) may be transformed to substituted or unsubstituted spirocyclopanes (9-4) through different carbene additions. Also, alkene (9-3) can be epoxidized to form the spiroepoxide (9-6) in a variety of mild conditions, such as but not limited to mCPBA, DMDO, H ₂ O ₂ , or the like. In addition, alkene (9-3) can be oxidized to diol (9-5) in various dihydroxylation conditions, which can be further transformed into the cyclic compound (9-8). Alkene (9-3) can be also ozonolyzed to generate ketone (9-7). It is well known in the art that a ketone may be further derivatized in many ways. For example, compound (9-7) reacts with a hydroxylamine (Ri-O-NH ₂ ) to afford an oxime (9-9) in a variety of mild conditions; or compound (9-7) reacts with a substituted or unsubstituted hydrazine (H ₂ N-NRiR ₂ ) to generate a hydrazone (9-10).

Scheme 9

It will be appreciated that, with appropriate manipulation and protection of any chemical functionality, synthesis of compounds of the present invention is accomplished by methods analogous to those above and to those described in the Experimental section. Suitable protecting groups can be found, but are not restricted to, those found in T W Greene and P G M Wuts "Protective Groups in Organic Synthesis", 3rd Ed (1999), J Wiley and Sons.

EXAMPLES The compounds and processes of the present invention will be better understood in connection with the following examples, which are intended as an illustration only and not limiting of the scope of the invention. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art and such changes and modifications including, without limitation, those relating to the chemical structures, substituents, derivatives, formulations and/or methods of the invention may be made without departing from the spirit of the invention and the scope of the appended claims.

Although the invention has been described with respect to various preferred embodiments, it is not intended to be limited thereto, but rather those skilled in the art will recognize that variations and modifications may be made therein which are within the spirit of the invention and the scope of the appended claims.

With respect to each principle embodiment of the invention, the original formulae numbers from its respective priority document has been retained and corresponds to the subsection referenced above. As such, it will be seen that a plurality of formulae have the number (Ia), for example. However, it should be understood that where it appears with respect to a first, second, third, etc. principle embodiment, the formula refers to the specific subsection set forth above.

I. First Principle Invention

Example 1. Compound of Formula (Ia), wherein M = ferf-butoxyl, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxycarbonyl, J = lH-pyrazol-1-ylmethyl.

Step Ia. Into a suspension of commercially available l-carboxy-2-pyrazol-l-yl- ammonium chloride (958 mg, 1.0 mmol) in t-butyl acetate (30.0 mL) was added perchloric acid (70%, 0.50 mL, 5.8 mmol). The mixture was stirred at room temperature for 64 hours before being diluted with ethyl acetate and neutralized with a combination of solid NaHCO ₃ and saturated NaHCO ₃ until no gas evolved. After separation, the aqueous was saturated with sodium chloride and extracted with ethyl acetate. The combined organics were dried (Na ₂ SO ₄ ) and evaporated to give the crude product (617 mg, 45.5%). ESIMS m/z = 212.12 [M+H] ⁺ of the free base parent ion.

¹³ C NMR (CDCl ₃ ) 175.7, 171.1, 140.1, 130.5, 105.6, 82.6, 55.1, 54.2, 27.9. Step Ib. Into a suspension of commercially available l-carboxy-2-pyrazol-l-yl- ammonium chloride (958 mg, 1.0 mmol) in t-butyl acetate (30.0 mL) was added perchloric acid (70%, 0.76 mL, 8.8 mmol). The mixture was stirred at room temperature for 22 hours before being diluted with ethyl acetate and neutralized with a combination of solid NaHCO ₃ and saturated NaHCO ₃ to pH ~ 8. After separation, the aqueous was saturated with sodium chloride and extracted with ethyl acetate. The combined organics were dried (Na ₂ SO ₄ ) and evaporated to give the crude product (633 mg, 60%). ESIMS m/z = 212.14 [M+H] ⁺ .

Step Ic. A mixture of the compound from step Ia (205 mg, 0.75 mmol), commercially available 2-formyl-l,3-thiazole (120 mg, 1.06 mmol), and activated molecular sieves (4A, 1.0 g) in anhydrous methylene chloride (5 mL) was stirred at room temperature for 15 hours before being filtered through Celite and washed

with methylene chloride. The combined organics were evaporated and the residue was used directly for next step. ESIMS m/z = 307.13 [M+H] ⁺ .

Step Id. A mixture of the compound from step Ib (160 mg, 0.76 mmol), commercially available 2-formyl-l,3-thiazole (151 mg, 1.34 mmol), and activated molecular sieves (4 A, 1.0 g) in anhydrous methylene chloride (5 mL) was stirred at room temperature for 15 hours before being filtered through Celite and washed with methylene chloride. The combined organics were evaporated and the residue was chromatographed (silica, hexanes-EtOAc) to give the desired compound (200 mg, 86%).

ESIMS m/z = 307.12 [M+H] ⁺ .

¹³ C NMR (CD ₃ OD) 168.2, 166.2, 159.0, 144.1, 139.8, 131.4, 123.3, 105.4, 82.7,

72.3, 53.1, 27.1.

Step Ie. Into a mixture of the crude compound from step Ic (0.75 mmol at most) in THF (5 mL) was added commercially available methyl 2-fluoroacrylate (156 mg, 1.5 mmol), lithium bromide (130 mg, 1.5 mmol), and Et ₃ N (0.21 mL, 1.5 mmol). The resulted mixture was stirred at room temperature for 17 hours before being partitioned (EtO Ac- water). The organics were washed with water, brine, dried (Na ₂ SO ₄ ), and evaporated. The residue was chromatographed (silica, hexanes-EtOAc) to give the desired compound (201 mg, 64.8% two steps). ESIMS m/z = 411.08 [M+H] ⁺ .

¹³ C NMR (CDCl ₃ ) 171.7, 168.9, 168.0, 143.4, 140.0, 131.1, 120.2, 105.9, 102.6, 82.9, 69.5, 68.1, 58.4, 52.9, 41.3, 28.1. Step If. A mixture of the commercially available 4-t-butyl-3-methoxybenzoic acid (2.082 g, 10.0 mmol) in thionyl chloride (5.0 mL) was refluxed for 2.5 hours before being evaporated. Toluene (twice) was added to the residue and the mixture was evaporated. The residue was dried in vacuum to get a crystalline (2.258 g, 99.6%). Step Ig. Into a mixture of the compound from step Ie (190 mg, 0.46 mmol) in CH ₂ Cl ₂ (5.0 mL) was added Et ₃ N (0.13 mL, 0.93 mmol) and the compound from step If (158 mg, 0.70 mmol). The resulted mixture was stirred at room temperature for 64 hours before being diluted with EtOAc. The organics were washed with saturated NaHCO ₃ , water, brine, dried (Na ₂ SO ₄ ), and evaporated. The residue was

chromatographed (silica, hexanes-EtOAc) to give the desired compound (114 mg, 41.0%) and the recovered compound from step Ie (98 mg, 52%). ESIMS m/z = 601.02 [M+H] ⁺ .

¹³ C NMR (CDCl ₃ ) 170.3, 169.4, 166.0, 158.7, 142.1, 141.0, 139.6, 134.5, 132.1, 127.0, 121.1, 118.7, 110.4, 105.8, 102.0, 83.2, 70.8, 69.6, 55.3, 53.5, 53.0, 39.7, 35.2, 29.7, 28.2.

Alternatively the compound of example 1 could be prepared through step Ih to Ij. Step Ih. Into a mixture of the crude compound from step Ic (1.34 mmol at most) in THF (5 mL) was added methyl acrylate (0.24 mL, 2.68 mmol), lithium bromide (232 mg, 2.68 mmol), and Et ₃ N (0.37 mL, 2.65 mmol). The resulted mixture was stirred at room temperature for 14 hours before being partitioned (EtO Ac-water). The organics were washed with water, brine, dried (Na ₂ SO ₄ ), and evaporated. The residue was chromatographed (silica, hexanes-EtOAc) to give the desired compound (255 mg, 48.6%). ESIMS m/z = 393.12 [M+H] ⁺ .

¹³ C NMR (CDCl ₃ ) 172.6, 171.5, 170.8, 142.5, 139.5, 131.0, 119.0, 105.7, 82.4, 69.7, 61.7, 59.4, 51.7, 48.6, 34.2, 27.9. Step Ii. Into a mixture of the compound from step Ih (240 mg, 0.61 mmol) in CH ₂ Cl ₂ (5.0 mL) was added Et ₃ N (0.28 mL, 2.0 mmol) and the compound from step If (227 mg, 1.0 mmol). The resulted mixture was stirred at room temperature for 19 hours before being diluted with EtOAc. The organics were washed with saturated NaHCO ₃ , water, brine, dried (Na ₂ SO ₄ ), and evaporated. The residue was chromatographed (silica, hexanes-EtOAc) to give the desired compound (277 mg, 77.8%).

ESIMS m/z = 583.16 [M+H] ⁺ .

¹³ C NMR (CDCl ₃ ) 170.0, 167.6, 158.6, 141.6, 140.6, 140.5, 134.8, 131.5, 126.9,

120.3, 118.0, 110.0, 106.5, 82.9, 70.1, 62.2, 55.1, 53.7, 52.0, 46.3, 35.6, 35.1, 29.7,

28.2. Step Ij. Into a solution of LDA [made from n-BuLi (2.5 M in hexanes, 16.0 μL, 40 μmol) and diisopropylamine (5.6 μL, 40 μmol) in THF (1.0 mL) was added a solution of the compound from step Ii (5.8 mg, 10 μmol) in THF (1.0 mL) at - 78 ⁰ C. It was warmed up to room temperature. The mixture was re-cooled to -78 ⁰ C

when JV-fluorobenzenesulfonimide (12.6 mg, 40 μmol) was added in THF (0.5 niL). The title compound was detected in 5 min by ESIMS m/z = 601.13 [M+H] ⁺ . Example 2. Compound of Formula (Ia), wherein M = ferf-butoxy, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = hydroxymethyl, J = 1 H-pyrazol- 1 -ylmethyl.

A mixture of the compound from step Ig (100 mg, 0.17 mmol) in ethanol (4.75 mL) and methanol (0.25 mL) was treated with NaBH ₄ (25 mg, 0.66 mmol) at room temperature with stirring for 22 hours before partition EtO Ac/water. The organics were washed with water, brine, dried (Na ₂ SO ₄ ), and evaporated to give the title compound (94 mg, 98.6%). ESIMS m/z = 573.23 [M+H] ⁺ .

¹³ C NMR (CDCl ₃ ) 170.4, 169.9, 167.2, 158.5, 142.5, 140.7, 139.7, 134.6, 132.4, 126.7, 120.8, 118.6, 110.2, 105.6, 105.3, 83.4, 71.1, 70.0, 63.9, 55.2, 53.5, 39.3, 35.1, 29.7, 28.3. Example 3. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-ferf-butyl- 3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = hydroxymethyl, J = IH- pyrazol- 1 -ylmethyl.

A mixture of the compound from example 2 (6.0 mg) in CH ₂ Cl ₂ (0.5 mL) and TFA (0.5 mL) was stood at room temperature for 4 hours. The volatile was evaporated off by a slow stream of nitrogen. The residue was chromaographed (silica, CH ₂ Cl ₂ - MeOH) to a 3.5:1 mixture of the title compound and its trifluoroacetate ester (6.3 mg). ESIMS m/z = 517.08 [M+H] ⁺ for the title compound, 613.13 [M+H] ⁺ for the trifluoroacetate of the title compound. A solution of the above mixture in methanol (4.0 mL) was microwaved (Biotage Initiator, 15O ⁰ C, 10 minutes) before evaporation to give the title compound (5.4 mg, 100%).

ESIMS m/z = 517.07 [M+H] ⁺ .

¹³ C NMR (CDCl ₃ ) 171.5, 170.9, 169.0, 158.8, 141.15, 141.08, 139.7, 133.9, 133.1, 126.9, 122.2, 117.7, 109.3, 105.9, 105.3, 70.4, 69.0, 63.2, 55.3, 54.7, 37.8, 35.2, 29.6.

Example 4. Compound of Formula (Ia), wherein M = tert-butoxy, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, J = 1 H-pyrazol- 1 -ylmethyl.

A mixture of the compound from example 2 (20 mg, 34.9 μmol), tetrabutylammnium iodide (2.5 mg, 6.7 μmol) in methyl iodide (1.0 mL) was treated with sodium hydroxide (50% in water, 5.0 mL) at room temperature for 4.5 hours before being partitioned (EtO Ac- water). The organics were washed with water, brine, dried (Na ₂ SO ₄ ), and evaporated. The residue was chromatographed (silica, hexanes-EtOAc; then reverse phase HPLC, ODS, MeCN and 20 mM NH ₄ HCO ₃ ) to give the title compound (11 mg). ESIMS m/z = 587.23 [M+H] ⁺ . 1 ³ C NMR (CDCl ₃ ) 170.4, 169.8, 165.7, 158.5, 142.1, 140.5, 138.9, 134.8, 133.0, 126.7, 120.6, 118.4, 109.9, 105.4, 103.3, 83.2, 73.0, 72.9, 70.6, 69.5, 59.7, 55.2, 53.8, 39.9, 35.1, 29.7, 28.3.

Example 5. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butγ\- 3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, J = IH- pyrazol- 1 -ylmethyl. A solution of the compound of example 4 (11 mg) in dichloromethane (1 mL) was treated TFA (1 mL) at room temperature for 2.5 hours and the volatiles were removed by N ₂ flow. The residue was purified by flash column chromatography (silica, CH ₂ Cl2-methanol) to give the title compound (6.2 mg, 63%) as a light yellow film. ESIMS m/z = 531.04 [M+H] ⁺ .

¹³ C NMR (CD ₃ OD) 172.7, 171.7, 168.5, 158.6, 140.7, 140.5, 139.1, 132.9, 126.5,

122.7, 117.8, 109.1, 105.5, 71.9, 71.7, 69.8, 58.3, 54.4, 54.2, 54.2, 38.7, 34.7, 29.3,

28.7.

Example 6. Compound of Formula (Ia), wherein M = tert-butyl, Q = 4-tert-butyl- 3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = carbamoyl, J = IH- pyrazol- 1 -ylmethyl.

A solution of the compound from example 1 (9.9 mg) in methanolic ammonia (7N, 3.0 mL) was stirred at room temperature for 23 hours before being evaporated to give the title compound (8.8 mg, 92%). ESIMS m/z = 586.15 [M+H] ⁺ .

¹³ C NMR (CDCl ₃ ) 170.1, 169.5, 167.2, 166.6, 158.3, 141.8, 140.2, 139.8, 134.3, 132.5, 126.5, 121.4, 118.1, 109.9, 105.8, 104.5, 84.1, 72.2, 70.7, 55.1, 53.6, 39.9, 35.0, 29.6, 28.5.

Example 7. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butγ\- 3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = carbamoyl, J = IH- pyrazol- 1 -ylmethyl. A solution of the compound of example 6 (8.8 mg) in dichloromethane (1 mL) was treated TFA (1.5 mL) at room temperature for 5 hours and the volatiles were removed by N ₂ flow. The residue was purified by flash column chromatography (silica, CH ₂ Cl ₂ -methanol) to give the title compound (7.5 mg, 94%) as an off- white solid. ESIMS m/z = 530.02 [M+H] ⁺ .

¹³ C NMR (CD ₃ OD) 172.5, 171.6, 167.6, 158.6, 140.6, 139.4, 133.9, 132.9, 126.5, 122.5, 117.8, 109.2, 105.6, 70.3, 70.0, 69.9, 54.4, 53.7, 39.4, 34.6, 28.7. Example 8. Compound of Formula (Ia), wherein M = tert-butyi, Q = 4-tert-buty{- 3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = 2,2,2- trichloroacetylcarbamoyloxymethyl, J = lH-pyrazol-l-ylmethyl.

Into a solution of the compound from example 2 (10.3 mg, 18 μmol) and triethylamine (5.0 μL, 36 μmol) in CH ₂ Cl ₂ (1.0 mL) was treated with trichloroacetyl isocyanate (3.2 μL, 27 μmol) with stirring at room temperature for 50 minutes before more triethylamine (20 μL) and trichloroacetyl isocyanate (4.8 μL) were charged. It was stirred for another 1 hour before being partitioned

(EtO Ac-saturated NaHCO ₃ ). The organics were washed with water, brine, dried

(Na ₂ SO ₄ ), and evaporated to give the crude title compound.

ESIMS m/z = 760.03/762.03 [M+H] ⁺ .

Example 9. Compound of Formula (Ia), wherein M = tert-butyi, Q = 4-tert-butyi- 3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = carbamoyloxymethyl, J = 1 H-pyrazol- 1 -ylmethyl.

A solution of the crude compound from example 8 in methanol (4.0 mL) was microwaved (Biotage Initiator, 15O ⁰ C, 10 minutes) before evaporation, giving the crude title compound (10.7 mg) as a light-yellow film. ESIMS m/z = 616.07 [M+H] ⁺ .

Example 10. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyi- 3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = carbamoyloxymethyl, J = 1 H-pyrazol- 1 -ylmethyl.

A solution of the compound of example 9 (10.7 mg) in dichloromethane (1 mL) was treated TFA (1.5 mL) at room temperature for 5 hours and the volatiles were removed by evaporation. The residue was purified by preparative TLC (silica, CH ₂ Cl ₂ -MeOH) to give the title compound (3.7 mg). ESIMS m/z = 560.02 [M+H] ⁺ .

Example 11. Compound of Formula (Ia), wherein M = tert-butyi, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = Me, Y = methoxycarbonyl, J = 1 H-pyrazol- 1 -ylmethyl. Step 11a. Into a mixture of the crude compound from step Id (200 mg, 0.65 mmol) in THF (5 mL) was added lithium bromide (113 mg, 1.3 mmol), methyl methacrylate (130 mg, 1.3 mmol), and Et ₃ N (131 mg, 1.3 mmol). The resulted mixture was stirred at room temperature for 17 hours before being partitioned (EtO Ac-saturated NaHCO ₃ ). The organics were washed with water, brine, dried (Na ₂ SO ₄ ), and evaporated. The residue was chromatographed (silica, hexanes- EtOAc) to give the desired compound (260 mg, 98%). ESIMS m/z = 407.05 [M+H] ⁺ .

¹³ C NMR (CDCl ₃ ) 174.4, 172.7, 167.4, 142.7, 139.4, 131.4, 118.7, 106.1, 82.4, 70.0, 69.8, 59.7, 55.1, 51.8, 44.8, 28.1, 21.9. Step lib. Into a mixture of the compound from step 11a (132 mg, 0.33 mmol) in CH ₂ Cl ₂ (3.0 mL) was added Et ₃ N (0.14 mL, 0.983 mmol) and the compound from step If (158 mg, 0.70 mmol). The resulted mixture was stirred at room temperature for 72 hours before partition (EtO Ac-saturated NaHCO ₃ ). The organics were washed with water, brine, dried (Na ₂ SO ₄ ), and evaporated. The residue was chromatographed (silica, hexanes-EtOAc) to give the title compound (68 mg) and the recovered compound from step l la (70 mg). ESIMS m/z = 597.14 [M+H] ⁺ .

¹³ C NMR (CDCl ₃ ) 174.5, 171.1, 169.2, 167.3, 158.8, 141.5, 139.7, 132.7, 131.8, 126.9, 120.08, 118.8, 118.2, 111.0, 106.4, 82.4, 71.9, 69.9, 55.3, 53.8, 52.1, 41.4, 35.3, 29.8, 28.4, 25.1. Example 12. Compound of Formula (Ia), wherein M = tert-butyi, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = methoxycarbonylmethyl, Y = methoxycarbonyl, J = lH-pyrazol-l-ylmethyl.

Step 12a. A mixture of the compound from step Id (100 mg, 0.33mmol), lithium bromide (57 mg, 0.66 mmol), 2-methylene succinic acid dimethyl ester (104 mg,

0.66 mmol) and Et ₃ N (0.1 niL) in THF (2.5 niL) was stirred under nitrogen at room temperature for 17 hours before being quenched with saturated aqueous NaHCO ₃ (5 mL). The aqueous layer was separated and extracted with EtOAc (3 X 5 mL). The combined organics were washed with brine (5 mL), dried by Na ₂ SO ₄ , filtered and evaporated. The residue was purified by flash column chromatography (silica, hexane-ethyl acetate) to give the desired compound as a colorless oil (120 mg, 79%).

ESIMS m/z = 465.05 [M+H] ⁺ . 1 ³ C NMR (CDCl ₃ ) 172.6, 172.5, 171.7, 166.4, 143.1, 139.6, 131.7, 118.9, 106.2, 82.6, 69.7, 68.6, 59.5, 57.1, 52.1, 52.0, 43.4, 40.6, 28.2.

Step 12b. A solution of the compound from step 12a (120 mg, 0.26 mmol), Et ₃ N (0.14 mL, 0.98 mmol) and 4-tert-butyl-3-methoxy-benzoyl chloride (111 mg, 0.49 mmol) in anhydrous dichloromethane (3 mL) was stirred at room temperature under nitrogen for 96 hours before being quenched with saturated aqueous NaHCO ₃ (5 mL). The aqueous layer was separated and extracted with EtOAc (3 X 5 mL). The combined organics were washed with brine (10 mL), dried (Na ₂ SO ₄ ), and evaporated. The residue was purified by flash column chromatography (silica, hexanes-ethyl acetate) to give the title compound as a light yellow oil (55 mg) with recovery of the compound of step 12a (60 mg). ESIMS m/z = 655.11 [M+H] ⁺ .

¹³ C NMR (CDCl ₃ ) 171.8, 171.2, 170.5, 169.1, 167.9, 158.3, 141.5, 140.0, 140.3, 135.2, 132.8, 126.3, 120.4, 118.5, 110.7, 106.0, 82.7, 72.4, 70.6, 55.6, 55.2, 53.5, 52.4, 52.1, 42.7, 41.3, 35.1, 29.6, 28.3. Example 13. Compound of Formula (Ia), wherein M = tert-butyi, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = 2-hydroxyethyl, Y = hydroxymethyl, J = lH-pyrazol-1-ylmethyl.

A solution of the compound from step 12b (50 mg, 0.076 mmol) in anhydrous THF was treated with lithium borohydride (17 mg, 0.76 mmol) with stirring under N ₂ for 18 hours before it was quenched with K ₂ CO ₃ solution (2M in water, 1 mL). The aqueous layer was separated and extracted with EtOAc (3 X 5 mL). The combined organic layers were dried by Na ₂ SO ₄ , filtered and evaporated. The residue was purified by flash column chromatography (silica, hexanes-ethyl acetate) to afford the title compound (23 mg) as a colorless oil. ESIMS m/z = 599.08 [M+H] ⁺ .

¹³ C NMR (CDCl ₃ ): 170.8, 170.3, 169.2, 157.9, 141.5, 140.2, 140.0, 135.3, 133.3,

126.1, 120.0, 119.1, 110.7, 105.8, 83.1, 71.9, 71.6, 65.0, 58.9, 55.2, 52.9, 49.9,

40.4, 40.3, 35.0, 29.6, 28.3.

Example 14. Compound of Formula (Ia), wherein M = tert-butyl, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = chloro, Y = methoxycarbonyl, J

= lH-pyrazol-1-ylmethyl.

Step 14a. A solution of the compound from step Id (51 mg, 0.17 mmol), lithium bromide (30 mg, 0.34 mmol), 2-chloro-acrylic acid methyl ester (41 mg, 0.34 mmol) and Et ₃ N (0.05 mL) in THF (2 mL) was stirred under nitrogen at room temperature for 17 hours before being quenched with saturated aqueous NaHCO ₃

(3 mL). The aqueous layer was separated and extracted with EtOAc (3 X 3 mL).

The combined organics were washed with brine (5 mL), dried by Na ₂ SO ₄ , filtered and evaporated. The residue was purified by flash column chromatography (silica, hexanes-ethyl acetate) to give the desired compound as a colorless oil (70 mg, 100%).

ESIMS m/z = 427.06/429.06 [M+H] ⁺ .

¹³ C NMR (CDCl ₃ ): 171.9, 168.7, 165.0, 142.7, 139.7, 131.2, 119.8, 106.1, 83.0,

72.7, 71.0, 69.2, 59.7, 53.2, 46.1, 28.2.

Step 14b. The title compound is prepared from the compounds from step 15a and If following a similar procedure to that described in step Ig.

Example 15. Compound of Formula (Ia), wherein M = tert-butyi, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = acetamido, Y = methoxycarbonyl, J = lH-pyrazol-l-ylmethyl.

Step 15a. Into a mixture of the crude compound from step Ic (113 mg, 0.369 mmol at most) in THF (5 mL) was added lithium bromide (97.4 mg, 1.11 mmol), methyl 2-acetamidoacrylate (106 mg, 0.738 mmol), and Et ₃ N (113 mg, 1.11 mmol). The resulted mixture was stirred at room temperature for 12 hours before quenched with 2ml sat. NH ₄ Cl. The mixture was diluted with EtOAc and the organics were washed with water, brine, dried (Na ₂ SO ₄ ), and evaporated. The residue was chromatographed (silica, EtOAc then CH ₂ Cl ₂ -MeOH) to give 112 mg of the desired compound as a light yellow oil.

ESIMS m/z = 450.00 [M+H] ⁺ .

¹³ C NMR (CDCl ₃ ) 171.8, 171.2, 170.8, 166.5, 143.1, 139.4, 131.0, 119.3, 105.8,

82.6, 69.6, 69.4, 65.5, 58.8, 52.7, 43.0, 28.0, 23.9.

Step 15b. The title compound is prepared from the compounds from step 15a and If following a similar procedure to that described in step Ig. Example 16. Compound of Formula (Ia), wherein M = tert-butyl, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = Me, Y = hydroxymethyl, J = 1 H-pyrazol- 1 -ylmethyl.

Into a solution of the compound from step 1 Ib (53.2 mg, 88.9 μmol) in THF (5 mL) at -78 ⁰ C under N ₂ was charged LiAlH ₄ (1.0 M in Et ₂ O, 0.1 mL). After the addition, the mixture was warmed up to -40 ⁰ C. It was kept at this temperature for 8 hours while additional LiAlH ₄ solution was added (3 X 0.03 mL). The reaction was quenched with (K ₂ CO ₃ , 1 M, 2.5 mL) and the mixture was diluted with EtOAc. The organics were washed with water, brine, dried (Na ₂ SO ₄ ), and evaporated. The residue was chromatographed (silica, hexanes-EtOAc) to give 10.6 mg of the title compound as a light yellow oil. ESIMS m/z = 569.10 [M+H] ⁺ . Example 17. Compound of Formula (Ia), wherein M = tert-butyi, Q = 4-tert- butyl-3-methoxybenzoyl. Z = 1.3-thiazol-2-yl. X = Me. Y = forrnyl. J = IH- pyrazol- 1 -ylmethyl.

Into a solution of the compound from step 1 Ib (53.2 mg, 88.9 μmol) in THF (5 mL) at -78 ⁰ C under N ₂ was charged LiAlH ₄ (1.0 M in Et ₂ O, 0.1 mL). After the addition, the mixture was warmed up to -40 ⁰ C. It was kept at this temperature for 8 hours while additional LiAlH ₄ solution was added (3 X 0.03 mL). The reaction was quenched with (K2CO3, 1 M, 2.5 mL) and the mixture was diluted with EtOAc. The organics were washed with water, brine, dried (Na ₂ SO ₄ ), and evaporated. The residue was chromatographed (silica, hexanes-EtOAc) to give 27.5 mg of the title compound as a light yellow oil. ESIMS m/z = 567.06 [M+H] ⁺ .

Example 18. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyi- 3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = Me, Y = formyl, J = lH-pyrazol-1- ylmethyl. A solution of the compound from example 17 (17.6 mg) in dichloromethane (1.5 mL) was treated TFA (3.0 mL) at room temperature for 8 hours and the volatiles were removed by N ₂ flow. The residue was purified by

flash column chromatography (silica, CH ₂ Cl ₂ -methanol) to give 10.0 mg of the title compound as a white solid.

ESIMS m/z = 511.21 [M+H] ⁺ .

Example 19. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl- 3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = Me, Y = methoxyimino-methyl, J =

1 H-pyrazol- 1 -ylmethyl.

A solution of the compound from step 18 (7.0 mg, 12.4 μmol) in dichloromethane (1.2 mL) was treated with O-methylhydroxylamine hydrochloride

(2.1 mg, 24.7 μmol) at room temperature for 4 hours. It was concentrated and purified by flash column chromatography (silica, CH ₂ Cl ₂ -methanol) to give 6.0 mg of the title compound as a white solid film.

ESIMS m/z = 540.27 [M+H] ⁺ .

Example 20. Compound of Formula (Ia), wherein M = tert-butγl, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = Me, Y = methoxymethyl, J = 1 H-pyrazol- 1 -ylmethyl.

A mixture of the compound from example 16 (10.6 mg, 18.7 μmol), tetrabutylamonium iodide (0.7 mg, 1.9 μmol), methyl iodide (53.0 mg, 0.373 mmol) in 0.5 mL CH ₂ Cl ₂ was treated with sodium hydroxide (50% in water, 1.5 mL) at room temperature for 8 hours before being partitioned (EtO Ac-water). The organics were washed with water, brine, dried (Na ₂ SO ₄ ), and evaporated. The residue was chromatographed (silica, hexanes-EtOAc) to give the title compound

(1.0 mg) as a colorless oil.

ESIMS m/z = 527.06 [M+H] ⁺ .

Example 21. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butγ\- 3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = Me, Y = methoxymethyl, J = IH- pyrazol- 1 -ylmethyl.

The title compound is prepared from the compound from example 20 following a similar procedure to that described in example 18.

Example 22. Compound of Formula (Ia), wherein M = tert-butyi, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = acetoxy, Y = cyano, J = IH- pyrazol- 1 -ylmethyl.

The title compound is prepared from the compound from Ic following a similar procedure to that described in example 15, by replacing methyl 2- acetamidoacrylate with commercially available 2-acetoxyacrylonitrile.

Example 23. Compound of Formula (Ia), wherein M = tert-butyl, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = trifluoromethyl, Y = methoxycarbonyl, J = lH-pyrazol-1-ylmethyl.

The title compound is prepared from the compound from Ic following a similar procedure to that described in example 15, by replacing methyl 2- acetamidoacrylate with commercially available methyl 2-trifluoromethylacrylate. Example 24. Compound of Formula (Ia), wherein M = hydroxy, Q = 3-bromo-4- ferf-butylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, J = IH- pyrazol- 1 -ylmethyl.

The title compound is prepared from the compound from Ic following a similar procedure to that described in examples 1, 2 and 4, by replacing the compound of step If with 3 -bromo-4-te/t-butylbenzoyl chloride (WO

2007/039145).

Example 25. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butγ\-

3-vinylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, J = IH- pyrazol- 1 -ylmethyl. The title compound is prepared from the compound from Ic following a similar procedure to that described in examples 1, 2 and 4, by replacing the compound of step If with 4-te/t-butyl-5-vinylbenzoyl chloride (WO

2007/039143).

Example 26. Compound of Formula (Ia), wherein M = hydroxy, Q = 2-fluoro-4- ferf-butyl-5-vinylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, J

= lH-pyrazol-1 -ylmethyl.

The title compound is prepared from the compound from Ic following a similar procedure to that described in examples 1, 2 and 4, by replacing the compound of step If with 2-fluoro-4-te/t-butyl-5-vinylbenzoyl chloride (WO 2007/039143).

Example 27. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-ferf-butyl-

3-methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, J = 1,3- thiazol-4-ylmethyl.

The title compound is prepared from tert-butyl 2-amino-3-(l,3-thiazol-4- yl)propanoate (WO 2006/045613) and commercially methyl 2-fluoroacrylate following a similar procedure to that described in examples 1, 2 and 4, by replacing the compound of step Ib with tert-butyl 2-amino-3-(l,3-thiazol-4- yl)propanoate.

Example 28. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl- 3-methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, J = 1,3- thiazol-2-ylmethyl.

The title compound is prepared from tert-butyl 2-amino-3-(l,3-thiazol-2- yl)propanoate (WO 2006/045613) and commercially available methyl 2- fluoroacrylate following a similar procedure to that described in examples 1 , 2 and

4, by replacing the compound of step Ib with tert-butyl 2-amino-3-(l,3-thiazol-2- yl)propanoate.

Example 29. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl- 3-methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, J = 1,2- thiazol-3-ylmethyl.

The title compound is prepared from tert-butyl 2-amino-3-(l,2-thiazol-3- yl)propanoate (WO 2006/045613) and commercially available methyl 2- fluoroacrylate following a similar procedure to that described in examples 1 , 2 and 4, by replacing the compound of step Ib with tert-butyl 2-amino-3-(l,2-thiazol-3- yl)propanoate.

Example 30. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl- 3-methoxylbenzoyl, Z = 5-methylisoxazol-3-yl, X = fluoro, Y = methoxymethyl, J = lH-pyrazol-1-ylmethyl. The title compound is prepared from 5-methylisoxazole-3-carboxaldehyde

(WO 2007/039145) following a similar procedure to that described in examples 1, 2 and 4, by replacing 2-formyl-l,3-thiazole with 5-methylisoxazole-3- carboxaldehyde. Example 31. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl- 3-methoxylbenzoyl, Z = thiophen-2-yl, X = fluoro, Y = methoxymethyl, J = IH- pyrazol- 1 -ylmethyl.

The title compound is prepared from commercially available 2- formylthiophene following a similar procedure to that described in examples 1 , 2 and 4, by replacing 2-formyl-l,3-thiazole with 2-formylthiophene.

Example 32. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butγ\-

3-methoxylbenzoyl, Z = thiophen-3-yl, X = fluoro, Y = methoxymethyl, J = IH- pyrazol- 1 -ylmethyl.

The title compound is prepared from commercially available 3- formylthiophene following a similar procedure to that described in examples 1 , 2 and 4, by replacing 2-formyl-l,3-thiazole with 3 -formylthiophene.

Example 33. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyi-

3-methoxylbenzoyl, Z = furan-2-yl, X = fluoro, Y = methoxymethyl, J = IH- pyrazol- 1 -ylmethyl. The title compound is prepared from commercially available 2-formylfuran following a similar procedure to that described in examples 1, 2 and 4, by replacing 2-formyl-l,3-thiazole with 2-formylfuran.

Example 34. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-

3-methoxylbenzoyl, Z = furan-3-yl, X = fluoro, Y = methoxymethyl, J = IH- pyrazol- 1 -ylmethyl.

The title compound is prepared from commercially available 3-formylfuran following a similar procedure to that described in examples 1, 2 and 4, by replacing 2-formyl-l,3-thiazole with 3-formylfuran.

Example 35. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butγ\- 3-methoxylbenzoyl, Z = l,3-oxazol-2-yl, X = fluoro, Y = methoxymethyl, J = IH- pyrazol- 1 -ylmethyl.

The title compound is prepared from commercially available 2- formyloxazole following a similar procedure to that described in examples 1 , 2 and

4, by replacing 2-formyl-l,3-thiazole with 2-formyloxazole. Example 36. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyi-

3-methoxylbenzoyl, Z = phenyl, X = fluoro, Y = methoxymethyl, J = lH-pyrazol-

1 -ylmethyl.

The title compound is prepared from commercially available benzaldehyde following a similar procedure to that described in examples 1, 2 and 4, by replacing 2-formyl- 1 ,3-thiazole with benzaldehyde.

Example 37. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-

3-methoxylbenzoyl, Z = pyridin-2-yl, X = fluoro, Y = methoxymethyl, J = IH- pyrazol- 1 -ylmethyl.

The title compound is prepared from commercially available 2- formylpyridine following a similar procedure to that described in examples 1 , 2 and 4, by replacing 2-formyl-l,3-thiazole with 2-formylpyridine. Example 38. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl- 3-methoxylbenzoyl, Z = pyridin-3-yl, X = fluoro, Y = methoxymethyl, J = IH- pyrazol- 1 -ylmethyl.

The title compound is prepared from commercially available 3- formylpyridine following a similar procedure to that described in examples 1 , 2 and 4, by replacing 2-formyl-l,3-thiazole with 3-formylpyridine. Example 39. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butγ\- 3-methoxylbenzoyl, Z = pyridin-4-yl, X = fluoro, Y = methoxymethyl, J = IH- pyrazol- 1 -ylmethyl.

The title compound is prepared from commercially available 4- formylpyridine following a similar procedure to that described in examples 1 , 2 and 4, by replacing 2-formyl- 1 ,3-thiazole with 4-formylpyridine.

Example 40. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyi- 3-methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, J = thiophen-2-yl.

The title compound is prepared from commercially available C-carboxy-C- thiophen-2-yl-methyl-ammonium chloride following a similar procedure to that described in examples 1, 2 and 4, by replacing l-carboxy-2-pyrazol-l-yl- ammonium chloride with C-carboxy-C-thiophen-2-yl-methyl-ammonium chloride. Example 41. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-ferf-butyl- 3-methoxylbenzoyl, Z = thiazol-2-yl-methyl, X = fluoro, Y = methoxymethyl, J = 1 H-pyrazol- 1 -ylmethyl.

The title compound is prepared from l,3-thiazol-2-yl-acetaldehyde following a similar procedure to that described in examples 1, 2 and 4, by replacing 2-formyl- 1,3-thiazole with l,3-thiazol-2-yl-acetaldehyde.

The title compounds of Example 42-135 can be prepared using similar procedures described herein and/or through simple tranformations which are known to those in the art.

Example 42. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl-

3-methoxylbenzoyl, Z = 1.3-thiazol-2-yl, X = fluoro, Y = -CHO, J = lH-pyrazol-

1-ylmethyl.

ESIMS m/z = 515.34 [M+H] ⁺ . Example 43. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl-

3-methoxylbenzoyl, Z = 1.3-thiazol-2-yl, X = fluoro, Y = -CH=NOMe. J = IH- pyrazol- 1 -ylmethyl.

ESIMS m/z = 544.23 [M+H] ⁺ .

Example 44. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butγ\- 3-methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = -CH=NOEt, J = IH- pyrazol- 1 -ylmethyl.

ESIMS m/z = 558.24 [M+H] ⁺ .

Example 45. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl-

3-methoxylbenzoyl, Z = 1.3-thiazol-2-yl, X = fluoro, Y = -CH=NO"Pr, J = IH- pyrazol- 1 -ylmethyl.

ESIMS m/z = 572.26 [M+H] ⁺ .

Example 46. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl-

3-methoxylbenzoyl, Z = 1.3-thiazol-2-yl, X = fluoro, Y = -CH=NO-allyl, J = IH- pyrazol- 1 -ylmethyl. ESIMS m/z = 570.27 [M+H] ⁺ .

Example 47. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butγ\-

3-methoxylbenzoyl, Z = 1.3-thiazol-2-yl, X = fluoro, Y = -CH=NOCH ₇ CO ₇ Me. J

= lH-pyrazol-1 -ylmethyl.

ESIMS m/z = 588.25 [M+H] ⁺ . Example 48. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl-

3-methoxylbenzoyl, Z = 1.3-thiazol-2-yl, X = fluoro, Y = -CH=NOPh, J = IH- pyrazol- 1 -ylmethyl.

ESIMS m/z = 606.28 [M+H] ⁺ .

Example 49. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl- 3-methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = -CH=NO-Bn, J = IH- pyrazol- 1 -ylmethyl.

ESIMS m/z = 620.35 [M+H] ⁺ .

Example 50. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butγ\-

3-methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = -CH=NO-(2- chlorophenyl), J = lH-pyrazol-1-ylmethyl.

ESIMS m/z = 640.23/642.23 [M+H] ⁺ . Example 51. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl-

3-methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = -CH=NO-(3- chlorophenyl), J = lH-pyrazol-l-ylmethyl.

ESIMS m/z = 640.32/642.32 [M+H] ⁺ .

Example 52. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{- 3-methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = -CH=NO-(4- chlorophenyl), J = lH-pyrazol-1-ylmethyl.

ESIMS m/z = 640.32/642.32 [M+H] ⁺ .

Example 53. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyi-

3-methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = -CH=NO-(2- fluorophenyl), J = lH-pyrazol-1-ylmethyl.

ESIMS m/z = 624.35 [M+H] ⁺ .

Example 54. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl-

3-methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = -CH=NO-(3- fluorophenyl), J = lH-pyrazol-l-ylmethyl. ESIMS m/z = 624.30 [M+H] ⁺ .

Example 55. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-

3-methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = -CH=NO-(4- fluorophenyl), J = lH-pyrazol-1-ylmethyl.

ESIMS m/z = 624.24 [M+H] ⁺ . Example 56. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyi-

3-methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = -CH=NO-(2- cyanophenyl), J = lH-pyrazol-l-ylmethyl.

Example 57. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butγ\-

3-methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = -CH=NO-(3- cyanophenyl), J = lH-pyrazol-1-ylmethyl.

Example 58. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl-

3-methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = -CH=NO-(4- cyanophenyl), J = lH-pyrazol-l-ylmethyl.

ESIMS m/z = 631.38 [M+H] ⁺

Example 59. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butγ\-

3-methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = -CH=NO-(4- methylphenyl), J = lH-pyrazol-1-ylmethyl. Example 60. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl-

3-methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = -CH=NO-(4- trifluoromethylphenyl), J = lH-pyrazol-l-ylmethyl.

Example 61. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-

3-methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = -CH=NO-(4- acetamidophenyl), J = lH-pyrazol-1-ylmethyl.

Example 62. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-

3-methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = -CH=NO-(4- methoxycarbonylaminophenyl), J = lH-pyrazol-l-ylmethyl.

Example 63. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyi- 3-methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = -CH=NO-(4- methanesulfonylaminophenyl), J = lH-pyrazol-l-ylmethyl.

Example 64. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-

3-methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = -CH=NO-(2,4- difluorophenyl), J = lH-pyrazol-1-ylmethyl. Example 65. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl-

3-methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = -CH=NO-(3.4- difluorophenyl), J = lH-pyrazol-l-ylmethyl.

Example 66. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl-

3-methoxylbenzoyl. Z = 1.3-thiazol-2-yl. X = fluoro. Y = -CH=NO-(2-chloro-4- fluorophenyl), J = lH-pyrazol-1-ylmethyl.

Example 67. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{- benzenesulfonyl, Z = l,3-thiazol-2-yl, X is cyano, Y is acetoxy, J = lH-pyrazol-1- ylmethyl.

Example 68. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\- phenylcarbamoyl, Z = l,3-thiazol-2-yl, X is cyano, Y is acetoxy, J = lH-pyrazol-1- ylmethyl.

Example 69. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl- benzenesulfonyl. Z = l,3-thiazol-2-yl, X is fluoro, Y = -CH=NOMe. J = IH- pyrazol- 1 -ylmethyl.

Example 70. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl- phenylcarbamoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = -CH=NOMe. J = IH- pyrazol- 1 -ylmethyl.

Example 71. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl- benzenesulfonyl, Z = l,3-thiazol-2-yl, X is fluoro, Y is methoxymethyl, J = IH- pyrazol- 1 -ylmethyl. Example 72. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl- phenylcarbamoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y is methoxymethyl, J = IH- pyrazol- 1 -ylmethyl.

Example 73. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl-

3-methoxylbenzoyl, Z = 1.3-thiazol-2-yl, X = Y = methoxymethyl, J = hydrogen. Example 74. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl-

3-methoxylbenzoyl, Z = 1.3-thiazol-2-yl, X is methoxymethyl, Y = benzyloxymethyl, J = hydrogen.

Example 75. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl-

3-methoxylbenzoyl, Z = 1.3-thiazol-2-yl, X = lH-pyrazol-l-ylmethyl, Y = benzyloxymethyl, J = hydrogen.

Example 76. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl-

3-methoxylbenzoyl, Z = 1.3-thiazol-2-yl, X = -CH ₂ OC(O)NMe ₂ , Y = benzyloxymethyl, J = hydrogen.

Example 77. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl- 3-methoxylbenzoyl, Z = 1.3-thiazol-2-yl, X = -CH ₇ NSO ₇ Me. Y = benzyloxymethyl, J = hydrogen.

Example 78. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl-

3-methoxylbenzoyl, Z = 1.3-thiazol-2-yl, X = -CH ₇ ON=CMe ₇ . Y = benzyloxymethyl, J = hydrogen. Example 79. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butγ\-

3-methoxylbenzoyl, Z = 1.3-thiazol-2-yl, X is fluoro, Y is -C(Me)=NOPh, J = IH- pyrazol- 1 -ylmethyl.

Example 80. Compound of Formula (Ha), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxylbenzovL Z = 1.3-thiazol-2-yl. X' = -CH=NOPh. J = lH-pyrazol-

1-ylmethyl.

Example 81. Compound of Formula (Ha), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxylbenzovL Z = U-thiazol-2-vL X' = -C(Me)=NOPh. J = IH- pyrazol- 1 -ylmethyl.

Example 82. Compound of Formula (Ha), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxylbenzoyl, Z = l,3-thiazol-2-yl, X' = -O-allyl, J = lH-pyrazol-1- ylmethyl. Example 83. Compound of Formula (Ha), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxylbenzoyl, Z = l,3-thiazol-2-yl, X' = -Q-CH ₇ CH ₇ Ph, J = IH- pyrazol- 1 -ylmethyl.

Example 84. Compound of Formula (Ha), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxylbenzoyl, Z = l,3-thiazol-2-yl, X' = -NKaUyI) ₇ , J = lH-pyrazol-1- ylmethyl.

Example 85. Compound of Formula (Ha), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxylbenzoyl, Z = l,3-thiazol-2-yl, X' = -NHC(O)CH ₇ Ph, J = IH- pyrazol- 1 -ylmethyl.

Example 86. Compound of Formula (Ha), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxylbenzoyl. Z = 1.3-thiazol-2-yl. X' = 4-morpholinyl. J = IH- pyrazol- 1 -ylmethyl.

Example 87. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-ferf-butyl-

3-methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = lH-pyrazol-l-ylmethyl, Y = methoxymethyl, J = hydrogen. Example 88. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-hvXy\-

3-methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = -CH ₇ OC(O)NMe ₇ . Y = methoxymethyl, J = hydrogen.

Example 89. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-ferf-butyl-

3-methoxylbenzoyl. Z = 1.3-thiazol-2-yl. X = -CH ₇ NSO ₇ Me. Y = methoxymethyl. J = hydrogen.

Example 90. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-ferf-butyl-

3-methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = -CH=NO-^-Bu, J = IH- pyrazol- 1 -ylmethyl.

ESIMS m/z = 587.29 [M+H] ⁺ .

Example 91. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butγ\-

3-methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = -CH ₂ OCH ₂ Ph, J = IH- pyrazol- 1 -ylmethyl. ESIMS m/z = 607.28 [M+H] ⁺ .

Example 92. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl-

3-methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = -Ac, J = lH-pyrazol-1- ylmethyl.

ESIMS m/z = 529.23 [M+H] ⁺ . Example 93. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyi-

3-methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = -C(Me)=NO-(4- fluorophenyl), J = lH-pyrazol-l-ylmethyl.

ESIMS m/z = 638.37 [M+H] ⁺ .

Example 94. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butγ\- 3-methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = -CH=NO-Z-Pr, J = IH- pyrazol- 1 -ylmethyl.

ESIMS m/z = 572.17 [M+H] ⁺ .

Example 95. Compound of Formula (Ha), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxylbenzoyl. Z = 1.3-thiazol-2-yl. X' = -CH=NO-(4-fluorophenyl). J = lH-pyrazol-1-ylmethyl.

ESIMS m/z = 606.28 [M+H] ⁺ .

Example 96. Compound of Formula (Ha), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = -CH=NO-phenyl. J = IH- pyrazol- 1 -ylmethyl. ESIMS m/z = 588.29 [M+H] ⁺ .

Example 97. Compound of Formula (Ia), wherein M = tert-butoxγ, Q = 4-tert- butyl-3-methoxylbenzoyl. Z = 1.3-thiazol-2-yl. X = fluoro. Y = -CH ₇ OMe. J = hydroxymethyl.

ESIMS m/z = 537.29 [M+H] ⁺ . Example 98. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-ferf-butyl-

3-methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = -NHAc. Y = -CO ₇ Me. J = IH- pyrazol- 1 -ylmethyl.

ESIMS m/z = 584.25 [M+H] ⁺ .

Example 99. Compound of Formula (Ia), wherein M = tert-butoxy, Q = 4-tert- butyl-3-methoxylbenzovL Z = 1.3-thiazol-2-yl. X = fluoro. Y = -C(O)N(Me)OMe.

J = lH-pyrazol-1-ylmethyl.

ESIMS m/z = 630.39 [M+H] ⁺ . Example 100. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = -NHAc. Y = -CH ₇ OH, J =

1 H-pyrazol- 1 -ylmethyl.

ESIMS m/z = 556.28 [M+H] ⁺ .

Example 101. Compound of Formula (Ia), wherein M = tert-butoxy, Q = 4-tert- butyl-3-methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = -CH(OH)Me. J =

1 H-pyrazol- 1 -ylmethyl.

ESIMS m/z = 587.37 [M+H] ⁺ .

Example 102. Compound of Formula (Ia), wherein M = tert-butoxy, Q = 4-tert- butyl-3-methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = -CH ₇ OH, Y = -CH ₇ OMe. J = -CH ₇ QH.

ESIMS m/z = 549.32 [M+H] ⁺ .

Example 103. Compound of Formula (Ia), wherein M = tert-butoxy, Q = 4-tert- butyl-3-methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = -CH ₇ Br, Y = -CO ₇ Et, J = IH- pyrazol- 1 -ylmethyl. ESIMS m/z = 691.38/689.38 [M+H] ⁺ .

Example 104. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = -CH=N-OH, J =

1 H-pyrazol- 1 -ylmethyl.

¹ H NMR (CD ₃ OD, 500MHz) 7.94(d, IH), 7.76 (s, IH), 7.59 (d, IH), 7.51 (s, IH), 7.28 (d, IH), 7.19 (d, IH), 6.78 (d, IH), 6.63 (s, IH), 6.29 (s, IH), 6.00 (d, IH),

5.13 (d, IH), 5.01 (d, IH), 3.72 (s, 3H), 3.20 (dd, IH), 2.78 (m, IH), 1.31 (s, 9H).

Example 105. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = -CN. J = IH- pyrazol- 1 -ylmethyl. ESIMS m/z = 512.13 [M+H] ⁺ .

Example 106. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = -C(O)NHMe. J =

1 H-pyrazol- 1 -ylmethyl.

¹ H NMR (CD ₃ OD, 500MHz) 8.40 (s, IH), 7.89 (d, IH), 7.85 (s, IH), 7.56 (d, IH),

7.52 (s, IH), 7.18 (d, IH), 6.80 (d, IH), 6.66 (s, IH), 6.30 (s, IH), 5.79 (d, IH),

5.12 (d, IH), 5.00 (d, IH), 3.72 (s, 3H), 3.34 (m, IH), 2.80 (m, IH), 2.56 (s, 3H),

1.31 (s, 9H). Example 107. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = -C(O)NHEt, J =

1 H-pyrazol- 1 -ylmethyl.

¹ H NMR (CD ₃ OD, 500MHz) 8.40 (s, IH), 7.90 (d, IH), 7.76 (s, IH), 7.56 (d, IH),

7.51 (s, IH), 7.18 (d, IH), 6.80 (d, IH), 6.65 (s, IH), 6.30 (s, IH), 5.83 (d, IH), 5.13 (d, IH), 4.98 (d, IH), 3.73 (s, 3H), 3.34 (m, IH), 3.00 (m, 2H), 2.80 (m, IH),

1.31 (s, 9H), 1.01 (t, 3H).

Example 108. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = -C(O)NHOH, J =

1 H-pyrazol- 1 -ylmethyl. 1H NMR (CD ₃ OD, 500MHz) 7.90 (d, IH), 7.76 (s, IH), 7.73 (m, IH), 7.63 (m,

IH), 7.58 (m, IH), 7.51 (s, IH), 7.19 (d, IH), 6.80 (d, IH), 6.64 (s, IH), 6.30 (s,

IH), 5.83 (d, IH), 5.13 (d, IH), 4.99 (d, IH), 3.72 (s, 3H), 3.36 (s, IH), 3.34 (m,

IH), 2.80 (m, IH), 1.31 (s, 9H).

Example 109. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = -C(O)NHBn, J =

1 H-pyrazol- 1 -ylmethyl.

ESIMS m/z = 620.25 [M+H] ⁺ .

Example 110. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxylbenzoyl. Z = 1.3-thiazol-2-yl. X = fluoro. Y = -CH ₂ OBz. J = IH- pyrazol- 1 -ylmethyl.

ESIMS m/z = 621.42 [M+H] ⁺ .

Example 111. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxylbenzoyl. Z = 1.3-thiazol-2-yl. X = fluoro. Y = -CH ₇ OMs. J = IH- pyrazol- 1 -ylmethyl. ESIMS m/z = 595.24 [M+H] ⁺ .

Example 112. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = -(/J)-CH=CHCN.

J = lH-pyrazol-l-ylmethyl.

ESIMS m/z = 537.99 [M+H] ⁺ .

Example 113. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = -(^)-CH=CHCN.

J = lH-pyrazol-1-ylmethyl. ESIMS m/z = 537.94 [M+H] ⁺ .

Example 114. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = -CH ₇ CH ₇ CN. J =

1 H-pyrazol- 1 -ylmethyl.

ESIMS m/z = 539.95 [M+H] ⁺ . Example 115. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = -CH ₇ O-propargyl,

J = lH-pyrazol-l-ylmethyl.

ESIMS m/z = 555.11 [M+H] ⁺ .

Example 116. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxylbenzoyl. Z = 1.3-thiazol-2-yl. X = fluoro. Y = -CH ₇ O-allyl. J =

1 H-pyrazol- 1 -ylmethyl.

ESIMS m/z = 557.17 [M+H] ⁺ .

Example 117. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = 3-(pyridin-2-yl)- prop-2-ynyloxymethyl, J = 1 H-pyrazol- 1 -ylmethyl.

ESIMS m/z = 632.22 [M+H] ⁺ .

Example 118. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = -CH ₇ ON=CMe ₇ . J

= lH-pyrazol-l-ylmethyl. ESIMS m/z = 572.15 [M+H] ⁺ .

Example 119. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxylbenzoyl. Z = 1.3-thiazol-2-yl. X = fluoro. Y = -CH ₇ N^. J = IH- pyrazol- 1 -ylmethyl.

ESIMS m/z = 542.37 [M+H] ⁺ . Example 120. Compound of Formula (Ia), wherein M = hydroxy, Q = benzoyl, Z

= l,3-thiazol-2-yl, X = fluoro, Y = -CH ₇ N^. J = lH-pyrazol-l-ylmethyl.

ESIMS m/z = 456.06 [M+H] ⁺ .

Example 121. Compound of Formula (Ia), wherein M = hydroxy, Q = 3- methoxylbenzoyl. Z = 1.3-thiazol-2-yl. X = fluoro. Y = -CHxNk J = lH-pyrazol-1- ylmethyl.

ESIMS m/z = 486.09 [M+H] ⁺ . Example 122. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- butyl-benzoyl. Z = 1.3-thiazol-2-yl. X = fluoro. Y = -CHxNk J = lH-pyrazol-1- ylmethyl.

ESIMS m/z = 512.13 [M+H] ⁺ .

Example 123. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = -CH ₇ NHBz, J =

1 H-pyrazol- 1 -ylmethyl.

ESIMS m/z = 620.26 [M+H] ⁺ .

Example 124. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = -CH ₇ NHSO ₇ Ph, J = 1 H-pyrazol- 1 -ylmethyl.

ESIMS m/z = 656.27 [M+H] ⁺ .

Example 125. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxylbenzoyl. Z = 1.3-thiazol-2-yl. X = fluoro. Y = -CH ₇ NHAc. J =

1 H-pyrazol- 1 -ylmethyl. ESIMS m/z = 558.25 [M+H] ⁺ .

Example 126. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = -CH ₇ NHMs. J =

1 H-pyrazol- 1 -ylmethyl.

ESIMS m/z = 594.25 [M+H] ⁺ . Example 127. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = -CH ₇ NHCO ₇ Me. J

= lH-pyrazol-l-ylmethyl.

ESIMS m/z = 574.27 [M+H] ⁺ .

Example 128. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxylbenzoyl. Z = 1.3-thiazol-2-yl. X = fluoro. Y = -CH ₇ NMe ₇ . J =

1 H-pyrazol- 1 -ylmethyl.

ESIMS m/z = 544.02 [M+H] ⁺ .

Example 129. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-

N V \ /) butyl-3-methoxylbenzoyl. Z = 1.3-thiazol-2-yl. X = fluoro. Y = -CH/ ^{* N \} _ ^/ _^ j = lH-pyrazol-1-ylmethyl. ESIMS m/z = 645.23 [M+H] ⁺ . Example 130. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-

butyl-3-methoxylbenzoyl. Z = 1.3-thiazol-2-yl. X = fluoro. Y = -CH ₂ ^ ^N Y-/ ^J = lH-pyrazol-l-ylmethyl. ESIMS m/z = 630.30 [M+H] ⁺ .

Example 131. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = l,3-oxazol-2-yl, J = lH-pyrazol-l-ylmethyl. ESIMS m/z = 554.15 [M+H] ⁺ . Example 132. Compound of Formula (Ia), wherein M = ferf-butoxy, Q = 4-tert-

= lH-pyrazol-l-ylmethyl.

-,+

ESIMS m/z = 718.13 [M+H]"

Example 133. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-

= lH-pyrazol-l-ylmethyl. ESIMS m/z = 622.17 [M+H] ⁺ .

Example 134. Compound of Formula (Ia), wherein M = ferf-butoxy, Q = 4-tert- butyl-3-methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = -COOH, J = IH- pyrazol- 1 -ylmethyl.

ESIMS m/z = 587.25 [M+H] ⁺ . Example 135. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- = lH-pyrazol-l-ylmethyl. ESIMS m/z = 644.14 [M+H] ⁺ .

Example 136. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxylbenzoyl. Z = 1.3-thiazol-2-yl. X = fluoro. Y = -C(O)NH- cyclopropyl, J = lH-pyrazol-1-ylmethyl.

Into a solution of the compound from step Ig (10.0 mg) and cyclopropylamine (0.65 mL) in THF (1.0 mL) was stirred at 70 ⁰ C for 1 h. All volatiles was removed by rotavap and the residue was chromatographed (silica, hexanes-EtOAc) to give the desired intermediate, which was redissolved in dichloromethane (0.5 mL) and TFA (0.5 mL). The mixture was stirred at temperature for 2.5 hours and the volatiles were removed by N ₂ flow. The residue was purified by flash column chromatography (silica, CH ₂ Cl ₂ -methanol) to give the title compound as a light yellow film.

¹ H NMR (CD ₃ OD, 500MHz) 8.56 (s, IH), 7.89(d, IH), 7.76 (s, IH), 7.58 (d, IH), 7.51 (s, IH), 7.18 (d, IH), 6.78 (d, IH), 6.65 (s, IH), 6.29 (s, IH), 5.82 (d, IH), 5.12 (d, IH), 4.98 (d, IH), 3.73 (s, 3H), 3.36 (m, IH), 2.81 (m, IH), 2.40 (m, IH), 1.31 (s, 9H), 0.91 (m, IH), 0.60 (m, IH), 0.48 (m, IH), 0.40 (m, IH).

Example 137. Compound of Formula (Ia), wherein M = tert-butoxy, Q = 4-tert- butyl-3-methoxylbenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon atom to which they attached form C=CH ₂ , J = lH-pyrazol-l-ylmethyl. To a solution of the compound of example 2 (6.4 g, 11.5 mmol) in 180 mL THF are added 2-nitrophenyl selenocyanate (5.8 g, 25.5 mmol) and tri-n-butylphosphine (5.2 g, 25.5 mmol) and the mixture is stirred at rt for 0.5 h. Hydrogen peroxide (30% in water, 25 mL) is added dropwise and the mixture is stirred at rt for 4 h. The crude reaction mixture is diluted with EtOAc (150 mL), washed with water (2 x 30 mL), 10% Na ₂ S ₂ O ₃ solution (30 mL) and brine (30 mL). The organic layer is dried (Na ₂ SO ₄ ), filtered and evaporated. The residue is purified by flash chromatography (silica, hexane-ethyl acetate) to give the title compound as a white solid (2.2 g, 36%).

ESIMS m/z = 537.20 [M+H] ⁺ .

Example 138. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxylbenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon atom to which they attached form C=CH ₂ , J = lH-pyrazol-1-ylmethyl. A solution of the compound of example 137 (5.2 mg, 0.01 mmol) in a mixture of trifluoroacetic acid and dichloromethane (1 mL, 1 : 1 by volume) is stirred at rt for 7

h. Evaporated and the residue is purified by preparative TLC (10% MeOH in CH ₂ Cl ₂ ) to give the title compound as a white solid (2.9 mg, 60%). ESIMS m/z = 481.18 [M+H] ⁺ .

Example 139. Compound of Formula (Ia), wherein M = tert-butoxy, Q = 4-tert- butyl-3-methoxylbenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon atom to which they attached form a carbonyl, J = lH-pyrazol-1-ylmethyl. A solution of the compound of example 137 (100 mg, 0.19 mmol) and CSA (86.6 mg, 0.37 mmol) in 10 mL MeOH is cooled to -78 ⁰ C. Ozone is passed through for 5 min and the bluish solution is treated with dimethylsulfide (173 mg, 2.8 mmol) for 15 min. The solution is taken up in CH ₂ Cl ₂ , washed with NaHCO ₃ solution, brineand dried (Na ₂ SO ₄ ). Filtered, evaporated and the residue is purified by flash chromatography (silica, hexane-ethyl acetate) to give the desired compound as a white solid (50 mg, 50%).

ESIMS m/z = 539.27 [M+H] ⁺ . Example 140. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxylbenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon atom to which they attached form a carbonyl, J = lH-pyrazol-1-ylmethyl. A solution of the compound of example 139 (10 mg, 0.04 mmol) in trifluoroacetic acid (1 mL) is stirred at rt for 6 h. Evaporated and the residue is purified by Prep TLC (10% MeOH in CH ₂ Cl ₂ ) to give the desired compound as a white solid (4 mg, 37%).

ESIMS m/z = 483.09 [M+H] ⁺ .

Example 141. Compound of Formula (Ia), wherein M = tert-butoxy, Q = 4-tert- butyl-3-methoxylbenzoyl. Z = 1.3-thiazol-2-yl. X = fluoro. Y = -CH ₇ N^. J = IH- pyrazol- 1 -ylmethyl.

A solution of the compound of example 2 (200mg, 0.35mmol) in dichloromethane (10 mL) was sequentially added DEAD (0.17 mL, 1.05mmol), triphenylphosphine (276 mg, 1.05 mmol) and diphenylphosphoryl azide (0.23, 1.05 mmol). The resulting mixture was stirred at rt for 16 hours before quenched with water. The organic phase was washed with brine, dried (Na ₂ SO ₄ ) and evaporated. The residue was chromatographed (silica, hexane-EtOAc) to give the title compound (178 mg, 86%). ESIMS m/z = 598.14 [M+H] ⁺ .

Example 142. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxylbenzoyl. Z = 1.3-thiazol-2-yl. X = fluoro. Y = -CH ₇ ON=CMe ₇ . J

= lH-pyrazol-1-ylmethyl.

A solution of the compound of example 133 (5 mg, 8 μmol) in dichloromethane (1 mL) and MeOH (0.1 mL) was added hydrazine monohydrate (1.5 mg, 24 μmol).

The resulting mixture was stirred at rt for 30 min before it added acetone (0.1 mL).

The volatiles were evaporated and the resulting residue was chromatographed

(silica, MeOH-dichloromethane) to give the title compound (3mg, 68%).

ESIMS m/z = 572.17 [M+H] ⁺ . Example 143. Compound of Formula (Ia), wherein M = tert-butoxy, Q = 4-tert- butyl-3-methoxylbenzovL Z = 1.3-thiazol-2-yl. X = fluoro. Y = -CH ₇ NH ₇ . J = IH- pyrazol- 1 -ylmethyl.

A solution of the compound of example 141 (33 mg, 0.055mmol) in water (O.lmL) and THF (2 mL) was added triphenylphosphine (50 mg). The resulting mixture was stirred at 50 ⁰ C for 12 hours before it was partitioned in water and EtOAc. The organic phase was washed with brine, dried (Na ₂ SO ₄ ) and evaporated. The residue was chromatographed (silica, MeOH-dichloromethane ) to give the title compound

(27mg, 85%).

ESIMS m/z = 572.24 [M+H] ⁺ . Example 144. Compound of Formula (Ia), wherein M = tert-butoxy, Q = 4-tert- butyl-3-methoxylbenzoyl. Z = 1.3-thiazol-2-yl. X = fluoro. Y = -CH ₇ NHBz. J =

1 H-pyrazol- 1 -ylmethyl.

A solution of the compound of example 143 (5.5 mg, 9.2 μmmol) in pyridine (1 mL) was added benzoyl chloride (0.015 mL). The resulting mixture was stirred at rt for Ih before it was partitioned in water and EtOAc. The organic phase was washed with brine, dried (Na ₂ SO ₄ ) and evaporated. The residue was chromatographed (silica, hexane-EtOAc) to give the title compound (6mg, 100%).

ESIMS m/z = 676.30 [M+H] ⁺ .

Example 145. Compound of Formula (Ia), wherein M = tert-butoxy, Q = 4-tert- butyl-3-methoxylbenzoyl. Z = 1.3-thiazol-2-yl. X = fluoro. Y = -CH ₇ NMe ₇ . J =

1 H-pyrazol- 1 -ylmethyl.

A solution of the compound of example 143 (12 mg, 0.021mmol) in acetonitrile (1 mL) was sequentially added formaldehyde (37% aqueous solution, 5 μL), sodium

cyanoborohydride (5 mg) and AcOH (10 μL). The resulting mixture was stirred at rt for 30 min before quenched with water and diluted with EtOAc. The organic phase was washed with brine, dried (Na ₂ SO ₄ ) and evaporated. The residue was chromatographed (silica, hexane-EtOAc) to give the title compound (7 mg, 56%). ESIMS m/z = 600.11 [M+H] ⁺ .

Example 146. Compound of Formula (Ia), wherein M = tert-butoxy, Q = 4-tert-

butyl-3-methoxylbenzoyl. Z = 1.3-thiazol-2-yl. X = fluoro. Y = -CH ₂ ^/NV/ ^—^ _± 2

= lH-pyrazol-1-ylmethyl.

A solution of the compound of example 141 (5 mg, 9 μmol) in water (0.5mL) and tert-butanol (0.25 mL) was sequentially added ethynylbenzene (0.025 mL), sodium ascorbate (10 mg), and CuSO ₄ H ₂ O (3 mg). The resulting mixture was stirred at 60 ⁰ C for 12 hours before it was partitioned in water and EtOAc. The organic phase was washed with brine, dried (Na ₂ SO ₄ ) and evaporated. The residue was chromatographed (silica, hexane-EtOAc) to give the title compound (4.5mg, 82%). ESIMS m/z = 700.49 [M+H] ⁺ .

Example 147. Compound of Formula (Ia), wherein M = tert-butoxy, Q = 4-tert- butyl-3-methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = -C(O)NHCH ₂ CH ₂ OH, J = lH-pyrazol-l-ylmethyl. A solution of the compound of example 134 (lOOmg, 0.17mmol) in acetonitrile (5 mL) was sequentially added HATU (195, 0.51mmol), ethanol amine (0.05 mL, 0.51mmol) and di-ώo-propylethylamine (0.1 mL, 0.51 mmol). The resulting mixture was stirred at rt for 16 hours before quenched with water. The organic phase was washed with brine, dried (Na ₂ SO ₄ ) and evaporated. The residue was chromatographed (silica, hexane-EtOAc) to give the title compound (100 mg, 93%).

ESIMS m/z = 630.06 [M+H] ⁺ .

Example 148. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxylbenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = l,3-oxazol-2-yl, J = lH-pyrazol-1-ylmethyl. A solution of the compound of example 147 (56mg, 0.089 mmol) in dichloromethane (2 mL) was sequentially added Dess-Martin periodinane (150 mg, 0.27 mmol),NaHCO ₃ (150 mg) and tert-butanol (0.025 mL) at 0 ⁰ C. The resulting mixture was stirred at rt for 2 hours before concentrated with N ₂ flow. The

resulting residue was uptake by Et ₂ O and purified by a short column (silica, Et ₂ O) to provide the desired aldehyde as a film.

The aldehyde was dissolved in4 mL of dichloromethane. The solution was sequentially added triphenylphosphine (140 mg), di-ώo-propylethylamine (0.14 mL) and 1 ,2-dibromotetrachloroethane (160 mg). The resulting mixture was stirred at rt for 3 h before it was quenched with water. The organic phase was washed with brine, dried (Na ₂ SO ₄ ) and evaporated. The residue was chromatographed

(silica, hexane-EtOAc) to give the title compound.

ESIMS m/z = 610.19 [M+H] ⁺ . Example 149. Compound of Formula (Iaa), wherein M = te/t-butoxy, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = hydroxymethyl, J =

1 H-pyrazol- 1 -ylmethyl.

Step 149a. A solution of 2-fluoroacrylic acid (2 g, 22 mmol) in dichloromethane

(80 mL) was added DCC (4.58 g, 22 mmol). at 0 ⁰ C. The resulting mixture was stirred at 0 ⁰ C for 15 min before addition of a solution of methyl (R)-(-)-mandelate

(4.06g, 24 mmol) and DMAP (136 mg, 0.11 mmol) in 20 mL of dichloromethane.

The micture was stirred at rt for 16 h before being filtered and the organic solution was washed with brine, dried (Na ₂ SO ₄ ) and evaporated. The residue was chromatographed (silica, hexane-EtOAc) to give the desired compound (2.9 g, 55%) as white crystals.

¹ H NMR (CDCl ₃ ) 7.50 (m, 2H), 7.43 (m, 3H), 6.09 (s, IH), 5.83 (dd, IH), 5.45

(dd, IH), 3.77 (s, 3H).

¹³ C NMR (CDCl ₃ ): 168.7, 159.7 (d), 152.9 (d), 133.3, 129.8, 129.2, 127.9, 104.3,

75.6, 53.0. Step 149b. A solution of the compound from step 149a (2.9 g, 12 mmol) and the compound from step Ic (4.6g, 14.2 mmol) in THF (50 mL) was sequentially added lithium bromide (1.56 g, 18 mmol) and triethylamine (5.2 mL, 36 mmol) at 0 ⁰ C.

The resulting mixture was stirred at rt for 3 h before it was partitioned between

EtOAc and water. The organic solution was washed with brine, dried (Na ₂ SO ₄ ) and evaporated. The residue was chromatographed (silica, hexane-EtOAc) to give the desired compound (2.85g, 50%).

ESIMS m/z = 545.35 [M+H] ⁺ .

¹ H NMR (CDCl ₃ ): 7.57 (m, 2H), 7.52 (m, IH), 7.36 (m, 4H), 7.14 (m, IH), 6.26 (m, IH), 5.69 (s, IH), 4.80 (dd, IH), 4.53 (dd, 2H), 3.95 (dd, IH), 3.68 (s, 3H), 3.19 (dd, IH), 2.71 (dd, IH), 1.45 (s, 9H).

Step 149c. A solution of the compound from step 149b (2.57 g, 4.7 mmol) and the compound from step Ie (1.61, 7.1 mmol) in dichloromethane (11 mL) was added triethylamine (2.0 mL). The resulting mixture was stirred at rt for 16 h before it was partitioned between water and EtOAc. The organic solution was washed with brine, dried (Na ₂ SO ₄ ) and evaporated. The residue was chromatographed (silica, hexane -EtOAc) to give the desired compound (2.7Og, 80%). The stereogenic center in the madelate moiety was epimerized during the reaction and the resulting two diastereomers were not separable in flash column. ESIMS m/z = 735.30 [M+H] ⁺ .

¹ H NMR (CDCl ₃ ): 7.65 (m, IH), 7.55 (m, IH), 7.31 (m, 7H), 7.18 (m, IH), 7.05 and 7.00 (m, IH), 6.96 (m, IH), 6.28 (s, IH), 5.86 (dd, IH), 5.64 and 5.59 (s, IH), 5.17 (dd, IH), 5.04 (dd, IH), 3.74 (s, 3H), 3.66 and 3.59 (s, 3H), 3.51 (m, IH), 3.32 (m, IH), 1.44 (m, 9H), 1.35 (m, 9H).

Step 149d. A solution of the compound from step 149c (2.7 g, 3.68 mmol) in MeOH (7.5 mL) was added sodium borohydride (420 mg, 11 mmol). The resulting mixture was stirred at rt for 12 h before it was partitioned between water and EtOAc. The organic solution was treated with trisamine (2 g), washed with brine, dried (Na ₂ SO ₄ ) and evaporated. The residue was chromatographed (silica, MeOH- dichloromethane) to give the title compound (1.98g, 96%). ESIMS m/z = 573.27 [M+H] ⁺ .

II. Second Prinicple Invention

Example 1. Compound of Formula (Ia), wherein M = tert-butoxy, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the

carbon atom to which they are attached is X ^* *^°, J = lH-pyrazol-l-ylmethyl. Step Ia. Into a suspension of commercially available l-carboxy-2-pyrazol-l-yl- ammonium chloride (958 mg, 1.0 mmol) in t-butyl acetate (30.0 mL) was added perchloric acid (70%, 0.50 mL, 5.8 mmol). The mixture was stirred at room temperature for 64 hours before being diluted with ethyl acetate and neutralized with a combination of solid NaHCO ₃ and saturated NaHCO ₃ until no gas evolved.

After separation, the aqueous was saturated with sodium chloride and extracted with ethyl acetate. The combined organics were dried (Na ₂ SO ₄ ) and evaporated to give the crude product (617 mg, 45.5%). ESIMS m/z = 212.12 [M+H] ⁺ of the free base parent ion. 1 ³ C NMR (CDCl ₃ ) 175.7, 171.1, 140.1, 130.5, 105.6, 82.6, 55.1, 54.2, 27.9.

Step Ib. Into a suspension of commercially available l-carboxy-2-pyrazol-l-yl- ammonium chloride (958 mg, 1.0 mmol) in t-butyl acetate (30.0 mL) was added perchloric acid (70%, 0.76 mL, 8.8 mmol). The mixture was stirred at room temperature for 22 hours before being diluted with ethyl acetate and neutralized with a combination of solid NaHCO ₃ and saturated NaHCO ₃ to pH ~ 8. After separation, the aqueous was saturated with sodium chloride and extracted with ethyl acetate. The combined organics were dried (Na ₂ SO ₄ ) and evaporated to give the crude product (633 mg, 60%). ESIMS m/z = 212.14 [M+H] ⁺ . Step Ic. A mixture of the compound from step Ia (205 mg, 0.75 mmol), commercially available 2-formyl-l,3-thiazole (120 mg, 1.06 mmol), and activated molecular sieves (4 A, 1.0 g) in anhydrous methylene chloride (5 mL) was stirred at room temperature for 15 hours before being filtered through Celite and washed with methylene chloride. The combined organics were evaporated and the residue was used directly for next step. ESIMS m/z = 307.13 [M+H] ⁺ .

Step Id. A mixture of the compound from step Ib (160 mg, 0.76 mmol), commercially available 2-formyl-l,3-thiazole (151 mg, 1.34 mmol), and activated molecular sieves (4 A, 1.0 g) in anhydrous methylene chloride (5 mL) was stirred at room temperature for 15 hours before being filtered through Celite and washed with methylene chloride. The combined organics were evaporated and the residue was chromatographed (silica, hexanes-EtOAc) to give the desired compound (200 mg, 86%). ESIMS m/z = 307.12 [M+H] ⁺ . 1 ³ C NMR (CD ₃ OD) 168.2, 166.2, 159.0, 144.1, 139.8, 131.4, 123.3, 105.4, 82.7, 72.3, 53.1, 27.1.

Step Ie. A mixture of the compound from step Id (100 mg, 0.33mmol), lithium bromide (57 mg, 0.66 mmol), 2-methylene succinic acid dimethyl ester (104 mg, 0.66 mmol) and Et ₃ N (0.1 mL) in THF (2.5 mL) was stirred under nitrogen at room

temperature for 17 hours before being quenched with saturated aqueous NaHCCh (5 mL). The aqueous layer was separated and extracted with EtOAc (3 X 5 mL). The combined organics were washed with brine (5 mL), dried by Na ₂ SO ₄ , filtered and evaporated. The residue was purified by flash column chromatography (silica, hexane-ethyl acetate) to give the desired compound as a colorless oil (120 mg, 79%).

ESIMS m/z = 465.05 [M+H] ⁺ .

¹³ C NMR (CDCl ₃ ) 172.6, 172.5, 171.7, 166.4, 143.1, 139.6, 131.7, 118.9, 106.2, 82.6, 69.7, 68.6, 59.5, 57.1, 52.1, 52.0, 43.4, 40.6, 28.2. Step If. A mixture of the commercially available 4-£-butyl-3-methoxybenzoic acid (2.082 g, 10.0 mmol) in thionyl chloride (5.0 mL) was refluxed for 2.5 hours before being evaporated. Toluene (twice) was added to the residue and the mixture was evaporated. The residue was dried in vacuum to get a crystalline (2.258 g, 99.6%). Step Ig. A solution of the compound from step Ie (120 mg, 0.26 mmol), Et ₃ N (0.14 mL, 0.98 mmol) and the compound from step If (111 mg, 0.49 mmol) in anhydrous dichloromethane (3 mL) was stirred at room temperature under nitrogen for 96 hours before being quenched with saturated aqueous NaHCO ₃ (5 mL). The aqueous layer was separated and extracted with EtOAc (3 X 5 mL). The combined organics were washed with brine (10 mL), dried (Na ₂ SO ₄ ), and evaporated. The residue was purified by flash column chromatography (silica, hexanes-ethyl acetate) to give the desired compound as a light yellow oil (55 mg) with recovery of the compound from step Ie (60 mg). ESIMS m/z = 655.11 [M+H] ⁺ . 1 ³ C NMR (CDCl ₃ ) 171.8, 171.2, 170.5, 169.1, 167.9, 158.3, 141.5, 140.0, 140.3, 135.2, 132.8, 126.3, 120.4, 118.5, 110.7, 106.0, 82.7, 72.4, 70.6, 55.6, 55.2, 53.5, 52.4, 52.1, 42.7, 41.3, 35.1, 29.6, 28.3.

Step Ih. A solution of the compound from step Ig (50 mg, 0.076 mmol) in anhydrous THF was treated with lithium borohydride (17 mg, 0.76 mmol) with stirring under N ₂ for 7 hours before it was quenched with K ₂ CO ₃ solution (2M in water, 5 mL). The aqueous layer was separated and extracted with EtOAc (3 X 5 mL). The combined organic layers were dried by Na ₂ SO ₄ , filtered and evaporated. The residue was purified by flash column chromatography (silica, hexanes-ethyl acetate) to afford the desired compound as a colorless oil (23 mg).

ESIMS m/z = 599.08 [M+H] ⁺ .

¹³ C NMR (CDCl ₃ ): 170.8, 170.3, 169.2, 157.9, 141.5, 140.2, 140.0, 135.3, 133.3, 126.1, 120.0, 119.1, 110.7, 105.8, 83.1, 71.9, 71.6, 65.0, 58.9, 55.2, 52.9, 49.9, 40.4, 40.3, 35.0, 29.6, 28.3. Step Ii. A solution of the compound from step Ih (10 mg, 0.0167 mmol) in pyridine (4 mL) was treated with/?-toluenesulfonyl chloride (38 mg, 0.20 mmol) at 150 ⁰ C under microwave (Biotage Initiator) for 30 min before being cooled to room temperature. The volatiles were evaporated off and the residue was partitioned (EtOAc saturated NaHCO ₃ ). The aqueous layer was separated and extracted with EtOAc (3 X 5 mL). The combined organic layers were dried by Na ₂ SO ₄ , filtered and evaporated. The residue was purified by flash column chromatography (silica, hexanes-ethyl acetate) to afford the title compound as a colorless oil after KOH (2M) wash. ESIMS m/z = 581.39 [M+H] ⁺ . 1H NMR (CDCl ₃ ): δ 7.62 (d, IH), 7.46 (d, IH), 7.31 (d, IH), 7.05 (d, IH), 7.00 (d, IH), 6.52 (s, IH), 6.30 (s, IH), 5.33 (d, IH), 5.15 (s, IH), 4.71 (d, IH), 3.70 (s, 3H), 3.67 (m, IH), 3.60 (m, IH), 3.48 (q, 2H), 3.38 (d, IH), 2.56 (d, IH), 1.95 (m, 2H), 1.62 (s, 9H), 1.27 (s, 9H). Example 2. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butγ\- 3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

atom to which they are attached is >■ ""-- ⁰ , J = lH-pyrazol-1-ylmethyl. A solution of the compound of example 1 (6.2 mg) in dichloromethane (0.5 mL) was treated with TFA (0.5 mL) at room temperature for 2.5 hours. The volatiles were evaporated off and the residue was purified by chromatography (silica, CH2Cl2-methanol) to give the title compound (5 mg) as a white solid. ESIMS m/z = 525.33 [M+H] ⁺ .

¹ H NMR (CD ₃ OD): δ 7.76 (d, IH), 7.64 (d, IH), 7.52 (s, IH), 7.08 (d, IH), 6.67 (d, IH), 6.48 (s, IH), 6.27 (s, IH), 5.17 (s, IH), 5.08 (d, IH), 4.86 (d, IH), 3.76 (m, 2H), 3.56 (s, 3H), 3.15 (d, IH), 2.96 (d, IH), 2.56 (q, 2H), 1.87 (m, 2H), 1.22 (s, 9H).

Example 3. Compound of Formula (Ia), wherein M = tert-butoxγ, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the

carbon atom to which they are attached is ^* —o °, J = lH-pyrazol-1-ylmethyl. A solution of the compound of example 1 (12 mg, 20 μmol) and pyridine (0.05 mL) in CH ₂ Cl ₂ (1.5 mL) was treated with triphosgene (6 mg, 20 μmol) at -78 ⁰ C for 40 min before being quenched with saturated aqueous NaHCO ₃ (5 mL). The aqueous layer was separated and extracted with EtOAc (3 X 5 mL). The combined organic layers were dried by Na ₂ SO ₄ , filtered and evaporated. The residue was purified by chromatography (silica, hexanes-ethyl acetate) to afford the title compound (8 mg) as a colorless oil. ESIMS m/z = 625.33 [M+H] ⁺ .

¹ H NMR (CDCl ₃ ): 7.62 (d, IH), 7.38 (d, IH), 7.35 (d, IH), 7.03 (d, IH), 6.91 (d, IH), 6.47 (s, IH), 6.38 (d, IH), 6.30 (m, IH), 5.35 (d, IH), 4.91 (s, IH), 4.63 (d, IH), 4.56 (d, IH), 4.21 (m, IH), 4.13 (m, IH), 3.69 (s, 3H), 3.35 (d, IH), 3.16 (m, IH), 2.85 (d, IH), 2.16 (m, IH), 1.90 (d, IH), 1.71 (s, 9H), 1.22 (s, 9H).

Example 4. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butγ\- 3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon atom to which they are attached is ^* --o °, J = lH-pyrazol-1-ylmethyl.

The title compound was prepared from the compound of example 3 following a similar procedure to that described in example 2, by replacing the compound of example 1 with the compound of example 3.

ESIMS m/z = 569.29 [M+H] ⁺ .

¹ H NMR (CD ₃ OD): δ 7.71 (d, IH), 7.68 (s, IH), 7.59 (d, IH), 7.46 (d, IH), 7.08

(d, IH), 6.66 (d, IH), 6.59 (s, IH), 6.39 (s, IH), 5.23 (m 2H), 4.86 (d, IH), 4.25 (m, 2H), 4.17 (d, IH), 3.74 (s, 3H), 3.50 (d, IH), 2.88 (d, IH), 2.70 (d, IH), 2.12

(m, IH), 1.72 (d, IH), 1.29 (s, 9H).

Example 5. Compound of Formula (Ia), wherein M = tert-butoxy, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon atom to which they are attached is N ''-~° , J = lH-pyrazol-1-ylmethyl. Step 5a. A mixture of the crude compound from step Ic (113 mg, 0.37 mmol), lithium bromide (97 mg, 1.1 mmol), methyl 2-acetamidoacrylate (106 mg, 0.74

mmol) and Et ₃ N (0.16 niL) in THF (5 niL) was stirred under nitrogen at room temperature for 12 hours before being quenched with saturated aqueous NH ₄ Cl (5 mL). The aqueous layer was separated and extracted with EtOAc. The combined organics were washed with water and brine, dried (Na ₂ SO ₄ ), filtered and evaporated. The residue was purified by chromatography (silica, hexane-ethyl acetate) to give the desired compound as a light yellow oil (112 mg, 68%). ESIMS m/z = 450.00 [M+H] ⁺ .

¹³ C NMR (CDCl ₃ ) 171.8, 171.2, 170.8, 166.5, 143.1, 139.3, 131.0, 119.3, 105.8, 82.6, 69.6, 69.4, 65.5, 58.8, 52.7, 43.0, 28.0, 23.9. Step 5b. A solution of the compound from step 5a (412 mg, 0.92 mmol), Et ₃ N (0.40 mL, 2.7 mmol) and the compound from step If (332 mg, 1.5 mmol) in anhydrous dichloromethane (10 mL) was stirred at room temperature under nitrogen for 48 hours before being diluted with water (5 mL). The aqueous layer was separated and extracted with EtOAc. The combined organics were washed with brine, dried (Na ₂ SO ₄ ), and evaporated. The residue was purified by chromatography (silica, hexanes-ethyl acetate) to give the desired compound as a light yellow oil (223 mg) with a recovery of the compound from step 5a (212 mg). ESIMS m/z = 640.23 [M+H] ⁺ . 1 ³ C NMR (CDCl ₃ ) 171.0, 170.9, 170.2, 168.7, 165.9, 158.7, 141.5, 140.9, 139.7, 134.3, 133.9, 127.1, 120.5, 118.9, 109.9, 106.1, 82.7, 69.4, 68.7, 64.8, 56.3, 55.3, 52.6, 39.4, 35.2, 29.7, 28.0, 23.9, 14.4.

Step 5c. A solution of the compound from step 5b (100 mg, 0.15 mmol) in ethanol (10 mL) at 0 ⁰ C was charged with sodium borohydride (24 mg, 0.63 mmol) and anhydrous calcium chloride (35 mg, 0.31 mmol). The mixture was slowly warmed up to room temperature and stirred for 12 hours before being quenched with saturated aqueous NH ₄ Cl (5 mL). The aqueous layer was separated and extracted with EtOAc. The combined organics were washed with water and brine, dried (Na ₂ SO ₄ ), filtered and evaporated. The residue was purified by chromatography (silica, hexane-ethyl acetate) to give the desired compound as a colorless oil (75 mg, 78%).

ESIMS m/z = 612.37 [M+H] ⁺ .

¹³ C NMR (CDCl ₃ ) 172.7, 171.3, 170.5, 165.9, 158.7, 142.2, 140.7, 139.7, 134.8,

133.7, 127.1, 120.3, 118.1, 109.5, 106.2, 82.7, 69.8, 68.5, 65.9, 65.4, 56.6, 55.1,

38.2, 35.2, 29.7, 28.2, 23.9.

Step 5d. A solution of the compound from step 5c (60 mg, 98 μmol) in dimethoxyethane (6 mL) was treated with palladium chloride (17 mg, 98 μmol) and sodium acetate (20 mg, 0.25 mmol) in a sealed tube under carbon monoxide (50 psi) 80 ⁰ C for 24hours before being filtered through a pad of Celite. The filtrate was concentrated and purified by chromatography (silica, hexanes-ethyl acetate) to give the title compound as a colorless oil (22 mg) with recovery of the compound of step 5c (35 mg). ESIMS m/z = 638.12 [M+H] ⁺ .

¹³ C NMR (CDCl ₃ ) 172.1, 171.2, 170.2, 170.0, 164.1, 157.9, 143.3, 140.9, 140.4, 134.9, 132.0, 126.2, 120.3, 119.5, 111.0, 106.2, 84.1, 71.5, 69.9, 68.9, 63.7, 55.2, 51.0, 38.5, 35.1, 29.5, 28.2, 26.1.

Example 6. Compound of Formula (Ia), wherein M = tert-butoxγ, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the

carbon atom to which they are attached is V ''-^ ⁰ , J = lH-pyrazol-1-ylmethyl. A solution of the compound from step 5d (6 mg) in methanolic ammonia (7N, 3.0 mL) was stirred at room temperature for 12 hours before being evaporated and purified by chromatography (silica, hexanes-ethyl acetate) to give the title compound as a white solid (3.5 mg).

ESIMS m/z = 595.96 [M+H] ⁺ . 1H NMR (CDCl ₃ ) 7.68 (d, IH), 7.50 (d, IH), 7.46 (s, IH), 7.22 (s, IH), 7.11 (d,

IH), 7.09 (d, IH), 6.47 (d, IH), 6.42 (s, IH) 6.28 (d, IH), 5.44(d, IH), 5.25 (s, IH),

4.68 (d, IH), 4.05 (d, IH), 3.93 (d, IH), 3.66 (s, 3H), 3.12 (d, IH), 3.02 (d, IH),

1.98 (s, 3H), 1.38 (s, 9H), 1.27 (s, 9H).

Example 7. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butγ\- 3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon atom to which they are attached is N ^• *- ^* ° , J = lH-pyrazol-l-ylmethyl. A solution of the compound of step 5d (4 mg) in dichloromethane (1 mL) was treated with TFA (1.5 mL) at room temperature for 5 hours and the volatiles were removed by N ₂ flow. The residue was purified by flash column chromatography (silica, C^Cb-methanol) to give the title compound (3.1 mg, 85%) as an off-white solid. ESIMS m/z = 582.18 [M+H] ⁺ .

¹ H NMR (CD ₃ OD) 7.68 (s, IH), 7.55 (s, IH), 7.45 (s, IH), 7.42 (s, IH), 7.02 (d, IH), 6.72 (s, IH), 6.68 (d, IH), 6.42 (s, IH), 5.99 (s, IH), 5.44 (d, IH), 5.04 (d, IH), 4.81 (d, IH), 4.13 (t, 2H), 3.74 (s, 3H), 3.35 (d, IH), 2.45 (s, 3H), 2.37 (d, IH), 1.26 (s, 9H). Example 8. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-ferf-butyl- 3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

atom to which they are attached is >> ^*"" ⁰ , J = lH-pyrazol-1-ylmethyl.

A solution of the compound of example 6 (3.5 mg) in dichloromethane (1 mL) was treated with TFA (1.5 mL) at room temperature for 5 hours and the volatiles were removed by N ₂ flow. The residue was purified by flash column chromatography

(silica, CH ₂ Cl2-methanol) to give the title compound (3.1 mg, 98%) as an off- white solid.

ESIMS m/z = 540.24 [M+H] ⁺ .

¹ H NMR (CD ₃ OD) 7.71(s, IH), 7.52 (d, IH), 7.50 (d, IH), 7.35 (d, IH), 6.98 (d, IH), 6.57 (s, IH), 6.55 (s, IH), 6.38 (s, IH), 5.38 (d, IH), 5.07 (s, IH), 4.96 (d,

IH), 4.72 (d, IH), 4.10 (d, IH), 3.75 (s, 3H), 3.36 (t, 2H), 2.59 (d, IH), 1.25 (s,

9H).

Example 9. Compound of Formula (Ia), wherein M = tert-butoxy, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the

carbon atom to which they are attached is £ Xxϊ ^Ac , J = lH-pyrazol-l-ylmethyl.

Step 9a. A solution of the compound from step 5 c (30 mg, 49 μmol) in anhydrous dichloromethane (5 mL) at 0 ⁰ C was treated with triethylamine (0.14 mL, 0.98 mmol) and methanesulfonyl chloride (23 μL, 0.29 mmol) before being quenched with saturated sodium bicarbonate aqueous solution. The resultant mixture was partitioned (CH ₂ Cl ₂ -water) and the organics were washed with water, brine, dried (Na ₂ SO ₄ ), and evaporated. The residue was chromatographed (silica, hexanes- EtOAc) to give the desired compound (30 mg, 89%) as a colorless oil. ESIMS m/z = 690.37 [M+H] ⁺ . 1 ³ C NMR (CDCl ₃ ): 171.7, 170.9, 170.3, 164.9, 158.7, 143.0, 140.5, 139.8, 134.6, 133.8, 127.1, 120.8, 117.8, 109.3, 106.2, 83.1, 69.7, 69.2, 65.6, 64.9, 56.2, 55.1, 38.7, 37.2, 35.2, 31.8, 29.7, 28.2, 23.9.

Step 9b. A solution of the compound from step 9a (30 mg, 44 μmol) in anhydrous THF (5 mL) at 0 ⁰ C was treated with sodium hydride (60% in mineral oil, 2.9 mg, 66 μmol) before being quenched with acetic acid. The resultant mixture was partitioned (EtO Ac-water) and the organics were washed with water, brine, dried (Na ₂ SO ₄ ), and evaporated. The residue was chromatographed (silica, hexanes- EtOAc) to give the title compound (9 mg). ESIMS m/z = 594.27 [M+H] ⁺ .

Example 10. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-ferf-butyl- 3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

atom to which they are attached is V , J = lH-pyrazol-1-ylmethyl.

The title compound was prepared from the compound of example 9 following a similar procedure to that described in example 8, by replacing the compound of example 6 with the compound of example 9.

ESIMS m/z 538.42 (M+H) ⁺ . Example 11. Compound of Formula (Ia), wherein M = tert-butoxy, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the

carbon atom to which they are attached is fc o> , J = lH-pyrazol-1-ylmethyl. Step 11a. A solution of the ethyl 2-hydroxymethyl-acrylate (1.3 g, 10 mmol) in CH ₂ Cl ₂ (20 mL) was treated with TBSCl (1.8g, 12 mmol) in the presence Of Et ₃ N (2 mL) and DMAP (65 mg, 0.53 mmol) room temperature for 16 hours before being partitioned (EtO Ac-saturated aqueous NaHCO ₃ ). The aqueous layer was separated and extracted with EtOAc. The combined organic layers were dried (Na ₂ SO ₄ ), filtered and evaporated. The residue was purified by chromatography (silica, hexanes-ethyl acetate) to afford the desired compound as a colorless oil. ¹³ C NMR (CDCl ₃ ): 171.41, 145.35, 129.00, 66.94, 65.94, 31.31, 23.77, 19.64, 0.00.

Step lib. A mixture of the crude compound from step Ic (2.0 mmol at most), lithium bromide (348 mg, 4.0 mmol), the compound from step l la (576 mg, 2.36 mmol) and Et ₃ N (0.98 mL, 7.0 mmol) in THF (10 mL) was stirred under nitrogen at room temperature for 18.5 hours before being partitioned (EtO Ac-saturated aqueous NaHCO ₃ ). The organics were washed with water and brine, dried (Na ₂ SO ₄ ), filtered and evaporated. The residue was purified by chromatography

(silica, hexane-ethyl acetate) to give the desired compound as a yellow sirup (566 mg, 51%).

ESIMS m/z = 551.26 [M+H] ⁺ .

¹³ C NMR (CDCl ₃ ) 177.7, 177.6, 173.6, 148.0, 144.4, 136.0, 124.0, 111.0, 87.6, 74.7, 69.1, 68.7, 66.10, 66.06, 64.4, 46.0, 33.3, 31.4, 23.7, 19.2, 0.10, 0.00.

Step lie. A solution of the compound from step 1 Ib (566 mg, 1.03 mmol), Et ₃ N (0.43 mL, 3.1 mmol) and the compound from step If (350 mg, 1.54 mmol) in anhydrous dichloromethane (4 mL) was stirred at room temperature under nitrogen for 164 hours before being partitioned (EtO Ac-saturated aqueous NaHCO ₃ ). The organics were washed with water and brine, dried (Na ₂ SO ₄ ), filtered and evaporated. The residue was purified by chromatography (silica, hexane-ethyl acetate) to give the desired compound as a yellow sirup (545 mg, 73%). ESIMS m/z = 741.47 [M+H] ⁺ . 1 ³ C NMR (CDCl ₃ ) 177.1.1, 176.4, 174.8, 173.8, 164.0, 146.6, 145.8, 145.1, 140.9, 137.3, 131.7, 125.3, 123.7, 116.6, 111.1, 88.0, 77.0, 72.4, 71.3, 66.4, 65.1, 60.7, 58.7, 43.7, 40.5, 35.0, 33.6, 31.2, 23.6, 19.0, 0.07, 0.00.

Step Hd. A solution of the compound from step l ie (86 mg, 0.12 mmol) in THF (3.0 mL) was treated with TBAF (1 M in THF, 0.18 mL, 0.18 mmol) in the presence of/?-toluenesulfonic acid monohydrate (18.0 mg, 0.094 mmol) at room temperature for 45 minutes before being partitioned (EtO Ac-saturated aqueous NaHCO ₃ ). The organics were washed with water and brine, dried (Na ₂ SO ₄ ), filtered and evaporated. The residue was purified by chromatography (silica, hexane-ethyl acetate) to give the desired compound as a colorless form (73 mg, 100%). ESIMS m/z = 627.39 [M+H] ⁺ .

¹³ C NMR (CDCl ₃ ) 171.5, 170.8, 166.1, 159.0, 141.7, 141.2, 140.2, 134.8, 133.7,

127.1, 120.2, 118.4, 110.4, 106.2, 82.6, 69.9, 66.1, 65.0, 61.3, 60.4, 56.2, 55.3,

35.3, 34.1, 29.8, 28.1, 13.9.

Alternatively the desired compound of step 1 Id can be prepared through step l ie to Hh.

Step He. Into a mixture of the crude compound from step Ic (1.34 mmol at most) in THF (5 mL) was added methyl acrylate (0.24 mL, 2.68 mmol), lithium bromide (232 mg, 2.68 mmol), and Et ₃ N (0.37 mL, 2.65 mmol). The resulted mixture was stirred at room temperature for 14 hours before being partitioned (EtO Ac-water).

The organics were washed with water, brine, dried (Na ₂ SO ₄ ), and evaporated. The residue was chromatographed (silica, hexanes-EtOAc) to give the desired compound (255 mg, 48.6%). ESIMS m/z = 393.12 [M+H] ⁺ . 1 ³ C NMR (CDCl ₃ ) 172.6, 171.5, 170.8, 142.5, 139.5, 131.0, 119.0, 105.7, 82.4, 69.7, 61.7, 59.4, 51.7, 48.6, 34.2, 27.9.

Step Hf. Into a mixture of the compound from step l ie (240 mg, 0.61 mmol) in CH ₂ Cl ₂ (5.0 mL) was added Et ₃ N (0.28 mL, 2.0 mmol) and the compound from step If (227 mg, 1.0 mmol). The resulted mixture was stirred at room temperature for 19 hours before being diluted with EtOAc. The organics were washed with saturated NaHCO ₃ , water, brine, dried (Na ₂ SO ₄ ), and evaporated. The residue was chromatographed (silica, hexanes-EtOAc) to give the desired compound (277 mg,

77.8%).

ESIMS m/z = 583.16 [M+H] ⁺ . 1 ³ C NMR (CDCl ₃ ) 170.0, 167.6, 158.6, 141.6, 140.6, 140.5, 134.8, 131.5, 126.9, 120.3, 118.0, 110.0, 106.5, 82.9, 70.1, 62.2, 55.1, 53.7, 52.0, 46.3, 35.6, 35.1, 29.7, 28.2.

Step Hg. Into a solution of LDA [made from n-BuLi (2.5 M in hexanes, 16.0 μL, 40 μmol) and diisopropylamine (5.6 μL, 40 μmol) in THF (1.0 mL) is added a solution of the compound from step 1 If (5.8 mg, 10 μmol) in THF (1.0 mL) at - 78°C. It is warmed up to room temperature. The mixture is re-cooled to -78°C when DMF (7.3 mg, 0.1 mmol) is added. It is warmed up to room temperature in 1 hour before saturated NH ₄ Cl (0.1 mL) is added. It is diluted with EtOAc, washed with saturated NaHCO ₃ , water, brine, dried (Na ₂ SO ₄ ), and evaporated. The residue is chromatographed (silica, hexanes-EtOAc) to give the desired compound. Step Hh. A solution of the compound from step 1 Ig (6.1 mg) is treated with sodium borohydride (1.9 mg, 50 μmol) in ethanol (1.0 mL) at room temperature for 30 minutes before partition (EtO Ac- water). The organics are washed with saturated NaHCO ₃ , water, brine, dried (Na ₂ SO ₄ ), and evaporated. The residue is chromatographed (silica, hexanes-EtOAc) to give the desired compound.

Step Hi. A solution of the compound from step 1 Id (12.5 mg, 0.02 mmol) in methanol (1.0 mL) is treated with aqueous NaOH (1 M, 0.1 mL, 0.1 mmol) at room temperature for 14 hours before being acidified with aqueous HCl (1 M). It

is extracted with EtOAc. The organics are dried (Na ₂ SO ₄ ), filtered and evaporated. The residue is purified by chromatography (silica, hexane-ethyl acetate) to give the desired compound.

Step Hj. A solution of the compound from step 1 Ii (12 mg, 0.02 mmol) in THF (1.0 mL) is treated with DIAD (8 mg, 0.04 mmol) and triphenylphosphene (10.5 mg, 0.04 mmol) at room temperature for 18 hours before partition (EtO Ac- saturated aqueous NaHCOs). The organics are washed with water and brine, dried (Na ₂ SO ₄ ), filtered and evaporated. The residue is purified by chromatography (silica, hexane-ethyl acetate) to give the title compound. Example 12. Compound of Formula (Ia), wherein M = tert-butoxγ, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the

A carbon atom to which they are attached is X ' ^r/ , J = lH-pyrazol-1-ylmethyl. Step 12a. The desired compound is prepared from the compound of step 1 Id following a similar procedure to that described in step 5 c Step 12b. The title compound is prepared from the compound of step 12a following a similar procedure to that described in step Ii, by replacing the compound from step Ih with the compound from step 12a.

Example 13. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl- 3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

A atom to which they are attached is X ' ^φ/ , J = lH-pyrazol-l-ylmethyl.

The title compound is prepared from the compound of step 12b following a similar procedure to that described in example 7.

Example 14. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-ferf-butyl- 3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

atom to which they are attached i ,s.3 XC — oK , J. = lH-pyrazol-l-ylmethyl.

The title compound is prepared from the compound of step 12a following similar procedures to that described in examples 3 and 4.

Example 15. Compound of Formula (Ia), wherein M = tert-butoxy, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the

carbon atom to which they are attached ijs _S V > W ^* '— o ,, JJ =: lH-pyrazol-l-ylmethyl.

A mixture of the compound from step 12a (11.7 mg, 0.02 mmol) is treated with paraformylaldehyde (100 mg) in THF (1.0 mL) in the presence ofp- toluenesulfonic acid (5 mg) at room temperature for 18 hours before partition (EtO Ac-saturated aqueous NaHCOs). The organics are washed with water and brine, dried (Na ₂ SO ₄ ), filtered and evaporated. The residue is purified by chromatography (silica, hexane-ethyl acetate) to give the desired compound. Example 16. Compound of Formula (Ia), wherein M = tert-butoxy, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the

carbon atom to which they are attached is N ^* *^- ^NH , J = lH-pyrazol-l-ylmethyl. Step 16a. A mixture of the crude compound from step Ic (113 mg, 0.37 mmol), lithium bromide (97 mg, 1.1 mmol), methyl 2-acetoxyacrylonitrile (82 mg, 0.74 mmol) and Et ₃ N (0.16 mL) in THF (5 mL) is stirred under nitrogen at room temperature for 12 hours before being quenched with saturated aqueous NH ₄ Cl (5 mL). The aqueous layer is separated and extracted with EtOAc. The combined organics are washed with water and brine, dried (Na ₂ SO ₄ ), filtered and evaporated. The residue is purified by chromatography (silica, hexane-ethyl acetate) to give the desired compound.

Step 16b. A solution of the compound from step 16a (384 mg, 0.92 mmol), Et ₃ N (0.40 mL, 2.7 mmol) and the compound from step If (332 mg, 1.5 mmol) in anhydrous dichloromethane (10 mL) is stirred at room temperature under nitrogen for 48 hours before being diluted with water (5 mL). The aqueous layer is separated and extracted with EtOAc. The combined organics are washed with brine, dried (Na ₂ SO ₄ ), and evaporated. The residue is purified by chromatography (silica, hexanes-ethyl acetate) to give the desired compound. Step 16c. A solution of the compound from step 16b (91 mg, 0.15 mmol) in ethanol (5 mL) at room temperature is treated with NaBH ₄ (17 mg, 0.45 mmol) in the presence of cobalt chloride hexahydrate (17.8 mg, 0.075 mmol) for 2 hours before being quenched with saturated aqueous NH ₄ Cl (5 mL). The aqueous layer is separated and extracted with EtOAc. The combined organics is washed with water and brine, dried (Na ₂ SO ₄ ), filtered and evaporated. The residue is purified by chromatography (silica, hexane-ethyl acetate) to give the desired compound. Step 16d. A solution of the compound from step 16c (61 mg, 0.1 mmol) in methanol (3 mL) is treated with aqueous NaOH (1 M, 0.2 mmol) at room

temperature for 24 hours before partition (EtOAc and water). The organics are washed with water and brine, dried (Na ₂ SO ₄ ), filtered and evaporated. The residue is purified by chromatography (silica, hexane-ethyl acetate) to give the desired compound. Step 16e. The title compound is prepared from the compound of step 16d following a similar procedure to that described in example 3. Example 17. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyi- 3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

atom to which they are attached is N ^* *^- ^NH , J = lH-pyrazol-l-ylmethyl. The title compound is prepared from the compound of example 16 following a similar procedure to that described in example 7.

Example 18. Compound of Formula (Ia), wherein M = tert-butoxγ, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the

¹ VT carbon atom to which they are attached is ^ °"^o, J = lH-pyrazol-l-ylmethyl. Step 18a. The desired compound is obtained in step 16a as a diastereomer of the compound of step 16a.

Step 18b. The title compound is prepared from the compound of example 18a following similar procedures to that described through steps 16b to 16e, by replacing the compound of step 16a with the compound of step 18a. Example 19. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butγ\- 3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

atom to which they are attached is ^ ⁰ " ^* ^b, J = lH-pyrazol-l-ylmethyl. The title compound is prepared from the compound of example 18 following a similar procedure to that described in example 7. Example 20. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-ferf-butyl- benzenesulfonyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

atom to which they are attached is X ^* *^°, J = lH-pyrazol-l-ylmethyl. The title compound is prepared from the compound of step Ie following similar procedures to that described in steps Ig to Ii and example 2, by replacing the compound of step If with the commercially available 4-tert-butylbenzenesulfonyl chloride.

Example 21. Compound of Formula (Ia), wherein M = tert-butoxγ, Q = 4-tert- butyl-benzenesulfonyl, Z = l,3-thiazol-2-yl, X and Y taken together with the

carbon atom to which they are attached is V ''-^ ⁰ , J = lH-pyrazol-1-ylmethyl. The title compound is prepared from the compound of step 5 a following similar procedures to that described in steps 5b to 5d and example 6, by replacing the compound of step If with the commercially available 4-tert-butylbenzenesulfonyl chloride.

Example 22. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-ferf-butyl- benzenesulfonyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon atom to which they are attached is ^- ^* *-^° , J = lH-pyrazol-1-ylmethyl.

The title compound is prepared from the compound of example 20 following a similar procedure to that described in example 7.

Example 23. Compound of Formula (Ia), wherein M = tert-butoxy, Q = 4-tert- butyl- phenylcarbamoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the

carbon atom to which they are attached is N "-^ ⁰ , J = lH-pyrazol-1-ylmethyl. Step 23a. A solution of the compound from step Ie (120 mg, 0.26 mmol) in dichloromethane (5 mL) is treated with commercially available 4-tert-butylphenyl isocyanate (50 mg, 0.28 mmol) in the presence of triethylamine (0.1 mL, 0.72 mmol) and cuprous chloride (2.6 mg, 0.03 mmol) at room temperature for 18 hours before evaporation. The residue residue is purified by chromatography (silica, hexane-ethyl acetate) to give the desired compound.

Step 23b. The title compound is prepared from the compound of example 23a following similar procedures to that described in steps Ih and Ii. Example 24. Compound of Formula (Ia), wherein M = tert-butoxy, Q = 4-tert- butyl- phenylcarbamoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the

carbon atom to which they are attached is % ^* -*" ⁰ , J = lH-pyrazol-l-ylmethyl. The title compound is prepared from the compound of step 5 a following similar procedures to that described in step 23 a, 5 c to 5 d and example 6.

Example 25. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butγ\- phenylcarbamoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon atom to which they are attached is ^- ''-^ ⁰ , J = lH-pyrazol-1-ylmethyl. The title compound is prepared from the compound of example 24 following a similar procedure to that described in example 7.

Example 26. Compound of Formula (Ia), wherein M = hydroxy, Q = 3-bromo-4- ferf-butylbenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

atom to which they are attached is > '"^ ⁰ , J = lH-pyrazol-l-ylmethyl. The title compound is prepared from the compound from Ic following similar procedures to that described in examples 1 and 2, by replacing the compound of step If with 3-bromo-4-tert-butylbenzoyl chloride (WO 2007/039145). Example 27. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-ferf-butyl- 3-vinylbenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon atom to which they are attached is X '^ ⁰ , J = lH-pyrazol-l-ylmethyl. The title compound is prepared from the compound from Ic following similar procedures to that described in examples 5, 6 and 8, by replacing the compound of step If with 4-tert-butyl-5-vinylbenzoyl chloride (WO 2007/039143). Example 28. Compound of Formula (Ia), wherein M = hydroxy, Q = 2-fluoro-4- ferf-butyl-5-vinylbenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon atom to which they are attached is X ''^ ⁰ , J = lH-pyrazol-l-ylmethyl. The title compound is prepared from the compound from Ic following similar procedures to that described in examples 5, 6 and 8, by replacing the compound of step If with 02-fluoro-4-tert-butyl-5-vinylbenzoyl chloride (WO 2007/039143). Example 29. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-ferf-butyl- 3-methoxylbenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

atom to which they are attached is 6 VO ""-^ ⁰ , J = l,3-thiazol-4-ylmethyl. The title compound is prepared from tert-butyi 2-amino-3-(l,3-thiazol-4- yl)propanoate (WO 2006/045613) following a similar procedure to that described in examples 1 and 2, by replacing the compound of step Ib with tert-butyl 2- amino-3-(l ,3-thiazol-4-yl)propanoate.

Example 30. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butγ\- 3-methoxylbenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon atom to which they are attached is ^- ''-^ ⁰ , J = l,3-thiazol-2-ylmethyl. The title compound is prepared from tert-butyl 2-amino-3-(l,3-thiazol-2- yl)propanoate (WO 2006/045613) following a similar procedure to that described in examples 5, 6 and 84, by replacing the compound of step Ib with tert-butyl 2- amino-3-(l,3-thiazol-2-yl)propanoate.

Example 31. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-ferf-butyl- 3-methoxylbenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

atom to which they are attached is >■ ""-- ⁰ , J = l,2-thiazol-3-ylmethyl.

The title compound is prepared from tert-butyl 2-amino-3-(l,2-thiazol-3- yl)propanoate (WO 2006/045613) following a similar procedure to that described in examples 1 and 2, by replacing the compound of step Ib with tert-butyl 2- amino-3-(l,2-thiazol-3-yl)propanoate. Example 32. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl- 3-methoxylbenzoyl, Z = 5-methylisoxazol-3-yl, X and Y taken together with the carbon atom to which they are attached is ^- ^* *-^° , J = lH-pyrazol-1-ylmethyl. The title compound is prepared from 5-methylisoxazole-3-carboxaldehyde (WO 2007/039145) following a similar procedure to that described in examples 5, 6 and 8, by replacing 2-formyl-l ,3-thiazole with 5-methylisoxazole-3-carboxaldehyde. Example 33. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl- 3-methoxylbenzoyl, Z = thiophen-2-yl, X and Y taken together with the carbon

atom to which they are attached is ^» *-' ⁰ , J = lH-pyrazol-1-ylmethyl. The title compound is prepared from commercially available 2-formylthiophene following a similar procedure to that described in examples 1 and 2, by replacing 2-formyl-l, 3-thiazole with 2-formylthiophene.

Example 34. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl- 3-methoxylbenzoyl, Z = thiophen-3-yl, X and Y taken together with the carbon

The title compound is prepared from commercially available 3-formylthiophene following a similar procedure to that described in examples 5, 6 and 8, by replacing 2-formyl-l,3-thiazole with 3-formylthiophene.

Example 35. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl- 3-methoxylbenzoyl, Z = furan-2-yl, X and Y taken together with the carbon atom

to which they are attached is X ^** '^ ⁰ , J = lH-pyrazol-l-ylmethyl. The title compound is prepared from commercially available 2-formylfuran following a similar procedure to that described in examples 1 and 2, by replacing 2-formyl-l,3-thiazole with 2-formylfuran. Example 36. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl- 3-methoxylbenzoyl, Z = furan-3-yl, X and Y taken together with the carbon atom to which they are attached is X '^ ⁰ , J = lH-pyrazol-l-ylmethyl. The title compound is prepared from commercially available 3-formylfuran following a similar procedure to that described in examples 5, 6 and 8, by replacing 2-formyl- 1 ,3 -thiazole with 3-formylfuran.

Example 37. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyi- 3-methoxylbenzoyl, Z = l,3-oxazol-2-yl, X and Y taken together with the carbon

atom to which they are attached is X '"-^ ⁰ , J = lH-pyrazol-l-ylmethyl. The title compound is prepared from commercially available 2-formyloxazole following a similar procedure to that described in examples 1 and 2, by replacing 2-formyl-l,3-thiazole with 2-formyloxazole.

Example 38. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-ferf-butyl- 3-methoxylbenzoyl, Z = phenyl, X and Y taken together with the carbon atom to which they are attached is X ''^ ⁰ , J = lH-pyrazol-l-ylmethyl. The title compound is prepared from commercially available benzaldehyde following a similar procedure to that described in examples 5, 6 and 8, by replacing 2-formyl- 1,3-thiazole with benzaldehyde.

Example 39. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-ferf-butyl- 3-methoxylbenzoyl, Z = pyridin-2-yl, X and Y taken together with the carbon atom

The title compound is prepared from commercially available 2-formylpyridine following a similar procedure to that described in examples 1 and 2, by replacing 2-formyl-l,3-thiazole with 2-formylpyridine.

Example 40. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl- 3-methoxylbenzoyl, Z = pyridin-3-yl, X and Y taken together with the carbon atom

to which they are attached is N -*- ^*0 , J = lH-pyrazol-l-ylmethyl. The title compound is prepared from commercially available 3-formylpyridine following a similar procedure to that described in examples 5, 6 and 8, by replacing 2-formyl-l,3-thiazole with 3-formylpyridine. Example 41. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-ferf-butyl- 3-methoxylbenzoyl, Z = pyridin-4-yl, X and Y taken together with the carbon atom

to which they are attached is > ^% - ^* °, J = lH-pyrazol-l-ylmethyl. The title compound is prepared from commercially available 4-formylpyridine following a similar procedure to that described in examples 1 and 2, by replacing 2-formyl-l ,3-thiazole with 4-formylpyridine.

Example 42. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-ferf-butyl- 3-methoxylbenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon atom to which they are attached is >■ ''^ ⁰ , J = thiophen-2-yl. The title compound is prepared from commercially available C-carboxy-C- thiophen-2-yl-methyl-ammonium chloride following a similar procedure to that described in examples 5, 6 and 8, by replacing l-carboxy-2-pyrazol-l-yl- ammonium chloride with C-carboxy-C-thiophen-2-yl-methyl-ammonium chloride. Example 43. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-ferf-butyl- 3-methoxylbenzoyl, Z = l,3-thiazol-2-yl-methyl, X and Y taken together with the

carbon atom to which they are attached is X ^* *^°, J = lH-pyrazol-l-ylmethyl. The title compound is prepared from l,3-thiazol-2-yl-acetaldehyde following a similar procedure to that described in examples 1 and 2, by replacing 2-formyl-l, 3- thiazole with l,3-thiazol-2-yl-acetaldehyde.

Example 44. Compound of Formula (Ia), wherein M = tert-butoxγ, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the

carbon atom to which they are attached is N ''"° , J = lH-pyrazol-l-ylmethyl. A solution of the compound from step 9a (30 mg, 44 μmol) in anhydrous THF (5 mL) at 0 ⁰ C was treated with sodium hydride (60% in mineral oil, 2.9 mg, 66 μmol) before being quenched with acetic acid. The resultant mixture was partitioned (EtO Ac-water) and the organics were washed with water, brine, dried (Na ₂ SO ₄ ), and evaporated. The residue was chromatographed (silica, hexanes- EtOAc) to give the title compound (12 mg). ESIMS m/z = 594.29 [M+H] ⁺ .

Example 45. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-ferf-butyl- 3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

atom to which they are attached is >■ ''-"° , J = lH-pyrazol-l-ylmethyl. The title compound was prepared from the compound of example 44 following a similar procedure to that described in example 8. ESIMS m/z = 538.43 [M+H] ⁺ .

Example 46. Compound of Formula (Ia), wherein M = ferf-butoxy, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the Step 46a. A solution of the compound from step 1 Id (40 mg, 0.064 mmol) in

CH ₂ Cl ₂ (3.0 mL) was treated with MsCl (12.4 μL, 0.16 mmol) in the presence of triethylamine (44.5 μL, 0.32 mmol) at O ⁰ C for 3 hours before being partitioned (EtO Ac-saturated aqueous NaHCOs). The organics were washed with water and brine, dried (Na ₂ SO ₄ ), filtered and evaporated to give the desired compound as a colorless form (44.4 mg, 99%). ESIMS m/z = 705.27 [M+H] ⁺ .

¹³ C NMR (CDCl ₃ ) 171.0, 169.8, 168.8, 166.8, 158.7, 141.5, 140.9, 140.2, 135.1, 132.3, 126.8, 120.5, 118.6, 110.6, 106.6, 82.9, 71.7, 71.2, 66.0, 61.9, 57.3, 55.4, 53.5, 38.3, 37.7, 35.2, 29.7, 28.2, 13.8. Step 46b. A solution of the compound from step 46a (5 mg, 0.007 mmol) in THF (2.0 mL) was treated with sodium hydride (60% in mineral oil, -0.25 mmol) at

room temperature for 15 hours before being quenched (water) and partitioned (EtO Ac-saturated aqueous NaHCOs). The organics were washed with water and brine, dried (Na ₂ SO ₄ ), filtered and evaporated to give the title compound (3.2 mg). ESIMS m/z = 603.29 [M+H] ⁺ . Example 47. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyi- 3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

atom to which they are attached is " ^** *S»■T ^* "— ⁰ o) , J = lH-pyrazol-l-ylmethyl. The title compound is prepared from the compound of example 15 following a similar procedure to that described in example 8. Example 48. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butγ\- 3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

The title compound is prepared from the compound of example 46 following a similar procedure to that described in example 8.

III. Third Principle Invention

Example 1. Compound of Formula (Ia), wherein M = tert-butoxγ, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, J = -CH=NOMe. Step Ia. Into a suspension of the commercially available l-t-butoxycarbony-2- hydroxy-ethyl-ammonium chloride (H-Ser-Ot-Bu hydrochloride) (5.0 g, 25.3 mmol) in dichloromethane (250 mL) is added triethylamine (9.10 mL, 63.3 mmol), chloro t-butyldimethyl silane (4.58 g, 30.4 mmol) and 4-dimethylaminopyridine (0.31 g, 2.53 mmol). The mixture is stirred at room temperature for 3 hours before being quenched with saturated sodium bicarbonate solution. After partition

(EtO Ac-saturated NaHCOs), the combined organics are washed with water and brine, dried (Na ₂ SO ₄ ) and evaporated. The residue is chromatographed (silica, hexanes-EtOAc) to give the desired compound (7.05 g, 100%) as a colorless oil. ESIMS m/z = 276.27 [M+H] ⁺ . Step Ib. A mixture of the compound from step Ia (6.96 g, 25.3 mmol), the commercially available 2-formyl-l,3-thiazole (3.43 g, 30.4 mmol), and activated molecular sieves (4 A, 35 g) in anhydrous methylene chloride (175 mL) is stirred

at room temperature for 15 hours before being filtered through Celite and washed with methylene chloride. The combined organics are evaporated and the residue was used directly for next step. ESIMS m/z = 371.28 [M+H] ⁺ . Step Ic. Into a mixture of the crude compound from step Ib (25.3 mmol at most) in THF (200 mL) is added the commercially available methyl acrylate (4.55 mL, 50.6 mmol), lithium bromide (4.45 g, 50.6 mmol), and Et ₃ N (9.1 mL, 63.2 mmol). The resulted mixture is stirred at room temperature for 12 hours before being partitioned (EtO Ac-water). The organics are washed with water, brine, dried (Na ₂ SO ₄ ), and evaporated. The residue is chromatographed (silica, hexanes- EtOAc) to give the desired compound (5.73 g, 50% three steps) as a yellow oil. ESIMS m/z = 457.12 [M+H] ⁺ .

¹³ C NMR (CDCl ₃ ): 178.5, 177.7, 177.2, 148.0, 124.6, 86.7, 75.7, 74.8, 67.0, 57.1, 54.3, 38.5, 33.5, 31.3, 23.7, 0.1. Step Id. A mixture of the commercially available 4-£-butyl-3-methoxybenzoic acid (2.082 g, 10.0 mmol) in thionyl chloride (5.0 mL) is refluxed for 2.5 hours before being evaporated. Toluene (twice) is added to the residue and the mixture was evaporated. The residue is dried in vacuum to get a crystalline (2.258 g, 99.6%). Step Ie. Into a mixture of the compound from step Ic (1.0 g, 2.19 mmol) in

CH ₂ Cl ₂ (10 mL) is added Et ₃ N (0.95 mL, 6.58 mmol) and the compound from step Id (993 mg, 4.38 mmol). The resulted mixture is stirred at room temperature for 15 hours before being diluted with EtOAc. The organics are washed with saturated NaHCO ₃ , water, brine, dried (Na ₂ SO ₄ ), and evaporated. The residue is chromatographed (silica, hexanes-EtOAc) to give the desired compound (1.24 g, 88%) as a white solid. ESIMS m/z = 647.00 [M+H] ⁺ .

¹ H NMR (CDCl ₃ ): 7.34 (d, IH), 7.05 (d, IH), 7.02 (d, IH), 6.60 (d, IH), 6.39 (s, IH), 5.63 (d, IH), 4.51 (d, IH), 4.13 (m, IH), 3.90 (d, IH), 3.50 (s, 3H), 3.27 (s, 3H), 2.89 (t, IH), 2.26 (dd, IH), 1.37 (s, 9H), 1.17 (s, 9H), 0.84 (s, 9H), 0.05 (d, 6H).

Step If. A mixture of the compound from step Ie (1.24 g, 1.92 mmol) in THF (30 mL) is treated with tetrabutylammonium fluoride (1.0 M in THF) (2.88 mL, 2.88 mmol) in the presence of/?-toluenesulfonic acid monohydrate (292 mg, 1.54

mmol) at room temperature for 1.5 hours before being quenched with saturated ammonium chloride and partitioned (EtO Ac- water). The organics are washed with water, brine, dried (Na ₂ SO ₄ ), and evaporated. The residue is chromatographed (silica, hexanes-EtOAc) to give the desired compound (1.00 g, 98%) as a white solid.

¹ H NMR (CDCl ₃ ): 7.51 (d, IH), 7.19 (d, IH), 7.16 (d, IH), 6.74 (dd, IH), 6.51 (s, IH), 5.71 (d, IH), 4.32 (d, IH), 3.93 (d, IH), 3.87 (m, IH), 3.62 (s, 3H), 3.42 (s, 3H), 2.99 (t, IH), 2.65 (dd, IH), 1.52 (s, 9H), 1.30 (s, 9H). Step Ig. A mixture of the compound from step If (LOO g, 1.88 mmol) and Dess- Martin periodinane (1.19 g, 2.25 mmol) in dry CH ₂ Cl ₂ (40 mL) is stirred for Ih before being quenched with saturated sodium thiosulfate and sodium bicarbonate. The resulted mixture is partitioned (CH ₂ Cl ₂ , water) and the organics are washed with water, brine, dried (Na ₂ SO ₄ ), and evaporated. The residue is chromatographed (silica, hexanes-EtOAc) to give the desired compound (836 mg, 84%) as a white solid.

ESIMS m/z = 530.94 [M+H] ⁺ .

¹³ C NMR (CDCl ₃ ): 196.4, 170.6, 169.0, 168.8, 167.8, 158.4, 142.9, 141.5, 132.9, 126.9, 120.8, 119.1, 110.2, 84.1, 74.6, 63.1, 54.9, 52.4, 47.0, 35.2, 32.0, 29.6, 28.2. Step Ih. A mixture of the compound from step Ig (780 mg, 1.47 mmol) andp- toluenesulfonic acid monohydrate (28 mg, 0.15 mmol) in trimethyl ortho formate (25 mL) is stirred for 12h before being quenched with Et ₃ N (0.1 mL). The resulted mixture is concentrated and chromatographed (silica, hexanes-EtOAc) to give the desired compound (701 mg, 84%) as a white solid. ESIMS m/z = 577.29 [M+H] ⁺ . 1 ³ C NMR (CDCl ₃ ): 170.7, 170.1, 169.9, 169.6, 158.3, 142.0, 140.0, 135.0, 126.7, 120.3, 117.61, 109.4, 105.4, 82.5, 73.1, 63.3, 59.7, 58.8, 54.8, 51.9, 47.6, 35.0, 30.6, 29.6, 28.4.

Step Ii. Into a solution of the compound from step Ih (700 mg, 1.24 mmol) in THF (50 mL) at -78 ⁰ C under N ₂ is treated with LiAlH ₄ (1.0 M in Et ₂ O, 1.5 mL) before being warmed up to -40 ⁰ C. The reaction is kept at this temperature for 4h before being quenched with (K ₂ CO ₃ , 1 M, 30 mL) and partitioned (EtO Ac- water). The organics are washed with water, brine, dried (Na ₂ SO ₄ ), and evaporated. The residue is chromatographed (silica, hexanes-EtOAc) to give the desired compound (400 mg, 60%) as a white foam.

ESIMS m/z = 549.35 [M+H] ⁺ .

¹³ C NMR (CDCl ₃ ): 172.5, 171.0, 170.6, 158.1, 142.3, 139.8, 135.0, 126.4, 119.9, 118.0, 109.6, 105.3, 82.5, 74.0, 65.0, 62.0, 60.4, 59.7, 58.7, 54.8, 45.9, 34.9, 29.6, 28.4. Step Ij. A mixture of the compound from step Ii (100 mg, 186 μmol), tetrabutylammnium iodide (13.7 mg, 37.3 μmol) in methyl iodide (1.0 mL) and CH ₂ Cl ₂ (1 mL) is treated with sodium hydroxide (50% in water, 3.0 mL) at room temperature for 12 hours before being partitioned (EtO Ac-water). The organics are washed with water, brine, dried (Na ₂ SO ₄ ), and evaporated. The residue is chromatographed (silica, hexanes-EtOAc) to give the desired compound (37.5 mg) and the recovered compound from step Ii (20.0 mg). ESIMS m/z = 563.41 [M+H] ⁺ .

¹³ C NMR (CDCl ₃ ): 171.0, 170.7, 158.2, 142.0, 139.4, 135.5, 126.5, 119.6, 117.4, 109.2, 105.6, 82.4, 73.4, 72.0, 64.5, 59.1, 59.0, 54.9, 42.7, 35.0, 32.3, 29.7, 28.5. Step Ik. Into a mixture of the compound from step Ij (5 mg, 8.8 μmol) in dry acetone (1.0 mL) is treated with trimethylsilyl triflate (2.3 μL, 13.2 μmol) for 30 min before being quenched with saturated sodium bicarbonate and partitioned (EtO Ac-water). The organics are washed with water, brine, dried (Na ₂ SO ₄ ), and evaporated. The residue is chromatographed (silica, hexanes-EtOAc) to give the desired compound (1.2 mg). ESIMS m/z = 517.39 [M+H] ⁺ .

¹ H NMR (CDCl ₃ ): 10.0 (s, IH), 7.67 (d, IH), 7.29 (d, IH), 7.01 (d, IH), 6.58 (d, Ih), 6.53 (s, IH), 5.34 (d, IH), 3.48 (s, 3H), 3.00 (s, 3H), 2.94 (m, 2H), 2.76 (m, IH), 2.33 (dd, IH), 2.28 (t, IH), 1.54 (s, 9H), 1.22 (s, 9H). Step 11. A mixture of the compound from step Ik (1.0 mg, 1.9 μmol) in dry

CH ₂ Cl ₂ (1.5 mL) was treated with O-methyl hydroxylamine hydrochloride (1.6 mg, 19 μmol) for 64h before being concentrated and chromatographed (silica, hexanes- EtOAc) to give the title compound. ESIMS m/z = 546.30 [M+H] ⁺ . Example 2. Compound of Formula (Ia), wherein M = methoxy, Q = 4-ferf-butyl- 3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxycarbonyl, J = -CH=NOMe.

Step 2a. Into a suspension of the commercially available l-benzyloxycarbony-2- hydroxy-ethyl-ammonium chloride (H-Ser-OBzl hydrochloride) (5.0 g, 21.6 mmol) in dichloromethane (250 mL) is added triethylamine (9.21 mL, 64.0 mmol), chloro t-butyldimethyl silane (4.25 g, 28.2 mmol) and 4-dimethylaminopyridine (0.31 g, 2.56 mmol). The mixture is stirred at room temperature for 3 hours before being quenched with saturated sodium bicarbonate solution. After partition (EtOAc and saturated NaHCOs), the combined organics are washed with water and brine, dried (Na ₂ SO ₄ ) and evaporated. The residue is chromatographed (silica, hexanes-EtOAc) to give the desired compound (6.13 g, 92%) as a colorless oil. ESIMS m/z = 310.16 [M+H] ⁺ .

¹ H NMR (CDCl ₃ ) 7.16 (m, 5H), 5.07 (s, 2H), 3.86 (dd, IH), 3.73 (dd, IH), 3.33 (t, IH), 0.93 (s, 9H), 0.01 (d, 6H).

Step 2b. A mixture of the compound from step 2a (2.0 g, 7.35 mmol), the commercially available 2-formyl-l,3-thiazole (1.25 g, 11.0 mmol), and activated molecular sieves (4 A, 10 g) in anhydrous methylene chloride (50 mL) is stirred at room temperature for 15 hours before being filtered through Celite and washed with methylene chloride. The combined organics are evaporated and the residue is used directly for next step. ESIMS m/z = 405.15 [M+H] ⁺ . Step 2c. Into a mixture of the crude compound from step 2b (1.36 mmol at most) in THF (12 mL) is added the commercially available methyl acrylate (0.25 mL, 2.73 mmol), lithium bromide (240 mg, 2.73 mmol), and Et ₃ N (0.49 mL, 3.41 mmol). The resulted mixture is stirred at room temperature for 15 hours before being partitioned (EtO Ac- water). The organics are washed with water, brine, dried (Na ₂ SO ₄ ), and evaporated. The residue is chromatographed (silica, hexanes- EtOAc) to give the desired compound (521 mg, 66% two steps) as a yellow oil. ESIMS m/z = 491.22 [M+H] ⁺ .

¹ H NMR (CDCl ₃ ): 7.61(d, IH), 7.33 (m, 5H), 7.17 (d, IH), 5.17 (d, 2H), 4.95 (d, IH), 3.77 (d, IH), 3.64 (d, IH), 3.46 (dd, IH), 3.42 (s, 3H), 2.76 (dd, IH), 2.14 (dd, IH), 0.84 (s, 9H), 0.05 (d, 6H).

Step 2d. Into a mixture of the compound from step 2c (500 mg, 1.02 mmol) in CH ₂ Cl ₂ (8 mL) is added Et ₃ N (0.44 mL, 3.06 mmol) and the compound from step Id (462 mg, 2.04 mmol). The resulted mixture is stirred at room temperature for 48 hours before being diluted with EtOAc. The organics are washed with saturated

NaHCθ3, water, brine, dried (Na ₂ SO ₄ ), and evaporated. The residue is chromatographed (silica, hexanes-EtOAc) to give the desired compound (665 mg, 96%) as a yellow oil. ESIMS m/z = 681.33 [M+H] ⁺ . 1 ³ C NMR (CDCl ₃ ): 176.5, 175.5, 175.2, 174.0, 163.8, 146.8, 145.4, 141.1, 140.2, 134.4, 133.7, 132.0, 125.5, 123.1, 115.3, 75.6, 72.8, 69.9, 68.7, 60.4, 57.4, 53.1, 41.4, 40.4, 35.0, 31.6, 31.5, 23.7, 0.2, 0.0.

Step 2e. A solution of the compound from step 2d (665 mg, 978 μmol) in THF (15 mL) at -78 ⁰ C under N ₂ is treated with LiAlH ₄ (1.0 M in Et ₂ O, 1.1 mL) for 30 min before being quenched with (K ₂ CO ₃ , 1 M, 10 mL) and partitioned (EtO Ac- water). The organics are washed with water, brine, dried (Na ₂ SO ₄ ), and evaporated. The residue is chromatographed (silica, hexanes-EtOAc) to give the desired compound (70 mg, 11%) and recovered the compound from step 2d (472 mg, 71%). ESIMS m/z = 653.45 [M+H] ⁺ .

¹ H NMR (CDCl ₃ ): 7.37 (d, IH), 7.26 (m, 5H), 7.00 (d, IH), 6.99 (s, IH), 6.65 (d, IH), 6.45 (s, IH), 5.62 (d, IH), 5.29 (d, IH), 5.14 (d, IH), 4.56 (d, IH), 4.03 (d, IH), 3.56 (m, IH), 3.31 (m, IH), 2.67 (t, IH), 2.10 (dd, IH), 1.93 (m, IH), 1.17 (s, 9H), 0.85 (s, 9H), 0.03 (d, 6H). Step 2f. A mixture of the compound from step 2e (70 mg, 107 μmol), tetrabutylammnium iodide (7.9 mg, 21.5 μmol) in methyl iodide (1.0 mL) is treated with sodium hydroxide (50% in water, 3.0 mL) at room temperature for 1.5 hours before being partitioned (EtO Ac- water). The organics are washed with water, brine, dried (Na ₂ SO ₄ ), and evaporated. The residue is chromatographed (silica, hexanes-EtOAc) to give the desired compound (24.4 mg). ESIMS m/z = 591.56 [M+H] ⁺ .

¹ H NMR (CDCl ₃ ): 7.30 (d, IH), 7.06 (d, IH), 6.95 (d, IH), 6.54 (d, IH), 6.29 (s, IH), 5.44 (d, IH), 4.45 (d, IH), 3.93 (d, IH), 3.73 (s, 3H), 3.45 (s, 3H), 3.42 (m, IH), 2.90 (s, 3H), 2.88 (m, IH), 2.59 (t, IH), 2.25 (dd, IH), 2.15 (t, IH), 1.13 (s, 9H), 0.83 (s, 9H), 0.00 (s, 6H).

Step 2g. The desired compound is prepared from the compound of step 2f following a similar procedure to that described in step If.

Step 2h. The desired compound is prepared from the compound of step 2g following a similar procedure to that described in step Ig.

Step 2i. A mixture of the compound from step 2h (10 μmol) in ethanol (1.5 mL) is treated with O-methyl hydroxylamine hydrochloride (100 μmol) for 24 hours before being concentrated and chromatographed (silica, hexanes-EtOAc) to give the title compound.

Example 3. Compound of Formula (Ia), wherein M = tert-butoxy, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, J =

-CH=NOMe. Step 3a. The desired compound is prepared from the compound of step Ib and the commercially available methyl 2-fluoroacrylate following a similar procedure to that described in step Ic, by replacing methyl acrylate with methyl 2- fluoroacrylate.

Step 3b. The desired compound is prepared from the compound of step 3 a and the compound of step Id following a similar procedure to that described in step Ie.

Step 3c. A mixture of the compound from step 3b (113 mg, 0.17 mmol) in ethanol

(4.75 mL) and methanol (0.25 mL) is treated with NaBH ₄ (25 mg, 0.66 mmol) at room temperature with stirring for 22 hours before partition EtO Ac/water. The organics are washed with water, brine, dried (Na ₂ SO ₄ ), and evaporated to give the desired compound.

Step 3d. The desired compound is prepared from the compound of step 3c following a similar procedure to that described in step Ij.

Step 3e. The desired compound is prepared from the compound of step 3d following a similar procedure to that described in step If. Step 3f. The desired compound is prepared from the compound of step 3 e following a similar procedure to that described in step Ig.

Step 3g. The title compound is prepared from the compound of step 3f following a similar procedure to that described in step 2i.

Example 4. Compound of Formula (Ia), wherein M = tert-butoxy, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = methoxycarbonyl-methyl, Y = methoxycarbonyl, J = -CH=NOMe.

Step 4a. The desired compound is prepared from the compound of step Ib and the commercially available 2-methylene succinic acid dimethyl ester following a

similar procedure to that described in step Ic, by replacing methyl acrylate with 2- methylene succinic acid dimethyl ester.

Step 4b. The desired compound is prepared from the compound of step 4a and the compound of step Id following a similar procedure to that described in step Ie. Step 4c. The desired compound is prepared from the compound of step 4b following a similar procedure to that described in step If.

Step 4d. The desired compound is prepared from the compound of step 4c following a similar procedure to that described in step Ig.

Step 4e. The title compound is prepared from the compound of step 4d following a similar procedure to that described in step 2i.

Example 5. Compound of Formula (Ia), wherein M = tert-butoxy, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = acetamido, Y = methoxycarbonyl, J = -CH=NOMe.

Step 5a. The desired compound is prepared from the compound of step Ib and the commercially available methyl 2-acetamidoacrylate following a similar procedure to that described in step Ic, by replacing methyl acrylate with methyl 2- acetamidoacrylate.

Step 5b. The desired compound is prepared from the compound of step 5 a and the compound of step Id following a similar procedure to that described in step Ie. Step 5c. The desired compound is prepared from the compound of step 5b following a similar procedure to that described in step If.

Step 5d. The desired compound is prepared from the compound of step 5c following a similar procedure to that described in step Ig.

Step 5e. The title compound is prepared from the compound of step 5d following a similar procedure to that described in step 2i.

Example 6. Compound of Formula (Ia), wherein M = tert-butoxy, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = acetoxy, Y = cyano, J =

-CH=NOMe.

Step 6a. The desired compound is prepared from the compound of step Ib and the commercially available methyl 2-acetoxyacrylonitrile following a similar procedure to that described in step Ic, by replacing methyl acrylate with methyl 2- acetoxy acrylonitrile .

Step 6b. The desired compound is prepared from the compound of step 6a and the compound of step Id following a similar procedure to that described in step Ie. Step 6c. The desired compound is prepared from the compound of step 6b following a similar procedure to that described in step If. Step 6d. The desired compound is prepared from the compound of step 6c following a similar procedure to that described in step Ig.

Step 6e. The title compound is prepared from the compound of step 6d following a similar procedure to that described in step 2i. Example 7. Compound of Formula (Ia), wherein M = tert-butoxγ, Q = 4-tert- butyl-3-methoxybenzovL Z = 1.3-thiazol-2-yl. X = -CH=NOMe. Y = methoxycarbonyl, J = -CH=NOMe.

Step 7a. A solution of the commercially available ethyl 2-hydroxymethyl-acrylate (1.301 g, 10.0 mmol) in DMF (10 mL) is treated with chloro triethyl-silane (2.52 mL, 15.0 mmol) in the presence of imidazole (2.042 g, 30.0 mmol) at room temperature for 3 hours before partition (hexances- water). The organics are washed with water (3 x) and brine, dried (Na ₂ SO ₄ ) and evaporated to give the crude desired product as a colorless oil (2.91 g, -84% purity). Step 7b. The desired compound is prepared from the compound of step Ib and the compound of step 7a following a similar procedure to that described in step Ic, by replacing methyl acrylate with the compound of step 7a.

Step 7c. The desired compound is prepared from the compound of step 7b and the compound of step Id following a similar procedure to that described in step Ie. Step 7d. The desired compound is prepared from the compound of step 7c following a similar procedure to that described in step If but using tetrabutylammonium fluoride (3.0 eq) and/?-toluenesulfonic acid monohydrate (1.6 eq), by replacing the compound of step Ie with the compound of step 7c. Step 7e. The desired compound is prepared from the compound of step 7d following a similar procedure to that described in step Ig but using Dess-Martin Periodinane (3 eq), by replacing the compound of step If with the compound of step 7d.

Step 7f. The title compound is prepared from the compound of step 7e following a similar procedure to that described in step 2i.

Example 8. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butγ\- 3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, J = -CH=NOMe.

A solution of the compound of example 1 (10 mg) in dichloromethane (0.5 mL) is treated with TFA (1 mL) at room temperature for 2.5 hours and the volatiles are removed by N ₂ flow. The residue is purified by flash column chromatography (silica, CFtCb-methanol) to give the title compound.

Example 9. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{- 3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen. Y = -COOH, J = -CH=NOMe.

A solution of the compound of example 2 (20 mg) in THF (1.0 mL) and water (0.5 mL) is treated with NaOH (8 mg) at room temperature for 15 hours and the volatiles are evaporated off. The residue is purified by flash column chromatography (Cis-reverse phase, water then MeOH-water) to give the title compound.

Example 10. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl-

3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, J =

-CH=NOMe.

The title compound is prepared from the compound of example 3 following a similar procedure to that described in example 8.

Example 11. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyi- 3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = methoxycarbonyl-methyl, Y = methoxycarbonyl, J = -CH=NOMe. The title compound is prepared from the compound of example 4 following a similar procedure to that described in example 8.

Example 12. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butγ\-

3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = acetamido, Y = methoxycarbonyl, J =

-CH=NOMe.

The title compound is prepared from the compound of example 5 following a similar procedure to that described in example 8.

Example 13. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{- 3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = acetoxy, Y = cyano, J = -CH=NOMe.

The title compound is prepared from the compound of example 6 following a similar procedure to that described in example 8.

Example 14. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl- 3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = -CH=NOMe, Y = methoxycarbonyl, J = -CH=NOMe.

The title compound is prepared from the compound of example 7 following a similar procedure to that described in example 8.

Example 15. Compound of Formula (Ia), wherein M = tert-butoxy, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the

carbon atom to which they are attached is 6 ^-O ^* "-' ⁰ , J = -CH=N-OMe.

Step 15a. A solution of the compound from step 4b (55 mg, 0.076 mmol) in anhydrous THF is treated with lithium borohydride (17 mg, 0.76 mmol) with stirring under N ₂ for 7 hours before it is quenched with K2CO3 (2M in water, 5 mL). The aqueous layer is separated and extracted with EtOAc (3 X 5 mL). The combined organic layers are dried by Na ₂ SO ₄ , filtered and evaporated. The residue is purified by flash column chromatography (silica, hexanes-ethyl acetate) to afford the desired compound.

Step 15b. A solution of the compound from step 15a (11 mg, 0.0167 mmol) in pyridine (4 mL) is treated with/?-toluenesulfonyl chloride (38 mg, 0.20 mmol) at 150 ⁰ C under microwave (Biotage Initiator) for 30 min before being cooled to room temperature and quenched with water (1 mL). The volatiles are evaporated off and the residue is partitioned (EtO Ac-saturated NaHCOs). The organics are washed with water, brine, and dried (Na ₂ SO ₄ ), and evaporated. The residue is purified by flash column chromatography (silica, hexanes-ethyl acetate) to afford the desired compound.

Step 15c. The desired compound is prepared from the compound of step 15b following a similar procedure to that described in step If. Step 15d. The desired compound is prepared from the compound of step 15c following a similar procedure to that described in step Ig. Step 15e. The title compound is prepared from the compound of step 15d following a similar procedure to that described in step 11.

Example 16. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butγ\- 3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

atom to which they are attached is ^» ''-*- ⁰ , J = -CH=N-OMe. The title compound is prepared from the compound of example 15 following a similar procedure to that described in example 8.

Example 17. Compound of Formula (Ia), wherein M = tert-butoxy, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the

carbon atom to which they are attached is ^* -~o °, J = -CH=N-OMe.

Step 17a. A solution of the compound of step 15a (13 mg, 20 μmol) and pyridine (0.05 mL) in CH ₂ Cl ₂ (1.5 mL) is treated with triphosgene (6 mg, 20 μmol) at -78 ⁰ C for 40 min before being quenched with saturated aqueous NaHCO ₃ (5 mL). The aqueous layer is separated and extracted with EtOAc (3 X 5 mL). The combined organics are dried by Na ₂ SO ₄ , filtered and evaporated. The residue is purified by chromatography (silica, hexanes-ethyl acetate) to afford the desired compound. Step 17b. The desired compound is prepared from the compound of step 17a following a similar procedure to that described in step If. Step 17c. The desired compound is prepared from the compound of step 17b following a similar procedure to that described in step Ig. Step 17d. The title compound is prepared from the compound of step 17c following a similar procedure to that described in step 11.

Example 18. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyi- 3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon The title compound is prepared from the compound of example 17 following a similar procedure to that described in example 8.

Example 19. Compound of Formula (Ia), wherein M = tert-butoxy, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the Step 19a. A solution of the compound from step 5b (105 mg, 0.15 mmol) in ethanol (10 mL) at 0 ⁰ C is charged with sodium borohydride (24 mg, 0.63 mmol)

and anhydrous calcium chloride (35 mg, 0.31 mmol). The mixture is slowly warmed up to room temperature and stirred for 12 hours before being quenched with saturated aqueous NH ₄ Cl (5 mL). The aqueous layer is separated and extracted with EtOAc. The combined organics are washed with water and brine, dried (Na ₂ SO ₄ ), filtered and evaporated. The residue is purified by chromatography

(silica, hexane-ethyl acetate) to give the desired compound as a colorless oil.

Step 19b. A solution of the compound from step 19a (66 mg, 98 μmol) in dimethoxyethane (6 mL) is treated with palladium chloride (17 mg, 98 μmol) and sodium acetate (20 mg, 0.25 mmol) in a sealed tube under carbon monoxide (50 psϊ) at 80 ⁰ C for 24hours before being filtered through a pad of Celite. The filtrate is concentrated and purified by chromatography (silica, hexanes-ethyl acetate) to give the desired compound as a colorless oil.

Step 19c. The desired compound is prepared from the compound of step 19b following a similar procedure to that described in step If. Step 19d. The desired compound is prepared from the compound of step 19c following a similar procedure to that described in step Ig.

Step 19e. The title compound is prepared from the compound of step 19d following a similar procedure to that described in step 11.

Example 20. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-ferf-butyl- 3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon The title compound is prepared from the compound of example 19 following a similar procedure to that described in example 8.

Example 21. Compound of Formula (Ia), wherein M = tert-butoxy, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the A solution of the compound from example 19 (6 mg) in methanolic ammonia (7N, 3.0 mL) is stirred at room temperature for 12 hours before being evaporated and purified by chromatography (silica, hexanes-ethyl acetate) to give the title compound.

Example 22. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butγ\- 3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon The title compound is prepared from the compound of example 21 following a similar procedure to that described in example 8.

Example 23. Compound of Formula (Ia), wherein M = ferf-butoxy, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the

carbon atom to which they are attached is ^** *«• ^* ' , J = -CH=N-OMe. Step 23a. A solution of the compound from step 19a (33 mg, 49 μmol) in anhydrous dichloromethane (5 mL) at 0 ⁰ C is treated with triethylamine (0.14 mL, 0.98 mmol) and methanesulfonyl chloride (23 μL, 0.29 mmol) before being quenched with saturated sodium bicarbonate aqueous solution. The resultant mixture is partitioned (CH ₂ Cl2-water) and the organics are washed with water, brine, dried (Na ₂ SO ₄ ), and evaporated. The residue is chromatographed (silica, hexanes-EtOAc) to give the desired compound.

Step 23b. A solution of the compound from step 23 a (33 mg, 44 μmol) in anhydrous THF (5 mL) at 0 ⁰ C is treated with sodium hydride (60% in mineral oil, 2.9 mg, 66 μmol) before being quenched with acetic acid. The resultant mixture is partitioned (EtO Ac-water) and the organics were washed with water, brine, dried (Na ₂ SO ₄ ), and evaporated. The residue is chromatographed (silica, hexanes- EtOAc) to give the desired compound.

Step 23c~23e. The title compound is prepared from the compound of step 23b following similar procedures to that described in steps 2g ~ 2i. Example 24. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl- 3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

X _j1 NAc atom to which they are attached is X , J = -CH=N-OMe.

The title compound was prepared from the compound of example 23 following a similar procedure to that described in example 8.

Example 25. Compound of Formula (Ia), wherein M = tert-butoxγ, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the

carbon atom to which they are attached is N ^* '-- ⁰ , J = -CH=N-OMe. Step 25a. A solution of the compound from step 23 a (33 mg, 44 μmol) in anhydrous THF (5 mL) at 0 ⁰ C is treated with sodium hydride (60% in mineral oil, 2.9 mg, 66 μmol) before being quenched with acetic acid. The resultant mixture is partitioned (EtO Ac-water) and the organics are washed with water, brine, dried (Na ₂ SO ₄ ), and evaporated. The residue is chromatographed (silica, hexanes- EtOAc) to give the desired compound. Step 25b~25d. The title compound is prepared from the compound of step 25 a following similar procedures to that described in steps 2g ~ 2i. Example 26. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-ferf-butyl- 3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon κ atom to which they are attached is X ^%/ , J = -CH=N-OMe. Step 26a. The desired compound is prepared from the compound of step 7c following a similar procedure to that described in step 19a.

Step 26b. A solution of the compound of step 26a (30 mg) in acetonitrile (2 mL) is treated with HCl (1 M, 2 mL) at room temperature for 5 hours before partition

(EtO Ac-saturated NaHCOs). The organics are washed with water, brine, dried (Na ₂ SO ₄ ), and evaporated. The residue is chromatographed (silica, hexanes-

EtOAc) to give the desired compound.

Step 26c. The desired compound is prepared from the compound of step 26b following a similar procedure to that described in step 15b.

Steps 26d~26g. The title compound is prepared from the compound of step 25a following similar procedures to that described in steps 2g ~ 2i and example 8.

Example 27. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl-

3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

atom to which they are attached iiss X X^ ^*• -—oo , , JJ == --CCHH==NN--(OMe. The title compound is prepared from the compound of step 26b following similar procedures to that described in steps 17a, 2g ~ 2i and example 8.

Example 28. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butγ\- 3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

atom to which they are attached J i ₈ s - >C■ W ^' "'— o . , IJ ' = -CH=N-OMe. Step 28a. A mixture of the compound from step 26b (13 mg, 0.02 mmol) is treated with paraformylaldehyde (100 mg) in THF (1.0 mL) in the presence oϊp- toluenesulfonic acid (5 mg) at room temperature for 18 hours before partition (EtO Ac-saturated aqueous NaHCOs). The organics are washed with water and brine, dried (Na ₂ SO ₄ ), filtered and evaporated. The residue is purified by chromatography (silica, hexane-ethyl acetate) to give the desired compound. Steps 28b~28e. The title compound is prepared from the compound of step 26b following similar procedures to that described in steps 2g ~ 2i and example 8. Example 29. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-ferf-butyl- 3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

atom to which they are attached is \ ''^ ^m . J = -CH=N-OMe. Step 29a. A solution of the compound from step 6b (91 mg, 0.15 mmol) in ethanol (5 mL) at room temperature is treated with NaBH ₄ (17 mg, 0.45 mmol) in the presence of cobalt chloride hexahydrate (17.8 mg, 0.075 mmol) for 2 hours before being quenched with saturated aqueous NH ₄ Cl (5 mL). The aqueous layer is separated and extracted with EtOAc. The combined organics is washed with water and brine, dried (Na ₂ SO ₄ ), filtered and evaporated. The residue is purified by chromatography (silica, hexane-ethyl acetate) to give the desired compound. Step 29b. A solution of the compound from step 29a (61 mg, 0.1 mmol) in methanol (3 mL) is treated with aqueous NaOH (1 M, 0.2 mmol) at room temperature for 24 hours before partition (EtOAc and water). The organics are washed with water and brine, dried (Na ₂ SO ₄ ), filtered and evaporated. The residue is purified by chromatography (silica, hexane-ethyl acetate) to give the desired compound.

Step 29c. The title compound is prepared from the compound of step 29b following a similar procedure to that described in step 17a. Steps 29d~29g. The title compound is prepared from the compound of step 29c following similar procedures to that described in steps 2g ~ 2i and example 8.

Example 30. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butγ\- 3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X is cyano, Y is acetoxy, J = -CH=N- OMe.

Step 30a. The desired compound is obtained in step 6a as a diastereomer of the compound of step 6a.

Steps 30b~30e. The title compound is prepared from the compound of step 30a following similar procedures to that described in steps 6b ~ 6d and example 8. Example 31. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyi- 3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

atom to which they are attached is ^** * ^"0 ^o. J = -CH=N-OMe.

The title compound is prepared from the compound of example 30a following similar procedures to that described examples 6 and 29.

Example 32. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl- benzenesulfonyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

atom to which they are attached is X ^* *^°, J = -CH=N-OMe.

The title compound is prepared from the compound of step 4a following similar procedures to that described in steps Ie, 15a to 15e and example 16, by replacing the compound of step 1 d with the commercially available 4-tert- butylbenzenesulfonyl chloride. Example 33. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl- phenylcarbamoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

atom to which they are attached is >» ^> *- ^*0 , J = -CH=N-OMe.

Step 33a. A solution of the compound from step 4a (137 mg, 0.26 mmol) in dichloromethane (5 mL) is treated with commercially available 4-te/t-butylphenyl isocyanate (50 mg, 0.28 mmol) in the presence of triethylamine (0.1 mL, 0.72 mmol) and cuprous chloride (2.6 mg, 0.03 mmol) at room temperature for 18 hours before evaporation. The residue residue is purified by chromatography (silica, hexane-ethyl acetate) to give the desired compound.

Step 33b. The title compound is prepared from the compound of step 33a following similar procedures to that described in examples 15 and 16.

Example 34. Compound of Formula (Ia), wherein M = hydroxy, Q = 3-bromo-4- ferf-butylbenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

atom to which they are attached is ^» ''" ⁰ _^ J = -CH=N-OMe. The title compound is prepared from the compound of step 4a following similar procedures to that described in steps Ie, 15a to 15e and example 16, by replacing the compound of step Id with 3-bromo-4-te/t-butylbenzoyl chloride (WO 2007/039145).

Example 35. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-ferf-butyl- 3-vinylbenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon atom

to which they are attached is V ^% "°. J = -CH=N-OMe.

The title compound is prepared from the compound of step 4a following similar procedures to that described in steps Ie, 15a to 15e and example 16, by replacing the compound of step Id with 4-ter£-butyl-5-vinylbenzoyl chloride (WO 2007/039143). Example 36. Compound of Formula (Ia), wherein M = hydroxy, Q = 2-fluoro-4- ferf-butyl-5-vinylbenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the

carbon atom to which they are attached is ^" ^ ^* "^°, J = -CH=N-OMe. The title compound is prepared from the compound of step 4a following similar procedures to that described in steps Ie, 15a to 15e and example 16, by replacing the compound of step Id with 2-fluoro-4-te/t-butyl-5-vinylbenzoyl chloride (WO 2007/039143).

Example 37. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-ferf-butyl- 3-methoxylbenzoyl, Z = 5-methylisoxazol-3-yl, X and Y taken together with the

carbon atom to which they are attached is ^" ^ ^* "^°, J = -CH=N-OMe. The title compound is prepared from 5-methylisoxazole-3-carboxaldehyde (WO

2007/039145) following a similar procedure to that described in examples 4, 15, 16 and 8, by replacing 2-formyl-l,3-thiazole with 5-methylisoxazole-3- carboxaldehyde.

Example 38. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butγ\- 3-methoxylbenzoyl, Z = thiophen-2-yl, X and Y taken together with the carbon

atom to which they are attached is ^» ''"°, J = -CH=N-OMe. The title compound is prepared from commercially available 2-formylthiophene following a similar procedure to that described in examples 4, 15, 16 and 8, by replacing 2-formyl-l,3-thiazole with 2-formylthiophene.

Example 39. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-ferf-butyl- 3-methoxylbenzoyl, Z = thiophen-3-yl, X and Y taken together with the carbon

atom to which they are attached is % ^ ⁰ , J = -CH=N-OMe. The title compound is prepared from commercially available 3-formylthiophene following a similar procedure to that described in examples 4, 15, 16 and 8, by replacing 2-formyl-l,3-thiazole with 3-formylthiophene.

Example 40. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-ferf-butyl- 3-methoxylbenzoyl, Z = furan-2-yl, X and Y taken together with the carbon atom

to which they are attached is X ^% - ^*0 . J = -CH=N-OMe.

The title compound is prepared from commercially available 2-formylfuran following a similar procedure to that described in examples 4, 15, 16 and 8, by replacing 2-formyl-l,3-thiazole with 2-formylfuran.

Example 41. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyi- 3-methoxylbenzoyl, Z = furan-3-yl, X and Y taken together with the carbon atom

to which they are attached is X '"-- ⁰ , J = -CH=N-OMe. The title compound is prepared from commercially available 3-formylfuran following a similar procedure to that described in examples 4, 15, 16 and 8, by replacing 2-formyl-l,3-thiazole with 3-formylfuran. Example 42. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-ferf-butyl- 3-methoxylbenzoyl, Z = l,3-oxazol-2-yl, X and Y taken together with the carbon

atom to which they are attached is V ^* "- ^*0 , J = -CH=N-OMe. The title compound is prepared from commercially available 2-formyl-l,3-oxazole following a similar procedure to that described in examples 4, 15, 16 and 8, by replacing 2-formyl- 1 ,3-thiazole with 2-formyl- 1 ,3-oxazole.

Example 43. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butγ\- 3-methoxylbenzoyl, Z = phenyl, X and Y taken together with the carbon atom to

which they are attached is V ^' '^ ⁰ . J = -CH=N-OMe. The title compound is prepared from commercially available benzaldehyde following a similar procedure to that described in examples 4, 15, 16 and 8, by replacing 2-formyl-l,3-thiazole with benzaldehyde.

Example 44. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyi- 3-methoxylbenzoyl, Z = pyridin-2-yl, X and Y taken together with the carbon atom

to which they are attached is X ^' "'^ ⁰ . J = -CH=N-OMe. The title compound is prepared from commercially available 2-formylpyridine following a similar procedure to that described in examples 4, 15, 16 and 8, by replacing 2-formyl-l,3-thiazole with 2-formylpyridine.

Example 45. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyi- 3-methoxylbenzoyl, Z = pyridin-3-yl, X and Y taken together with the carbon atom

to which they are attached is X ^% - ^*0 . J = -CH=N-OMe.

The title compound is prepared from commercially available 3-formylpyridine following a similar procedure to that described in examples 4, 15, 16 and 8, by replacing 2-formyl-l,3-thiazole with 3-formylpyridine.

Example 46. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyi- 3-methoxylbenzoyl, Z = pyridin-4-yl, X and Y taken together with the carbon atom

to which they are attached is X ^* '^°, J = -CH=N-OMe.

The title compound is prepared from commercially available 4-formylpyridine following a similar procedure to that described in examples 4, 15, 16 and 8, by replacing 2-formyl-l,3-thiazole with 4-formylpyridine. Example 47. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{- 3-methoxylbenzoyl, Z = l,3-thiazol-2-yl-methyl, X and Y taken together with the

carbon atom to which they are attached is 6 XO ^* "^°, J = -CH=N-OMe. The title compound is prepared from l,3-thiazol-2-yl-acetaldehyde following a similar procedure to that described in examples 4, 15, 16 and 8, by replacing 2- formyl-l,3-thiazole with l,3-thiazol-2-yl-acetaldehyde.

Example 48. Compound of Formula (Ia), wherein M = tert-butoxγ, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the

carbon atom to which they are attached is o , J = -CH=N-OMe.

Step 48a. A solution of the compound of step 7c (30 mg) in acetonitrile (2 mL) is treated with HCl (1 M, 2 mL) at room temperature for 5 hours before partition

(EtO Ac-saturated NaHCOs). The organics are washed with water, brine, dried

(Na ₂ SO ₄ ), and evaporated. The residue is chromatographed (silica, hexanes-

EtOAc) to give the desired compound.

Step 48b. A solution of the compound from step 48a (44 mg, 0.064 mmol) in CH ₂ Cl ₂ (3.0 mL) is treated with MsCl (12.4 μL, 0.16 mmol) in the presence of triethylamine (44.5 μL, 0.32 mmol) at O ⁰ C for 3 hours before being partitioned

(EtO Ac-saturated aqueous NaHCOs). The organics are washed with water and brine, dried (Na ₂ SO ₄ ), filtered and evaporated to give the desired compound.

Step 48c. A solution of the compound from step 48b (5.4 mg, 0.007 mmol) in THF (2.0 mL) is treated with sodium hydride (60% in mineral oil, -0.25 mmol) at room temperature for 15 hours before being quenched (water) and partitioned

(EtO Ac-saturated aqueous NaHCOs). The organics are washed with water and brine, dried (Na ₂ SO ₄ ), filtered and evaporated to give the title compound.

Steps 48d. The title compound is prepared from the compound of step 48b following similar procedures to that described in steps 2g ~ 2i and example 8.

Example 49. Compound of Formula (Ia), wherein M = tert-butoxy, Q = 4-tert- butyl-3-methoxybenzoyl. Z = 1.3-thiazol-2-yl. X is H. Y is -CH ₇ OMe. J = -

CH=NNMe ₇ .

A solution of the compound of example 1 (2.0 mg, 3.8 μmol) in methanol (1 mL) is treated with N,N-dimethylhydrazine (38 μmol) at room temperature for 10 hours before partition (EtO Ac-saturated NaHCOs). The organics are washed with water, brine, dried (Na ₂ SO ₄ ), and evaporated. The residue is chromatographed (silica, hexanes-EtOAc) to give the title compound.

Example 50. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyi- 3-methoxybenzoyl. Z = 1.3-thiazol-2-yl. X is H. Y is -CH ₇ OMe. J = -

CH=NNMe ₇ .

A solution of the compound of example 49 (2.0 mg, 3.6 μmol) in dichloromethane

(0.5 mL) is treated with TFA (1 mL) at room temperature for 14 hours before evaporation. The residue is chromatographed (silica, CH ₂ Cl ₂ -MeOH) to give the title compound. Example 51—185 are prepared using the procedures similar to that described above.

Example 51. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl-

3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, J =

-CH=NOEt.

Example 52. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{- 3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, J =

-CH=NO-"Pr.

Example 53. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyi-

3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, J =

-CH=NO-allyl. Example 54. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-

3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, J =

-CH=NO-'Pr.

Example 55. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-

3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, J = -CH=NO-CH ₇ CQ ₇ H.

Example 56. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl-

3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, J =

-CH=NOPh.

Example 57. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{- 3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, J =

-CH=NOCH ₇ Ph.

Example 58. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyi-

3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, J =

-CH=NO-2-pyridine. Example 59. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyi-

3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, J =

-CH=NO-3-pyridine.

Example 60. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butγl-

3-methoxybenzoyl, Z = 1.3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, J =

-CH=NO-4-pyridine.

Example 61. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butγl- 3-methoxybenzoyl, Z = 1.3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, J =

-CH=NOCH7-2-pyridine.

Example 62. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butγl-

3-methoxybenzoyl, Z = 1.3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, J =

-CH=NOCH7-3-pyridine. Example 63. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butγ{-

3-methoxybenzoyl, Z = 1.3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, J =

-CH=NOCH ₂ -4-pyridine.

Example 64. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butγ{-

3-methoxybenzoyl, Z = 1.3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, J = -CH=NO-2-pyrimidine.

Example 65. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butγ{-

3-methoxybenzoyl, Z = 1.3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, J =

-CH=NO-4-pyrimidine.

Example 66. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butγl- 3-methoxybenzoyl, Z = 1.3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, J =

-CH=NO-5-pyrimidine.

Example 67. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butγl-

3-methoxybenzoyl, Z = 1.3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, J =

-CH=NOCH9-2-pyrimidine. Example 68. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butγ{-

3-methoxybenzoyl, Z = 1.3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, J =

-CH=NOCH ₂ -4-pyrimidine.

Example 69. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butγ{-

3-methoxybenzoyl, Z = 1.3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, J = -CH=NOCH7-5-pyrimidine.

Example 70. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butγ{-

3-methoxybenzoyl, Z = 1.3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, J =

-CH=NO-2-pyrazine.

Example 71. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butγ\-

3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, J =

-CH=NOCH ₂ -2-pyrazine.

Example 72. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butγ\- 3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, J =

-CH=NO-2-(l ,3-thiazole).

Example 73. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl-

3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, J =

-CH=NOCH7-2-(l,3-thiazole). Example 74. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-

3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, J =

-CH=NO-4-(l ,3-thiazole).

Example 75. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyi-

3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, J = -CH=NOCH9-4-(l,3-thiazole).

Example 76. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyi-

3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, J =

-CH=NO-5-(l ,3-thiazole).

Example 77. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butγ\- 3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, J =

-CH=NOCH7-5-(1.3-thiazole).

Example 78. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl-

3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, J =

-CH=NO-3-(l ,2-thiazole). Example 79. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-

3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, J =

-CH=NOCH ₂ -3-(l ,2-thiazole).

Example 80. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-

3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, J = -CH=NO-4-(l ,2-thiazole).

Example 81. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyi-

3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, J =

-CH=NOCH ₇ -4-(l ,2-thiazole).

Example 82. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butγ\-

3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, J =

-CH=NO-5-(l .2-thiazole).

Example 83. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butγ\- 3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, J =

-CH=NOCH7-5-(l.2-thiazole).

Example 84. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl-

3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, J =

-CH=NO-2-(l ,3-oxazole). Example 85. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-

3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, J =

-CH=NOCH ₂ -2-(l,3-oxazole).

Example 86. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyi-

3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, J = -CH=NO-4-(l ,3-oxazole).

Example 87. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyi-

3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, J =

-CH=NOCH7-4-(l,3-oxazole).

Example 88. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butγ\- 3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, J =

-CH=NO-5-(l ,3-oxazole).

Example 89. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl-

3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, J =

-CH=NOCH9-5-(l,3-oxazole). Example 90. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-

3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, J =

-CH=NO-3-(5-methyl-l,2-oxazole).

Example 91. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-

3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, J = -CH=NOCH7-3-(5-methyl-l,2-oxazole).

Example 92. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyi-

3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, J =

-CH=NO-4-(5-methyl-l,2-oxazole).

Example 93. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butγ\-

3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, J =

-CH=NOCH ₂ -4-(5-methyl- 1 ,2-oxazole).

Example 94. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butγ\- 3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, J =

-CH=NO-5-(l ,2-oxazole).

Example 95. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl-

3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, J =

-CH=NOCH7-5-(1.2-oxazole). Example 96. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-

3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, J =

-CH=NOEt.

Example 97. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyi-

3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, J = -CH=NO-"Pr.

Example 98. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyi-

3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, J =

-CH=NO-allyl.

Example 99. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butγ\- 3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, J =

-CH=N(VPr.

Example 100. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, J =

-CH=NO-CH ₇ CQ ₇ H. Example 101. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, J =

-CH=NOPh.

Example 102. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, J = -CH=NOCH ₇ Ph.

Example 103. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, J =

-CH=NO-2-pyridine.

Example 104. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, J =

-CH=NO-3-pyridine.

Example 105. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, J =

-CH=NO-4-pyridine.

Example 106. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, J =

-CH=NOCH7-2-pyridine. Example 107. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, J =

-CH=NOCH ₂ -3-pyridine.

Example 108. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, J = -CH=NOCH9-4-pyridine.

Example 109. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, J =

-CH=NO-2-pyrimidine.

Example 110. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, J =

-CH=NO-4-pyrimidine.

Example 111. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, J =

-CH=NO-5-pyrimidine. Example 112. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, J =

-CH=NOCH ₂ -2-pyrimidine.

Example 113. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, J = -CH=NOCH7-4-pyrimidine.

Example 114. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, J =

-CH=NOCH7-5-pyrimidine.

Example 115. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, J =

-CH=NO-2-pyrazine.

Example 116. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, J =

-CH=NOCH7-2-pyrazine.

Example 117. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, J =

-CH=NO-2-(l ,3-thiazole). Example 118. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, J =

-CH=NOCH ₂ -2-(l ,3-thiazole).

Example 119. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, J = -CH=NO-4-(l ,3-thiazole).

Example 120. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, J =

-CH=NOCH7-4-(l,3-thiazole).

Example 121. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, J =

-CH=NO-5-(l ,3-thiazole).

Example 122. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, J =

-CH=NOCH9-5-(1.3-thiazole). Example 123. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, J =

-CH=NO-3-(l ,2-thiazole).

Example 124. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, J = -CH=NOCH7-3-(1.2-thiazole).

Example 125. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, J =

-CH=NO-4-(l ,2-thiazole).

Example 126. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, J =

-CH=NOCH ₂ -4-α .2-thiazole).

Example 127. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, J =

-CH=NO-5-(l .2-thiazole).

Example 128. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, J =

-CH=NOCH7-5-(l.2-thiazole). Example 129. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, J =

-CH=NO-2-(l ,3-oxazole).

Example 130. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, J = -CH=NOCH9-2-(l,3-oxazole).

Example 131. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, J =

-CH=NO-4-(l ,3-oxazole).

Example 132. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, J =

-CH=NOCH7-4-(l,3-oxazole).

Example 133. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, J =

-CH=NO-5-(l ,3-oxazole). Example 134. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, J =

-CH=NOCH7-5-(1.3-oxazole).

Example 135. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, J = -CH=NO-3-(5-methyl-l,2-oxazole).

Example 136. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, J =

-CH=NOCH7-3-(5-methyl-l,2-oxazole).

Example 137. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, J = -CH=NO-4-(5-methyl-1.2-oxazole).

Example 138. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, J = -CH=NOCH7-4-(5-methyl-l,2-oxazole).

Example 139. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, J = -CH=NO-5-(l ,2-oxazole). Example 140. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, J =

-CH=NOCH ₂ -5-(1.2-oxazole).

Example 141. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the

A. carbon atom to which they are attached is > ^' ''"" ⁰ _^ J = -CH=NOEt.

Example 142. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the

carbon atom to which they are attached is 6 >O "^ ⁰ , J = -CH=NO-"Pr. Example 143. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the

carbon atom to which they are attached is > ^• *- ^* °, J = -CH=NO-allyl. Example 144. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the

carbon atom to which they are attached is > ^* '-- ⁰ , J = -CH=NO-'Pr. Example 145. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the

carbon atom to which they are attached is V ^•< -"°. J = -CH=NO-CH ₇ CO ₇ H.

Example 146. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the

carbon atom to which they are attached is ^- ^** -^°, J = -CH=NOPh. Example 147. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the

carbon atom to which they are attached is ^- ''-^ ⁰ , J = -CH=NOCH?Ph. Example 148. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the

carbon atom to which they are attached is X ^* "^°, J = -CH=NO-2 -pyridine. Example 149. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the

carbon atom to which they are attached is V ^* "^°, J = -CH=NO-3-pyridine. Example 150. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the

carbon atom to which they are attached is X ^* *^°, J = -CH=NO-4-pyridine. Example 151. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the

carbon atom to which they are attached is X ^* *^°, J = -CH=NOCH?-2 -pyridine. Example 152. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the

carbon atom to which they are attached is > ^* '-- ⁰ , J = -CH=NOCH7-3 -pyridine. Example 153. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the

carbon atom to which they are attached is > ^* '-- ⁰ , J = -CH=NOCH7-4-pyridine. Example 154. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the

carbon atom to which they are attached is ^- ^*< -' ⁰ , J = -CH=NO-2-pyrimidine.

Example 155. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the

carbon atom to which they are attached is X ^** -^°, J = -CH=NO-4-pyrimidine. Example 156. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the

carbon atom to which they are attached is X ^** -^°, J = -CH=NO-5-pyrimidine. Example 157. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the

carbon atom to which they are attached is X ^* "^°, J = -CH=NOCH?-2-pyrimidine. Example 158. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the

carbon atom to which they are attached is V ^* "^°, J = -CH=NOCH?-4-pyrimidine. Example 159. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the

carbon atom to which they are attached is X ^* *^°, J = -CH=NOCH?-5-pyrimidine. Example 160. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the

carbon atom to which they are attached is X ^* *^°, J = -CH=NO-2-pyrazine. Example 161. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the

carbon atom to which they are attached is X ^* '-- ⁰ , J = -CH=NOCH7-2-pyrazine. Example 162. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the

carbon atom to which they are attached is X ^* '-- ⁰ , J = -CH=NO-2-(l,3-thiazole). Example 163. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the

carbon atom to which they are attached is X ^% -"°. J = -CH=NOCH7-2-(1.3- thiazole).

Example 164. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the

carbon atom to which they are attached is X ^** -^°, J = -CH=NO-4-(l,3-thiazole). Example 165. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the

carbon atom to which they are attached is X ''-^ ⁰ , J = -CH=NOCH?-4-(l,3- thiazole).

Example 166. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the

carbon atom to which they are attached is X ^* *^°, J = -CH=NO-5-(l,3-thiazole). Example 167. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the

carbon atom to which they are attached is X ^% -- ⁰ . J = -CH=NOCH7-5-(1.3- thiazole). Example 168. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the

carbon atom to which they are attached is X ^** -- ⁰ , J = -CH=NO-3-(l,2-thiazole). Example 169. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the

carbon atom to which they are attached is X ^% -- ⁰ . J = -CH=NOCH7-3-(1.2- thiazole).

Example 170. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the

carbon atom to which they are attached is X ^* *^°, J = -CH=NO-4-(l,2-thiazole). Example 171. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the

carbon atom to which they are attached is X ^% -- ⁰ . J = -CH=NOCH7-4-(1.2- thiazole).

Example 172. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the

carbon atom to which they are attached is X ^** -^°, J = -CH=NO-5-(l,2-thiazole). Example 173. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the

carbon atom to which they are attached is X ^% "°. J = -CH=NOCH7-5-(1.2- thiazole).

Example 174. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the

carbon atom to which they are attached is X ^* *^°, J = -CH=NO-2-(l,3-oxazole). Example 175. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the

carbon atom to which they are attached is X ^% -- ⁰ . J = -CH=NOCH ₇ ^-(1.3- oxazole). Example 176. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the

carbon atom to which they are attached is X ^** -- ⁰ , J = -CH=NO-4-(l,3-oxazole). Example 177. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the

carbon atom to which they are attached is X ^% -- ⁰ . J = -CH=NOCH ₇ -4-(l,3- oxazole).

Example 178. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the

carbon atom to which they are attached is X ^* *^°, J = -CH=NO-5-(l,3-oxazole). Example 179. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the

carbon atom to which they are attached is X ^% -- ⁰ . J = -CH=NOCH7-5-(1.3- oxazole).

Example 180. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the

carbon atom to which they are attached is ^- ^* *-^°, J = -CH=NO-3 -(5 -methyl- 1,2- oxazole). Example 181. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, J = -CH=NOCH7-3-(5-methyl-l,2-oxazole).

Example 182. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the

carbon atom to which they are attached is N ^• --- ⁰ , J = -CH=NO-4-(5 -methyl- 1,2- oxazole).

Example 183. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the

carbon atom to which they are attached is ^- ^** -- ⁰ , J = -CH=NOCH?-4-(5-methyl- 1,2-oxazole).

Example 184. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the

carbon atom to which they are attached is X ^* *^°, J = -CH=NO-5-(l,2-oxazole). Example 185. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the

carbon atom to which they are attached is X ^% -- ⁰ . J = -CH=NOCH7-5-(1.2- oxazole).

IV. Fourth Principle Invention Example 1. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-ferf-butyl-

3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, W = fluoro, U = hydrogen, J = methyl.

Example 2. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-ferf-butyl-

3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, W = methoxy, U = hydrogen, J = methyl.

Example 3. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butγ\-

3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, W = acetoxy, U = hydrogen, J = methyl.

Example 4. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl- 3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, W = acetylamino, U = hydrogen, J = methyl.

Example 5. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyi-

3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, W = dimethylamino, U = hydrogen, J = methyl. Example 6. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-

3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, W = methylsulfanyl, U = methylsulfanyl, J = methyl.

Example 7. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-

3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, W = carbamoyloxy, U = hydrogen, J = methyl.

Example 8. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyi-

3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, W = ureido, U = hydrogen, J = methyl.

Example 9. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\- 3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, W = methoxycarbonylamino, U = hydrogen, J = methyl.

Example 10. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-

3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, W = fluoro, U = fluoro, J = lH-pyrazol-l-ylmethyl. Example 11. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyi-

3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, W = hydrogen, U = bromo, J = lH-pyrazol-l-ylmethyl.

Example 12. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl-

3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, W

and U taken together with the carbon atom to which they are attached is * , J = 1 H-pyrazol- 1 -ylmethyl.

Example 13. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\- 3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, W

and U taken together with the carbon atom to which they are attached is C=CIHb, J = lH-pyrazol-1-ylmethyl.

Example 14. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl- 3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, W and U taken together with the carbon atom to which they are attached is C=O, J = 1 H-pyrazol- 1 -ylmethyl.

Example 15. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyi- 3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, W and U taken together with the carbon atom to which they are attached is C=NOMe, J = lH-pyrazol-l-ylmethyl.

Example 16. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{- 3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, W and U taken together with the carbon atom to which they are attached is C=NNMe ₇ . J = lH-pyrazol-1-ylmethyl. Example 17. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\- 3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, W = hydrogen, U = hydroxy, J = lH-pyrazol-l-ylmethyl.

Example 18. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl- 3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, W = hydroxy, U = hydrogen, J = 1 H-pyrazol- 1 -ylmethyl.

Example 19. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyi- 3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, W

1 H-pyrazol- 1 -ylmethyl. Example 20. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-

3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = trifluoromethyl, Y = methoxymethyl,

W = fluoro, U = fluoro, J = lH-pyrazol-l-ylmethyl.

Example 21. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl-

3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = methyl, Y = methoxymethyl, W = bromo, U = hydrogen, J = 1 H-pyrazol- 1 -ylmethyl.

Example 22. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyi-

3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = methoxy, Y = methoxymethyl, W = fluoro, U = fluoro, J = lH-pyrazol-l-ylmethyl.

Example 23. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butγ\- 3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon atom to which they are attached is ^ ^' " ^* ° , W = fluoro, U = fluoro, J = IH- pyrazol- 1 -ylmethyl. Example 24. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-ferf-butyl- 3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = acetylamino, Y = methoxymethyl, W = fluoro, U = benzyl, J = lH-pyrazol-l-ylmethyl.

Example 25. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-ferf-butyl- 3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = cyano, Y = methoxymethyl, W and U

taken together with the carbon atom to which they are attached is ^* > ° , J = hydrogen.

Example 26. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-ferf-butyl-

3-methoxybenzoyl. Z = 1.3-thiazol-2-yl. X = fluoro. Y = -CH=NOMe. W = fluoro.

U = hydrogen, J = lH-pyrazol-l-ylmethyl. Example 27. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-ferf-butyl-

3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = -CH=NOPh, W = fluoro,

U = hydrogen, J = lH-pyrazol-l-ylmethyl.

Example 28. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-ferf-butyl-

3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, W = fluoro, U = hydrogen, J = lH-pyrazol-l-ylmethyl.

Example 29. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-ferf-butyl-

3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = -C(O)NHMe. W = fluoro, U = hydrogen, J = lH-pyrazol-1 -ylmethyl.

Example 30. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butγ\- 3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, W = methoxy, U = hydrogen, J = methyl.

Example 31. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl-

3-methoxybenzoyl, Z = thiophen-2-yl, X = hydrogen, Y = methoxymethyl, W = methoxy, U = hydrogen, J = methyl. Example 32. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyi-

3-methoxybenzoyl, Z = thiophen-3-yl, X = hydrogen, Y = methoxymethyl, W = methoxy, U = hydrogen, J = methyl.

Example 33. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl-

3-methoxybenzoyl, Z = isopropyl, X = hydrogen, Y = methoxymethyl, W = methoxy, U = hydrogen, J = methyl.

Example 34. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl- 3-methoxybenzoyl, Z = oxazol-2-yl, X = hydrogen, Y = methoxymethyl, W = methoxy, U = hydrogen, J = methyl.

Example 35. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl-

3-methoxybenzoyl, Z = 5-methyl-isoxazol-3-yl, X = hydrogen, Y = methoxymethyl, W = methoxy. U = hydrogen, J = methyl. Example 36. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl-

3-methoxybenzoyl, Z = furan-2-yl, X = hydrogen, Y = methoxymethyl, W = methoxy, U = hydrogen, J = methyl.

Example 37. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-

3-methoxybenzoyl, Z = furan-3-yl, X = hydrogen, Y = methoxymethyl, W = methoxy, U = hydrogen, J = methyl.

Example 38. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl-

3-methoxybenzoyl, Z = pyridin-2-yl, X = hydrogen, Y = methoxymethyl, W = methoxy, U = hydrogen, J = methyl.

Example 39. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl- 3-methoxybenzoyl, Z = pyridin-3-yl, X = hydrogen, Y = methoxymethyl, W = methoxy, U = hydrogen, J = methyl.

Example 40. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-

3-methoxybenzoyl, Z = pyridin-4-yl, X = hydrogen, Y = methoxymethyl, W = methoxy, U = hydrogen, J = methyl. Example 41. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl-

3-methoxybenzoyl, Z = phenyl, X = hydrogen, Y = methoxymethyl, W = methoxy,

U = hydrogen, J = methyl.

Example 42. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl-

3-methoxybenzoyl, Z = thiazol-2-ylmethyl, X = hydrogen, Y = methoxymethyl, W = methoxy, U = hydrogen. J = methyl.

Example 43. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-

3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, W = fluoro, U = hydrogen, J = lH-pyrazol-l-ylmethyl.

Example 44. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- butylbenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, W = fluoro, U = hydrogen, J = lH-pyrazol-l-ylmethyl.

Example 45. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl- 3-vinylbenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, W = fluoro, U = hydrogen, J = lH-pyrazol-l-ylmethyl.

Example 46. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyi-

2-fluoro-5-vinylbenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl,

W = fluoro, U = hydrogen, J = lH-pyrazol-l-ylmethyl. Example 47. Compound of Formula (Ia), wherein M = hydroxy, Q = 3-bromo-4- ferf-butylbenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, W = fluoro, U = hydrogen, J = lH-pyrazol-l-ylmethyl.

Example 48. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl- benzenesulfonyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, W = fluoro, U = hydrogen, J = lH-pyrazol-l-ylmethyl.

Example 49. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-Butyl- phenylcarbamoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, W = fluoro, U = hydrogen, J = lH-pyrazol-l-ylmethyl.

Example 50. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\- 3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, W = fluoro, U = hydrogen. J = -CH=NOMe.

Example 51. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl-

3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, W = fluoro, U = hydrogen. J = -CH=NOPh. Example 52. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-

3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, W = fluoro, U = hydrogen. J = -CH=NNMe ₂ .

Example 53. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyi-

3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, W = fluoro, U = hydrogen, J = hydrogen.

Example 54. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-

3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, W = fluoro, U = hydrogen, J = isobutyl.

Example 55. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butγ\-

3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, W = fluoro, U = hydrogen, J = thiazol-2-ylmethyl.

Example 56. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl- 3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, W = fluoro, U = hydrogen, J = isothiazol-3-ylmethyl.

Example 57. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyi-

3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, W = fluoro, U = hydrogen, J = thiazol-4-ylmethyl. Example 58. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butγ\-

3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, W = 3- tetrazol-1-ylmethyl, U = hydrogen, J = hydrogen.

Example 59. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-

3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, W = 3- tetrazol-1-ylmethyl, U = hydrogen, J = methyl.

Example 60. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyi-

3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, W = IH- pyrazol-1-ylmethyl, U = hydrogen, J = hydrogen.

Example 61. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butγ\- 3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoro, Y = methoxymethyl, W = IH- pyrazol-l-ylmethyl, U = hydrogen, J = methyl.

Example 62. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-

3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen. Y = -CH=NOPh, W =

-NHMs, U = hydrogen, J = methyl. Example 63. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-

3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen. Y = -CH=NOPh, W = methoxymethyl, U = hydrogen, J = methyl.

Example 64. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyi-

3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen. Y = -CH ₇ OBn, W = -CH ₂ NHMs. U = hydrogen. J = methyl.

Example 65. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyi-

3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen. Y = -CH ₇ OBn, W = methoxymethyl, U = hydrogen, J = methyl.

V. Fifth Principle Invention

Example 1. Compound of Formula (Ia), wherein M = tert-butoxy, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X and G taken together with the carbon atom to which they are attached is cyclopropane, Y = -CO?Et, U = W = hydrogen, J = lH-pyrazol-l-ylmethyl.

Step Ia. Into a suspension of commercially available l-carboxy-2-pyrazol-l-yl- ammonium chloride (958 mg, 1.0 mmol) in t-butyl acetate (30.0 mL) is added perchloric acid (70%, 0.50 mL, 5.8 mmol). The mixture is stirred at room temperature for 64 hours before being diluted with ethyl acetate and neutralized with a combination of solid NaHCO ₃ and saturated NaHCO ₃ until no gas evolved. After separation, the aqueous is saturated with sodium chloride and extracted with ethyl acetate. The combined organics are dried (Na ₂ SO ₄ ) and evaporated to give the crude product (617 mg, 45.5%). ESIMS m/z = 212.12 [M+H] ⁺ of the free base parent ion.

¹³ C NMR (CDCl ₃ ) 175.7, 171.1, 140.1, 130.5, 105.6, 82.6, 55.1, 54.2, 27.9. Step Ib. Into a suspension of commercially available l-carboxy-2-pyrazol-l-yl- ammonium chloride (958 mg, 1.0 mmol) in t-butyl acetate (30.0 mL) is added perchloric acid (70%, 0.76 mL, 8.8 mmol). The mixture is stirred at room temperature for 22 hours before being diluted with ethyl acetate and neutralized with a combination of solid NaHCO ₃ and saturated NaHCO ₃ to pH ~ 8. After separation, the aqueous is saturated with sodium chloride and extracted with ethyl acetate. The combined organics are dried (Na ₂ SO ₄ ) and evaporated to give the crude product (633 mg, 60%). ESIMS m/z = 212.14 [M+H] ⁺ .

Step Ic. A mixture of the compound from step Ia (205 mg, 0.75 mmol), commercially available 2-formyl-l,3-thiazole (120 mg, 1.06 mmol), and activated molecular sieves (4 A, 1.0 g) in anhydrous methylene chloride (5 mL) is stirred at room temperature for 15 hours before being filtered through Celite and washed with methylene chloride. The combined organics are evaporated and the residue is used directly for next step. ESIMS m/z = 307.13 [M+H] ⁺ .

Step Id. A mixture of the compound from step Ib (160 mg, 0.76 mmol), commercially available 2-formyl-l,3-thiazole (151 mg, 1.34 mmol), and activated molecular sieves (4 A, 1.0 g) in anhydrous methylene chloride (5 mL) is stirred at room temperature for 15 hours before being filtered through Celite and washed with methylene chloride. The combined organics are evaporated and the residue is chromatographed (silica, hexanes-EtOAc) to give the desired compound (200 mg, 86%).

ESIMS m/z = 307.12 [M+H] ⁺ . 1 ³ C NMR (CD ₃ OD) 168.2, 166.2, 159.0, 144.1, 139.8, 131.4, 123.3, 105.4, 82.7, 72.3, 53.1, 27.1.

Step Ie. A solution of the ethyl 2-hydroxymethyl-acrylate (1.3 g, 10 mmol) in CH ₂ Cl ₂ (20 mL) is treated with TBSCl (1.8g, 12 mmol) in the presence OfEt ₃ N (2 mL) and DMAP (65 mg, 0.53 mmol) room temperature for 16 hours before being partitioned (EtO Ac-saturated aqueous NaHCO ₃ ). The aqueous layer is separated and extracted with EtOAc. The combined organic layers are dried (Na ₂ SO ₄ ), filtered and evaporated. The residue is purified by chromatography (silica, hexanes-ethyl acetate) to afford the desired compound as a colorless oil. 1 ³ C NMR (CDCl ₃ ): 171.41, 145.35, 129.00, 66.94, 65.94, 31.31, 23.77, 19.64, 0.00. Step If. A mixture of the crude compound from step Ic (2.0 mmol at most), lithium bromide (348 mg, 4.0 mmol), the compound from step l la (576 mg, 2.36 mmol) and Et ₃ N (0.98 mL, 7.0 mmol) in THF (10 mL) is stirred under nitrogen at room temperature for 18.5 hours before being partitioned (EtO Ac-saturated aqueous NaHCO ₃ ). The organics are washed with water and brine, dried (Na ₂ SO ₄ ), filtered and evaporated. The residue is purified by chromatography (silica, hexane- ethyl acetate) to give the desired compound as a yellow sirup (566 mg, 51%). ESIMS m/z = 551.26 [M+H] ⁺ .

¹³ C NMR (CDCl ₃ ) 177.7, 177.6, 173.6, 148.0, 144.4, 136.0, 124.0, 111.0, 87.6, 74.7, 69.1, 68.7, 66.10, 66.06, 64.4, 46.0, 33.3, 31.4, 23.7, 19.2, 0.10, 0.00. Step Ig. A mixture of the commercially available 4-£-butyl-3-methoxybenzoic acid (2.082 g, 10.0 mmol) in thionyl chloride (5.0 mL) is refluxed for 2.5 hours before being evaporated. Toluene (twice) is added to the residue and the mixture was evaporated. The residue is dried in vacuum to get a crystalline (2.258 g, 99.6%).

Step Ih. A solution of the compound from step If (566 mg, 1.03 mmol), Et ₃ N (0.43 mL, 3.1 mmol) and the compound from step Ig (350 mg, 1.54 mmol) in anhydrous dichloromethane (4 mL) is stirred at room temperature under nitrogen for 164 hours before being partitioned (EtO Ac-saturated aqueous NaHCO ₃ ). The organics are washed with water and brine, dried (Na ₂ SO ₄ ), filtered and evaporated. The residue is purified by chromatography (silica, hexane-ethyl acetate) to give the desired compound as a yellow sirup (545 mg, 73%). ESIMS m/z = 741.47 [M+H] ⁺ . 1 ³ C NMR (CDCl ₃ ) 177.1.1, 176.4, 174.8, 173.8, 164.0, 146.6, 145.8, 145.1, 140.9, 137.3, 131.7, 125.3, 123.7, 116.6, 111.1, 88.0, 77.0, 72.4, 71.3, 66.4, 65.1, 60.7, 58.7, 43.7, 40.5, 35.0, 33.6, 31.2, 23.6, 19.0, 0.07, 0.00.

Step Ii. A solution of the compound from step Ih (86 mg, 0.12 mmol) in THF (3.0 mL) is treated with TBAF (1 M in THF, 0.18 mL, 0.18 mmol) in the presence of/?-toluenesulfonic acid monohydrate (18.0 mg, 0.094 mmol) at room temperature for 45 minutes before being partitioned (EtO Ac-saturated aqueous NaHCO ₃ ). The organics are washed with water and brine, dried (Na ₂ SO ₄ ), filtered and evaporated. The residue is purified by chromatography (silica, hexane-ethyl acetate) to give the desired compound as a colorless form (73 mg, 100%). ESIMS m/z = 627.39 [M+H] ⁺ . 1H NMR (CDCl ₃ ): 7.87 (d, J= 1.5 Hz, IH), 7.61 (d, J= 1.5 Hz, IH), 7.51 (d, J = 3.0 Hz, IH), 7.33 (d, J= 8.0 Hz, IH), 7.12 (d, J= 3.5 Hz, IH), 6.86 (d, J= 8.0 Hz, IH), 6.65 (s, IH), 6.35 (t, J= 2.0 Hz, IH), 5.58 (m, IH), 5.42 (d, J= 15.0 Hz, IH), 5.39 (s, IH), 4.74 (d, J= 14.5 Hz, IH), 4.00 (t, J= 11.0 Hz, IH), 3.84 (q, J= 7.0 Hz, 2H), 3.77 (m, IH), 3.76 (s, 3H), 3.32 (d, J= 14.5 Hz, IH), 2.77 (d, J= 15.0 Hz, IH), 1.40 (s, 9H), 1.39 (s, 9H), 0.86 (t, J= 7.5 Hz, 3H).

¹³ C NMR (CDCl ₃ ) 171.5, 170.8, 166.1, 159.0, 141.7, 141.2, 140.2, 134.8, 133.7,

127.1, 120.2, 118.4, 110.4, 106.2, 82.6, 69.9, 66.1, 65.0, 61.3, 60.4, 56.2, 55.3,

35.3, 34.1, 29.8, 28.1, 13.9.

Step Ij. Into a mixture of the compound from step Ii (50 mg, 79.8 μmol) in anhydrous dichloromethane (3 mL) are added triphenylphosphine (126 mg, 0.478 mmol) and N-bromosuccinimide (85.2 mg, 0.478 mmol) at 0 ⁰ C. The resultant mixture is warmed up to ambient temperature and stirred for 18 hours before being quenched with saturated aqueous sodium bicarbonate and partitioned between dichrolomethane and water. The organics are washed with brine, dried over

sodium sulfate and evaporated. The residue is chromatographed (silica, hexanes- EtOAc) to give the desired compound (34.2 mg, 62%) as a white solid with a recovery of compound from step Ii (15.0 mg, 30%). ESIMS m/z = 689.28/691.28 [M+H] ⁺ . 1H NMR (CDCl ₃ ): 7.57 (d, J= 1.5 Hz, IH), 7.45 (d, J= 2.0 Hz, IH), 7.28 (d, J = 3.0 Hz, IH), 7.10 (d, J= 8.0 Hz, IH), 7.04 (d, J= 3.0 Hz, IH), 6.60 (d, J= 8.0 Hz, IH), 6.57 (s, IH), 6.28 (t, J= 2.0 Hz, IH), 5.42 (d, J= 14.5 Hz, IH), 5.29 (s, IH), 4.65 (d, J= 14.5 Hz, IH), 3.75 (m, IH), 3.68 (s, 3H), 3.58 (m, IH), 3.52 (d, J = 15.0 Hz, IH), 3.19 (d, J= 9.5 Hz, IH), 3.18 (d, J= 15.5 Hz, IH), 2.86 (d, J= 9.5 Hz, IH), 1.46 (s, 9H), 1.26 (s, 9H), 0.78 (t, J= 7.5 Hz, 3H).

Step Ik. Into a mixture of the compound from step Ij (132 mg, 0.192 mmol) in anhydrous THF (10 mL) is added sodium hydride (60% in mineral oil, 76.6 mg, 19.2 mmol). The mixture is stirred at ambient temperature for 48 hours before being quenched with saturated aqueous ammonium chloride and partitioned between ethyl acetate and water. The organics are washed with brine, dried over sodium sulfate and evaporated. The residue is chromatographed (silica, hexanes- EtOAc) to give the title compound (33 mg, 23%) as a colorless oil. 1 ³ C NMR (CDCl ₃ ): 170.3, 169.9, 168.3, 164.7, 157.8, 141.1, 141.0, 139.9, 134.2, 132.3, 126.1, 121.3, 120.4, 111.5, 106.2, 83.5, 76.9, 61.4, 60.4, 55.2, 51.6, 41.3, 36.6, 35.1, 30.2, 29.7, 29.5, 28.4, 28.2, 13.6.

Example 2. Compound of Formula (Ia), wherein M = tert-butoxy, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X and G taken together with the carbon atom to which they are attached is cyclopropane, Y = -CO?H, U = W = hydrogen, J = lH-pyrazol-l-ylmethyl. Into a mixture of the compound from step Ij (132 mg, 0.192 mmol) in anhydrous THF (10 mL) is added sodium hydride (60% in mineral oil, 76.6 mg, 19.2 mmol). The mixture is stirred at ambient temperature for 48 hours before being quenched with saturated aqueous ammonium chloride and partitioned between ethyl acetate and water. The organics are washed with brine, dried over sodium sulfate and evaporated. The residue is chromatographed (silica, CH ₂ Cl ₂ -MeOH) to give the title compound (95 mg, 69%) as a white solid. ESIMS m/z = 581.41 [M+H] ⁺ .

¹³ C NMR (MeOD): 171.3, 170.1, 165.6, 157.7, 140.7, 140.3, 139.8, 134.2, 132.4, 126.0, 121.5, 120.2, 111.2, 106.1, 83.4, 76.2, 59.6, 54.3, 51.2, 48.4, 48.2, 47.9, 47.5, 47.3, 36.7, 34.6, 29.1, 28.7, 27.3.

Example 3. Compound of Formula (Ia), wherein M = tert-butoxy, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X and G taken together with the carbon atom to which they are attached is cyclopropane, Y = hydroxymethyl, U = W = hydrogen, J = lH-pyrazol-l-ylmethyl.

Step 3a. Into a mixture of the compound from example 2 (95 mg, 0.164 mmol) in anhydrous THF (8 mL) are added triethylamine (0.14 mL, 0.982 mmol) and ethyl chloroformate (50 μL, 0.491 mmol) at 0 ⁰ C. The resultant white cloudy mixture is gradually warmed up to ambient temperature and moniterd by mass spectrometry before being delivered to the next step. ESIMS m/z = 653.47 [M+H] ⁺ . Step 3b. Into a mixture of the crude compound from step 3a (0.164 mmol at most) in anhydrous THF (8 mL) at -78 ⁰ C are added sodium borohydride (61.9 mg, 1.64 mmol) and ethanol (0.8 mL, 8.19 mmol) slowly. The resultant mixture is gradually warmed up to 0 ⁰ C before being quenched with saturated aqueous ammonium chloride and partitioned between ethyl acetate and water. The organics are washed with brine, dried over sodium sulfate and evaporated. The residue is chromatographed (silica, hexanes-EtOAc) to give the title compound (78 mg, 2 steps 84%) as a colorless oil. ESIMS m/z = 567.43 [M+H] ⁺ .

¹³ C NMR (CDCl ₃ ): 170.9, 170.0, 166.9, 157.9, 141.3, 139.7, 134.5, 132.2, 126.2, 121.0, 120.6, 111.6, 106.1, 83.6, 76.5, 63.0, 57.3, 55.2, 51.6, 41.3, 37.0, 35.1, 29.6, 28.5, 28.4.

Example 4. Compound of Formula (Ia), wherein M = tert-butoxγ, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X and G taken together with the carbon atom to which they are attached is cyclopropane, Y = -CHO, U = W = hydrogen, J = lH-pyrazol-l-ylmethyl. Into a mixture of the compound from example 3 (30 mg, 53.0 μmol) in anhydrous dichloromethane (4 mL) is added Dess-Martin periodinane (67.4 mg, 0.159 mmol). The resultant mixture is stirred at room temperature for 1.5 hours before being quenched with a mixture of saturated aqueous sodium bicarbonate and sodium

thiosulfate. The mixture is partitioned between dichrolomethane and water and the organics are washed with brine, dried over sodium sulfate and evaporated. The residue is chromatographed (silica, hexanes-EtOAc) to give the title compound

(24.6 mg, 82%) as a white solid. ESIMS m/z = 565.44 [M+H] ⁺ .

¹³ C NMR (CDCl ₃ ): 195.9, 169.9, 169.7, 164.9, 157.8, 141.6, 141.1, 139.9, 133.9,

132.3, 126.2, 121.8, 120.7, 111.7, 106.3, 83.8, 76.8, 60.8, 55.2, 51.7, 48.9, 35.2,

33.3, 30.1, 29.5, 28.4.

Example 5. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butγ\- 3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X and G taken together with the carbon atom to which they are attached is cyclopropane, Y = -CHO, U = W = hydrogen, J

= lH-pyrazol-1-ylmethyl.

Into a mixture of the compound from example 4 (24.6 mg, 43.6 μmol) in anhydrous dichloromethane (3 mL) is added trifluoroacetic acid (4.5 mL). The resultant mixture is stirred at room temperature for 3.5 hours before removal of the solvent to afford the crude title compound as a yellow brown oil.

ESIMS m/z = 509.30 [M+H] ⁺ .

Example 6. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyi-

3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X and G taken together with the carbon atom to which they are attached is cyclopropane, Y = -CH=NOPh, U = W = hydrogen, J = lH-pyrazol-1-ylmethyl.

Into a mixture of the crude compound from example 5 (13.8 μmol at most) in anhydrous methonal (1 mL) is added O-phenyl hydroxylamine hydrochloride (21.1 mg, 0.145 mmol). The resultant mixture is stirred at room temperature for 16 hours before removal of the solvant. The residue is chromatographed (silica,

CH ₂ Cl ₂ -MeOH) to give the title compound as a white solid.

ESIMS m/z = 600.39 [M+H] ⁺ .

¹ H NMR (MeOD): 7.70 (d, J = 1.0 Hz, IH), 7.54 (d, J = 2.0 Hz, IH), 7.31 (d, J =

2.5 Hz, IH), 7.21 (m, 3H), 7.08 (d, J= 8.5 Hz, IH), 7.02 (s, IH), 6.95 (m, 3H), 6.86 (m, 3H), 6.46 (s, IH), 5.35 (d, J= 15.0 Hz, IH), 4.67 (d, J= 14.5 Hz, IH),

3.78 (s, 3H), 3.30 (m, 2H), 2.48 (d, J= 6.0 Hz, IH), 1.30 (s, 9H), 0.67 (d, J= 5.5

Hz, IH).

Example 7. Compound of Formula (Ia), wherein M = tert-butoxγ, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X and G taken together with the carbon atom to which they are attached is cyclopropane, Y = -CH?OMe, U = W = hydrogen, J = lH-pyrazol-1-ylmethyl. Into a mixture of the compound from example 3 (18 mg, 31.8 μmol) in methyl iodide (1 mL) are added tetra(n-butyl) ammonium iodide (2.3 mg, 6.3 μmol) and 50% NaOH aqueous solution (4 mL). The resultant white cloudy mixture is stirred for 2.5 hours at room temperature before being diluted with water. The mixture is partitioned between ethyl acetate and water and the organics are washed with brine, dried over sodium sulfate and evaporated. The residue is chromatographed (silica, hexanes-EtOAc) to give the desired compound (19.0 mg , 100%) as a colorless oil.

ESIMS m/z = 581.26 [M+H] ⁺ . 1 ³ C NMR (CDCl ₃ ): 170.4, 169.8, 166.9, 157.6, 141.0, 140.6, 139.7, 134.4, 132.2, 126.0, 120.8, 120.6, 111.9, 106.2, 83.2, 76.4, 73.4, 58.8, 57.1, 55.2, 51.8, 39.3, 38.2, 35.1, 29.6, 28.4, 28.2.

Example 8. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyi- 3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X and G taken together with the carbon atom to which they are attached is cyclopropane, Y = -CFbOMe, U = W = hydrogen, J = lH-pyrazol-1-ylmethyl.

Into a mixture of the compound from example 7 (9.5 mg, 16.3 μmol) in anhydrous dichloromethane (2 mL) is added trifluoroacetic acid (3 mL). The resultant mixture is stirred for 3 hours at room temperature before removal of the solvant. The residue is chromatographed (silica, CH ₂ Cl ₂ -MeOH) to give the desired compound (3.6 mg , 42%) as a white solid. ESIMS m/z = 525.25 [M+H] ⁺ .

¹ H NMR (MeOD): 7.41 (d, J= 1.5 Hz, IH), 7.25 (d, J= 1.5 Hz, IH), 7.05 (d, J = 3.5 Hz, IH), 6.93 (d, J= 3.5 Hz, IH), 6.81 (d, J= 8.0 Hz, IH), 6.62 (s, IH), 6.61 (d, J= 8.0 Hz, IH), 6.19 (t, J= 2.0 Hz, IH), 5.05 (d, J= 15.5 Hz, IH), 4.35 (d, J = 14.5 Hz, IH), 3.52 (s, 3H), 2.95 (d, J= 14.0 Hz, IH), 2.78 (s, 3H), 2.77 (d, J =

12.5 Hz, IH), 2.61 (d, J= 10.5 Hz, IH), 2.53 (d, J= 14.0 Hz, IH), 1.64 (d, J= 5.0 Hz, IH), 1.04 (s, 9H), 0.01 (d, J= 6.0 Hz, IH).

Example 9. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butγ\- 3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X and G taken together with the carbon atom to which they are attached is cyclopropane, Y = -CO?H, U = W = hydrogen, J = lH-pyrazol-1-ylmethyl. Into a mixture of the compound from example 2 (2 mg) in anhydrous dichloromethane (2 mL) is added trifluoroacetic acid (3.5 mL). The resultant mixture is stirred at room temperature for 3 hours before removal of the solvant. The residue is chromatographed (silica, CH ₂ Cl ₂ -MeOH) to give the desired compound as a white solid. ESIMS m/z = 525.33 [M+H] ⁺ .

Example 10. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butγ\- 3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X and G taken together with the carbon atom to which they are attached is cyclopropane, Y = -CH?OH, U = W = hydrogen, J = lH-pyrazol-l-ylmethyl. Example 11. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl- 3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X and G taken together with the carbon atom to which they are attached is cyclopropane, Y = -C(O)NH?, U = W = hydrogen, J = lH-pyrazol-1-ylmethyl. Example 12. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{- 3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X and G taken together with the carbon atom to which they are attached is cyclopropane, Y = -C(O)NHBn, U = W = hydrogen, J = lH-pyrazol-l-ylmethyl.

Example 13. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\- 3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X and G taken together with the carbon atom to which they are attached is cyclopropane, Y = -C(O)NHPh, U = W = hydrogen, J = lH-pyrazol-1-ylmethyl.

Example 14. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl- 3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X and G taken together with the carbon atom to which they are attached is cyclopropane, Y = -CH7θBn, U = W = hydrogen, J = lH-pyrazol-1-ylmethyl.

Example 15. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{- 3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X and G taken together with the carbon

atom to which they are attached is cyclopropane, Y = -SO?Ph, U = W = hydrogen, J = lH-pyrazol-1-ylmethyl.

Example 16. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butγ\- 3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X and G taken together with the carbon atom to which they are attached is cyclopropane, Y = -NHMs, U = W = hydrogen, J = lH-pyrazol-l-ylmethyl.

Example 17. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl- 3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X and G taken together with the carbon atom to which they are attached is cyclopropane, Y = -CO?Et, U = W = hydrogen, J = lH-pyrazol-1-ylmethyl.

Example 18. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{- 3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X and G taken together with the carbon atom to which they are attached is cyclopropane, Y = -CFbOC(O)NH?, U = W = hydrogen, J = lH-pyrazol-l-ylmethyl. Example 19. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\- 3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X and G taken together with the carbon atom to which they are attached is cyclopropane, Y = -CH?0Me, U = Me, W = hydrogen, J = lH-pyrazol-1-ylmethyl. Example 20. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl- 3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X and G taken together with the carbon atom to which they are attached is cyclopropane, Y = -CH=NOMe, U = F, W = hydrogen, J = lH-pyrazol-1-ylmethyl.

Example 21. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\- benzenesulfonyl, Z = l,3-thiazol-2-yl, X and G taken together with the carbon atom to which they are attached is cyclopropane, Y = -CH?OMe, U = W = hydrogen, J = lH-pyrazol-1-ylmethyl.

Example 22. Compound of Formula (Ia), wherein M = hydroxy, O = 4-tert-buty\- phenylcarbamoyl, Z = l,3-thiazol-2-yl, X and G taken together with the carbon atom to which they are attached is cyclopropane, Y = -CH?OMe, U = W = hydrogen, J = lH-pyrazol-1-ylmethyl.

Example 23. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\- 3-bromobenzoyl. Z = l,3-thiazol-2-yl, X and G taken together with the carbon

atom to which they are attached is cyclopropane, Y = -CFbOMe, U = W = hydrogen, J = lH-pyrazol-1-ylmethyl.

Example 24. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butγ\- 3-vinylbenzoyl, Z = l,3-thiazol-2-yl, X and G taken together with the carbon atom to which they are attached is cyclopropane, Y = -CFbOMe, U = W = hydrogen, J = lH-pyrazol-1-ylmethyl.

Example 25. Compound of Formula (Ia), wherein M = hydroxy, O = 2-fluoro-4- ferf-butyl-5-vinylbenzoyl, Z = l,3-thiazol-2-yl, X and G taken together with the carbon atom to which they are attached is cyclopropane, Y = -CFbOMe, U = W = hydrogen, J = lH-pyrazol-1-ylmethyl.

Example 26. Compound of Formula (Ia), wherein M = hydroxy, O = ferf-butyl-3- methoxybenzoyl. Z = l,3,4-thiadiazol-2-yl, X and G taken together with the carbon atom to which they are attached is cyclopropane, Y = -CFbOMe, U = W = hydrogen, J = lH-pyrazol-1-ylmethyl. Example 27. Compound of Formula (Ia), wherein M = hydroxy, Q = ferf-butyl-3- methoxybenzoyl. Z = 5-methylisoxazol-3-yl. X and G taken together with the carbon atom to which they are attached is cyclopropane, Y = -CFbOMe, U = W = hydrogen, J = lH-pyrazol-1-ylmethyl. Example 28. Compound of Formula (Ia), wherein M = hydroxy, Q = ferf-butyl-3- methoxybenzoyl, Z = thiophen-2-yl, X and G taken together with the carbon atom to which they are attached is cyclopropane, Y = -CFbOMe, U = W = hydrogen, J = lH-pyrazol-1-ylmethyl.

Example 29. Compound of Formula (Ia), wherein M = hydroxy, O = ferf-butyl-3- methoxybenzoyl, Z = thiophen-3-yl, X and G taken together with the carbon atom to which they are attached is cyclopropane, Y = -CFbOMe, U = W = hydrogen, J = lH-pyrazol-1-ylmethyl.

Example 30. Compound of Formula (Ia), wherein M = hydroxy, O = ferf-butyl-3- methoxybenzoyl, Z = furan-2-yl, X and G taken together with the carbon atom to which they are attached is cyclopropane, Y = -CFbOMe, U = W = hydrogen, J = lH-pyrazol-1-ylmethyl.

Example 31. Compound of Formula (Ia), wherein M = hydroxy, Q = ferf-butyl-3- methoxybenzoyl. Z = furan-3-yl. X and G taken together with the carbon atom to

which they are attached is cyclopropane, Y = -CH ₇ QMe, U = W = hydrogen, J = lH-pyrazol-1-ylmethyl.

Example 32. Compound of Formula (Ia), wherein M = hydroxy, Q = tert-butγ\-3- methoxybenzoyl, Z = l,3-oxazol-2-yl, X and G taken together with the carbon atom to which they are attached is cyclopropane, Y = -CH ₇ OMe, U = W = hydrogen, J = lH-pyrazol-1-ylmethyl.

Example 33. Compound of Formula (Ia), wherein M = hydroxy, O = ferf-butyl-3- methoxybenzoyl, Z = phenyl, X and G taken together with the carbon atom to which they are attached is cyclopropane, Y = -CFbOMe, U = W = hydrogen, J = lH-pyrazol-1-ylmethyl.

Example 34. Compound of Formula (Ia), wherein M = hydroxy, O = ferf-butyl-3- methoxybenzoyl, Z = pyridin-2-yl, X and G taken together with the carbon atom to which they are attached is cyclopropane, Y = -CFbOMe, U = W = hydrogen, J = lH-pyrazol-1-ylmethyl. Example 35. Compound of Formula (Ia), wherein M = hydroxy, Q = ferf-butyl-3- methoxybenzoyl. Z = pyridin-3-yl. X and G taken together with the carbon atom to which they are attached is cyclopropane, Y = -CFbOMe, U = W = hydrogen, J = lH-pyrazol-1-ylmethyl. Example 36. Compound of Formula (Ia), wherein M = hydroxy, Q = ferf-butyl-3- methoxybenzoyl, Z = pyridin-4-yl, X and G taken together with the carbon atom to which they are attached is cyclopropane, Y = -CFbOMe, U = W = hydrogen, J = lH-pyrazol-1-ylmethyl.

Example 37. Compound of Formula (Ia), wherein M = hydroxy, O = ferf-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and G taken together with the carbon atom to which they are attached is cyclopropane, Y = -CFbOMe, U = W = hydrogen, J = -CH=NOMe.

Example 38. Compound of Formula (Ia), wherein M = hydroxy, Q = ferf-butyl-3- methoxybenzoyl. Z = 1.3-thiazol-2-yl. X and G taken together with the carbon atom to which they are attached is cyclopropane, Y = -CFbOMe, U = W = hydrogen, J = -CH=NNMe ₇ .

Example 39. Compound of Formula (Ia), wherein M = hydroxy, O = ferf-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and G taken together with the carbon

atom to which they are attached is cyclopropane, Y = -CFbOMe, U = W = hydrogen, J = l,3-thiazol-4-ylmethyl.

Example 40. Compound of Formula (Ia), wherein M = hydroxy, Q = tert-butγ\-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and G taken together with the carbon atom to which they are attached is cyclopropane, Y = -CFbOMe, U = W = hydrogen, J = 1.3-thiazol-2-ylmethyl.

Example 41. Compound of Formula (Ia), wherein M = hydroxy, O = ferf-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and G taken together with the carbon atom to which they are attached is cyclopropane, Y = -CFbOMe, U = W = hydrogen, J = l,2-thiazol-3-ylmethyl.

Example 42. Compound of Formula (Ia), wherein M = hydroxy, O = ferf-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and G taken together with the carbon atom to which they are attached is cyclopropane, Y = -CFbOMe, U = W = hydrogen, J = isoxazol-3-ylmethyl. Example 43. Compound of Formula (Ia), wherein M = hydroxy, O = ferf-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and G taken together with the carbon atom to which they are attached is cyclopropane, Y = -CFbOMe, U = W = hydrogen, J = pyridin-2-ylmethyl. Example 44. Compound of Formula (Ia), wherein M = hydroxy, Q = ferf-butyl-3- methoxybenzoyl. Z = 1.3-thiazol-2-yl. X and G taken together with the carbon atom to which they are attached is cyclopropane, Y = -CFbOMe, U = W = hydrogen, J = pyrimidin-2-ylmethyl.

Example 45. Compound of Formula (Ia), wherein M = hydroxy, Q = ferf-butyl-3- methoxybenzoyl. Z = 1.3-thiazol-2-yl. X and G taken together with the carbon atom to which they are attached is cyclopropane, Y = -CFbOMe, U = W = hydrogen, J = 1.2-thiazol-5-yl.

Example 46. Compound of Formula (Ia), wherein M = hydroxy, Q = ferf-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and G taken together with the carbon atom to which they are attached is cyclopropane, Y = J = -CFbOMe, U = W = hydrogen.

Example 47. Compound of Formula (Ia), wherein M = hydroxy, O = ferf-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and G taken together with the carbon

atom to which they are attached is cyclopropane, Y = -CH ₂ OMe, U = W = hydrogen, J = -CH ₂ CH ₂ OMe.

Example 48. Compound of Formula (Ia), wherein M = hydroxy, O = ferf-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and G taken together with the carbon atom to which they are attached is cyclopropane, Y = -CH ₂ OMe, U = W = hydrogen, J = -CH ₂ NMe ₂ .

Example 49. Compound of Formula (Ia), wherein M = hydroxy, Q = ferf-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and G taken together with the carbon atom to which they are attached is cyclopropane, Y = -CH ₂ OMe, U = W = hydrogen, J = -CH ₂ CH ₂ NMe ₂ .

Example 50. Compound of Formula (Ia), wherein M = hydroxy, Q = ferf-butyl-3- methoxybenzoyl. Z = 1.3-thiazol-2-yl. X and G taken together with the carbon atom to which they are attached is cyclopropane, Y = -CH ₂ OMe, U = W = hydrogen, J = -CH ₂ NHMs. Example 51. Compound of Formula (Ia), wherein M = hydroxy, O = ferf-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and G taken together with the carbon atom to which they are attached is cyclopropane, Y = -CH ₂ OMe, U = W = hydrogen. J = -CH ₂ CH ₂ NHMs. Example 52. Compound of Formula (Ia), wherein M = hydroxy, Q = ferf-butyl-3- methoxybenzoyl. Z = 1.3-thiazol-2-yl. X and G taken together with the carbon atom to which they are attached is cyclopropane, Y = W = -CH ₂ OMe, U = hydrogen, J = Me.

Example 53. Compound of Formula (Ia), wherein M = hydroxy, Q = ferf-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and G taken together with the carbon atom to which they are attached is cyclopropane, Y = W = -CH ₂ OMe, U = J = hydrogen.

Example 54. Compound of Formula (Ia), wherein M = hydroxy, O = ferf-butyl-3- methoxybenzoyl, Z = l,3-thiazol-2-yl, X and G taken together with the carbon atom to which they are attached is cyclopropane, Y = -CH ₂ OMe, U = hydrogen, W = -CH ₂ NHMs. J = Me.

Example 55. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyi- 3-methoxybenzoyl, Z = l,3-thiazol-2-yl-methyl, X and G taken together with the

carbon atom to which they are attached is cyclopropane, Y = -CIHbOMe, U = W = hydrogen, J = lH-pyrazol-1-ylmethyl.

Example 56. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-ferf-butyl- 3-methoxybenzoyl, Z = isopropyl, X and G taken together with the carbon atom to which they are attached is cyclopropane, Y = -CH ₇ OMe, U = W = hydrogen, J = 1 H-pyrazol- 1 -ylmethyl.

Example 57. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-ferf-butyl- 3-methoxybenzoyl, Z = isopropyl, X and G taken together with the carbon atom to which they are attached is 2-cyclopentene, Y = -CH ₇ OMe, U = W = hydrogen, J = 1 H-pyrazol- 1 -ylmethyl.

Example 58. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyi- 3-methoxybenzoyl, Z = isopropyl, X and G taken together with the carbon atom to which they are attached is cyclopentane, Y = -CFbOMe, U = W = hydrogen, J = 1 H-pyrazol- 1 -ylmethyl. Example 59. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butγ\- 3-methoxybenzoyl, Z = isopropyl, X and G taken together with the carbon atom to J = 1 H-pyrazol- 1 -ylmethyl.

Example 60. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-ferf-butyl- 3-methoxybenzoyl, Z = isopropyl, X and G taken together with the carbon atom to which they are attached is * -~l~- , 2-cyclopentene, Y = -CN, U = W = hydrogen, = lH-pyrazol-l-ylmethyl.

VI. Sixth Principle Invention Example 1. Compound of Formula (Ia), wherein M = ferf-butoxy, Q = 4-tert- butyl-3-methoxybenzoyl. Z = 1.3-thiazol-2-yl. X = CH ₇ . Y = -CO ₇ Et. U = hydrogen, J = methyl.

Step Ia. To a 100 mL round-bottomed flask are added commercially available 2- formylthiazole (2.0 g, 17.7 mmol), L-alanine t-butyl ester hydrochloride (3.2 g, 17.7 mmol), 4A molecular sieve (5.0 g), anhydrous methylene chloride (50 mL) respectively at 0 ⁰ C followed by the addtion of triethylamine (2.96 mL, 21.2 mmol)

dropwisely. After stirred for 1 h at 0 ⁰ C for 1 h, the reaction mixture is warmed up to room temperature and stirred vigorously overnight. The mixture is filtered through a pad of celite and the insoluble is washed thoroughly with methylene chloride. The combined filtrate and washings are concentrated in vacuo, and then treated with diethyl ether (300 mL). The white precipitate is filtered off and the filtrate is concentrated to give a brown oil 4.99 g which is used directly for next step without further purification.

Step Ib. To a 100 mL 3-necked round-bottomed flask are added the compound from step Ia (2.5 g, 8.85 mmol), the commercially available ethyl A- bromocrotonate (1.37 mL, 10.6 mmol), lithium bromide (1.15 g, 13.3 mmol), and freshly distilled THF (40 mL) respectively at 0 ⁰ C followed by the addtion of triethylamine (3.7 mL, 26.6 mmol) dropwisely. After stirred for 1 h at 0 ⁰ C for 1 h, the reaction mixture is warmed up to room temperature and stirred for another 7 h. After being diluted with methylene chloride, the solution is washed with saturated NaHCθ3 and brine, and dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated. The residue is purified by flash chromatography with EtOAc/Hexanes (10-100%) to give the desired product (380 mg, 10% yield). ESIMS m/z = 433.13 [M+H] ⁺ . Step Ic A mixture of the commercially available 4-£-butyl-3-methoxybenzoic acid (2.082 g, 10.0 mmol) in thionyl chloride (5.0 mL) is refluxed for 2.5 hours before being evaporated. Toluene (twice) is added to the residue and the mixture is evaporated. The residue is dried in vacuum to get a crystalline (2.258 g, 99.6%). Step Id. A mixture of the compound from step Ib (380 mg, 0.88 mmol), the compound from step Ic (348 mg, 4.0 mmol), and triethylamine (368 μL, 2.64 mmol) in methylene chloride (4 mL) is stirred at room temperature for 2 days. The reaction mixture is concentrated and purified by flash chromatography with EtOAc/Hexanes (0-40%) to give the desired compound as a pale yellow foam (330 mg, 60%). ESIMS m/z = 623.23 [M+H] ⁺ . Step Ie. A solution of pyrazole (100 mg, 1.47 mmol) in freshly distilled THF (5 mL) is treated with n-BuLi (0.4 mL, 1 mmol, 2.5 M in hexanes) at -2O ⁰ C for 5 minutes. It is charged dropwisely to a solution of the compound from step Id (50 mg, 0.08 mmol) in freshly distilled THF (10 mL). The resulted mixture is stirred

for 2 h at room temperature and is quenched with saturated ammonium chloride and extracted with hexanes. The combined organics are washed with water and brine, dried (Na ₂ SO ₄ ) and evaporated. The residue is purified by flash chromatography (silica, hexane-ethyl acetate) to give the title compound as a white powder (44 mg, 99%).

ESIMS m/z = 543.43 [M+H] ⁺ .

Example 2. Compound of Formula (Ia), wherein M = tert-butoxy, Q = 4-tert- butyl-3-methoxybenzoyl. Z = U-thiazol-2-vL X = CH ₇ . Y = -CH ₇ OH. U = hydrogen, J = methyl. A solution of the compound from Example 1 (48 mg, 0.09 mmol) in THF (5 mL) is treated with lithium aluminum hydride (IM in THF, 0.5 mL, 0.5 mmol) at -45 — 35 ⁰ C for 100 min before being quenched with saturated ammonium chloride solution and extracted with hexanes. The combined organics are washed with water and brine, dried (Na ₂ SO ₄ ), and evaporated. The residue is purified by flash chromatography (silica, hexane-ethyl acetate) to give the title compound as a white solid (19.1 mg, 42%). ESIMS m/z = 501.35 [M+H] ⁺ .

Example 3. Compound of Formula (Ia), wherein M = tert-butoxy, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = CH ₇ , Y = -CH ₇ OCH^, U = hydrogen, J = methyl.

A mixture of the compound from Example 2 (4 mg, 0.008 mmol), NaOH (50% aqueous, 0.5 mL) and methyl iodide (0.5 mL) is stirred at roome temperature for 8 h in the presence of tetrabutylammonium bromide (1 mg), before partition (ethyl acetate and water). The organics are washed with water and brine, dried (Na ₂ SO ₄ ), and evaporated. The residue is purified by flash chromatography (silica, hexane- ethyl acetate) to give the title compound as a white solid (4 mg, 95%). ESIMS m/z = 515.39 [M+H] ⁺ .

Example 4. Compound of Formula (Ia), wherein M = hydroxyl, Q = 4-tert-butyi- 3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = CH ₇ , Y = -CH ₇ OCH^, U = hydrogen. J = methyl.

A solution of the compound from Example 3 (4 mg, 0.008 mmol) in trifluoroacetic acid (1 mL) is stirred at room temperature for 5 h before evaporation. The residue

is purified by preparative TLC (hexane-ethyl acetate) to give the title compound as a white solid (2 mg, 57%).

ESIMS m/z = 459.57 [M+H] ⁺ .

Example 5. Compound of Formula (Ia), wherein M = hydroxyl, Q = 4-tert-butyl- 3-methoxybenzoyl. Z = U-thiazol-2-vL X = CH ₇ . Y = -CH9OCOCK U = hydrogen, J = methyl.

A solution of the compound from Example 2 (5 mg, 0.01 mmol) in trifluoroacetic acid (0.5 mL) and methylene chloride (0.5 mL) is stirred at room temperature for

12 h before evaporation to give the crude title compound. ESIMS m/z = 541.22 [M+H] ⁺ .

Example 6. Compound of Formula (Ia), wherein M = hydroxyl, Q = 4-tert-buty\-

3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = CH ₇ , Y = -CH ₇ OH, U = hydrogen. J

= methyl.

A solution of the compound from Example 5 (4 mg, 0.01 mmol at most) in methanol (1 mL) is refluxed for 2 h before evaporation. The residue is purified by preparative TLC (hexane-ethyl acetate) to give the title compound as a white solid

(2.9 mg).

ESIMS m/z = 445.31 [M+H] ⁺ .

Example 7. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyi- 3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = CH ₇ , Y = -CH ₇ OCH^, U = hydrogen.

J = lH-pyrazol-l-ylmethyl.

Example 8. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-

3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = CH ₇ , Y = -C(O)NH ₇ , U = hydrogen.

J = lH-pyrazol-1-ylmethyl. Example 9. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl-

3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = CH ₇ , Y = -C(O)NHBn, U = hydrogen, J = lH-pyrazol-l-ylmethyl.

Example 10. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl-

3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = CH ₇ , Y = -C(O)NHPh, U = hydrogen, J = lH-pyrazol-1-ylmethyl.

Example 11. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-

3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = CH ₇ , Y = -CH ₇ OBn, U = hydrogen.

J = lH-pyrazol-l-ylmethyl.

Example 12. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butγ\-

3-methoxybenzoyl. Z = 1.3-thiazol-2-yl. X = CH ₇ . Y = -SO ₇ Ph. U = hydrogen. J = lH-pyrazol- 1 -ylmethyl.

Example 13. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butγ\- 3-methoxybenzoyl. Z = 1.3-thiazol-2-yl. X = CH ₇ . Y = -NHMs. U = hydrogen. J = lH-pyrazol- 1 -ylmethyl.

Example 14. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl-

3-methoxybenzoyl. Z = 1.3-thiazol-2-yl. X = CH ₇ . Y = -CO ₇ Et. U = hydrogen. J = lH-pyrazol- 1 -ylmethyl. Example 15. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-

3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = CH ₇ , Y = -CH ₇ OC(O)NH ₇ , U = hydrogen, J = lH-pyrazol-1 -ylmethyl.

Example 16. Compound of Formula (Ia), wherein M = hydroxy, O = 4-tert-buty\- benzenesulfonyl, Z = l,3-thiazol-2-yl, X = CH ₇ , Y = -CH ₇ OCH^, U = hydrogen. J = lH-pyrazol-l-ylmethyl.

Example 17. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\- phenylcarbamoyl. Z = 1.3-thiazol-2-yl. X = CH ₇ , Y = -CH ₇ OCH^, U = hydrogen. J

= lH-pyrazol-1 -ylmethyl.

Example 18. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-ferf-butyl- 3-bromobenzoyl, Z = l,3-thiazol-2-yl, X = CH ₇ , Y = -CH ₇ OCH^, U = hydrogen. J

= lH-pyrazol-l-ylmethyl.

Example 19. Compound of Formula (Ia), wherein M = hydroxy, O = 4-ferf-butyl-

3-vinylbenzoyl, Z = l,3-thiazol-2-yl, X = CH ₇ , Y = -CH ₇ OCH^, U = hydrogen. J = lH-pyrazol- 1 -ylmethyl. Example 20. Compound of Formula (Ia), wherein M = hydroxy, Q = 2-fluoro-4- fert-butyl-5-vinylbenzoyl, Z = l,3-thiazol-2-yl, X = CH ₇ , Y = -CH ₇ OCH^, U = hydrogen, J = lH-pyrazol-l-ylmethyl.

Example 21. Compound of Formula (Ia), wherein M = hydroxy, O = 4-ferf-butyl-

3-methoxybenzoyl, Z = l,3,4-thiadiazol-2-yl, X = CH ₇ , Y = -CH ₇ OCH^, U = hydrogen, J = lH-pyrazol-l-ylmethyl.

Example 22. Compound of Formula (Ia), wherein M = hydroxy, O = 4-ferf-butyl-

3-methoxybenzoyl. Z = 5-methylisoxazol-3-yl. X = CH ₇ . Y = -CH ₇ OCH^. U = hydrogen, J = lH-pyrazol-l-ylmethyl.

Example 23. Compound of Formula (Ia), wherein M = hydroxy, O = 4-tert-butγ\-

3-methoxybenzoyl. Z = thiophen-2-yl. X = CH ₇ . Y = -CH ₇ OCH^. U = hydrogen. J

= lH-pyrazol-1 -ylmethyl.

Example 24. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butγ\- 3-methoxybenzoyl. Z = thiophen-3-yl. X = CH ₇ . Y = -CH ₇ OCFR U = hydrogen. J

= lH-pyrazol-l-ylmethyl.

Example 25. Compound of Formula (Ia), wherein M = hydroxy, O = 4-ferf-butyl-

3-methoxybenzoyl. Z = furan-2-yl. X = CH ₇ . Y = -CH ₇ OCH^. U = hydrogen. J = lH-pyrazol- 1 -ylmethyl. Example 26. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-ferf-butyl-

3-methoxybenzoyl. Z = furan-3-yl. X = CH ₇ . Y = -CH ₇ OCH^. U = hydrogen. J = lH-pyrazol- 1 -ylmethyl.

Example 27. Compound of Formula (Ia), wherein M = hydroxy, O = 4-ferf-butyl-

3-methoxybenzoyl. Z = 1.3-oxazol-2-yl. X = CH ₇ . Y = -CH ₇ OCH^. U = hydrogen. J = lH-pyrazol-1 -ylmethyl.

Example 28. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-ferf-butyl-

3-methoxybenzoyl. Z = phenyl. X = CH ₇ . Y = -CH ₇ OCH ₁ . U = hydrogen. J = IH- pyrazol- 1 -ylmethyl.

Example 29. Compound of Formula (Ia), wherein M = hydroxy, O = 4-ferf-butyl- 3-methoxybenzoyl. Z = pyridin-2-yl. X = CH ₇ . Y = -CH ₇ OCH.. U = hydrogen. J = lH-pyrazol- 1 -ylmethyl.

Example 30. Compound of Formula (Ia), wherein M = hydroxy, O = 4-ferf-butyl-

3-methoxybenzoyl. Z = pyridin-3-yl. X = CH ₇ . Y = -CH ₇ OCH ₁ . U = hydrogen. J = lH-pyrazol- 1 -ylmethyl. Example 31. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-ferf-butyl-

3-methoxybenzoyl. Z = pyridin-4-yl. X = CH ₇ . Y = -CH ₇ OCH^. U = hydrogen. J = lH-pyrazol- 1 -ylmethyl.

Example 32. Compound of Formula (Ia), wherein M = hydroxy, O = 4-ferf-butyl-

3-methoxybenzoyl. Z = 1.3-thiazol-2-yl. X = CH ₇ . Y = -CH ₇ OCH^. U = hydrogen. J = -CH=NOMe.

Example 33. Compound of Formula (Ia), wherein M = hydroxy, O = 4-ferf-butyl-

3-methoxybenzoyl. Z = 1.3-thiazol-2-yl. X = CH ₇ . Y = -CH ₇ OCH^. U = hydrogen.

J = -CH=NNMe ₇ .

Example 34. Compound of Formula (Ia), wherein M = hydroxy, O = 4-tert-butγ\-

3-methoxybenzoyl. Z = 1.3-thiazol-2-yl. X = CH ₇ . Y = -CH ₇ OCH^. U = hydrogen.

J = l,3-thiazol-4-ylmethyl.

Example 35. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butγ\- 3-methoxybenzoyl. Z = 1.3-thiazol-2-yl. X = CH ₇ . Y = -CH ₇ OCFR U = hydrogen.

J = l,3-thiazol-2-ylmethyl.

Example 36. Compound of Formula (Ia), wherein M = hydroxy, O = 4-ferf-butyl-

3-methoxybenzoyl. Z = 1.3-thiazol-2-yl. X = CH ₇ . Y = -CH ₇ OCH^. U = hydrogen.

J = isoxazol-3-ylmethyl. Example 37. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-ferf-butyl-

3-methoxybenzoyl. Z = 1.3-thiazol-2-yl. X = CH ₇ . Y = -CH ₇ OCH^. U = hydrogen.

J = pyridin-2-ylmethyl.

Example 38. Compound of Formula (Ia), wherein M = hydroxy, O = 4-ferf-butyl-

3-methoxybenzoyl. Z = 1.3-thiazol-2-yl. X = CH ₇ . Y = -CH ₇ OCH^. U = hydrogen. J = -CH ₇ NMe ₇ .

Example 39. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-ferf-butyl-

3-methoxybenzoyl. Z = 1.3-thiazol-2-yl. X = CH ₇ . Y = -CH ₇ OCH ₁ . U = hydrogen.

J = -CH ₇ CH ₇ NMe ₇ .

Example 40. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-ferf-butyl- 3-methoxybenzoyl. Z = 1.3-thiazol-2-yl. X = CH ₇ . Y = -CH ₇ OCH ₁ . U = hydrogen.

J = -CH ₇ NHMs.

Example 41. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-ferf-butyl-

3-methoxybenzoyl. Z = 1.3-thiazol-2-yl. X = CH ₇ . Y = -CH ₇ OCH ₁ . U = hydrogen.

J = -CH ₇ CH ₇ NHMs. Example 42. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-ferf-butyl-

3-methoxybenzoyl. Z = 1.3-thiazol-2-yl-methyl. X = CH ₇ . Y = -CH ₇ OCH ₁ . U = hydrogen, J = lH-pyrazol-l-ylmethyl.

Example 43. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-ferf-butyl-

3-methoxybenzoyl, Z = isopropyl, X = CH ₇ , Y = -CH ₇ OCH ₁ , U = hydrogen, J = 1/f-pyrazol- 1 -ylmethyl.

Example 44. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-ferf-butyl-

3-methoxybenzoyl. Z = 1.3-thiazol-2-yl. X = CF ₇ . Y = -CH ₇ OCH^. U = hydrogen.

J = lH-pyrazol-1 -ylmethyl.

Example 45. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butγ\- 3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = -CH ₇ CF ₇ -. Y = -CH ₇ OCFR U = hydrogen, J = lH-pyrazol-1-ylmethyl.

Example 46. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butγ\- 3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = -OCH ₇ CF ₇ -, Y = -CH ₇ OCH^, U = hydrogen, J = lH-pyrazol-l-ylmethyl.

VII. Seventh Principle Invention

Example 1. Compound of Formula (Ia), wherein M = ferf-butoxy, Q = 4-tert- butyl-3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, W = hydrogen, J = methylene.

Step Ia. A mixture of commercially available L-glycine tert-butyl ester hydrochloride (1.675 g, 10.0 mmol), 2-formyl-l,3-thiazole (1.243 g, 11.0 mmol), and activated molecular sieves (4 A, 10.0 g) in anhydrous methylene chloride (50 mL) is stirred at room temperature for 15 hours before being filtered through Celite and washed with methylene chloride. The combined organics are evaporated and the residue is used directly for next step. ESIMS m/z = 227 '.09 [M+H] ⁺ . Step Ib. A mixture of methyl E-4-hydroxy-crotonate (prepared according to known procedure: Witiak et al, J. Med. Chem. 1981 , 24, 788, 40.0 mmol), triethylamine (11.5 mL, 80.0 mmol), t-butyldimethylsilyl chloride (6.64 g, 44.0 mmol) and 4-dimethylaminopyridine (977 mg, 8.0 mmol) is stirred in anhydrous methylene chloride (100 mL) at room temperature for 12 hours before being quenched with aq. NaHCO ₃ solution. The mixture is partitioned between dichloromethane and water, and the organics are washed with water, brine, dried (Na ₂ SO ₄ ), and evaporated. The residue is chromatographed (silica, hexanes- EtOAc) to give the desired compound (6.70 g, 73%).

Step Ic. Into a mixture of the crude compound from step Ia (10.0 mmol at most) in THF (80.0 mL) at 0 ⁰ C is added the compound from step Ib (2.30 g, 10.0 mmol), lithium bromide (1.74 g, 20.0 mmol), and Et ₃ N (2.88 mL, 20.0 mmol). The resulted mixture is stirred at 0 ⁰ C for 30 minutes before being partitioned (EtO Ac- water). The organics are washed with water, brine, dried (Na ₂ SO ₄ ), and

evaporated. The residue is chromatographed (silica, hexanes-EtOAc) to give the desired compound (4.482 g, 98% two steps). ESIMS m/z = 457.26 [M+H] ⁺ .

Step Id. A mixture of the commercially available 4-t-butyl-3-methoxybenzoic acid (2.082 g, 10.0 mmol) in thionyl chloride (5.0 mL) is refluxed for 2.5 hours before being evaporated. Toluene (twice) is added to the residue and the mixture is evaporated. The residue is dried in vacuum to get a crystalline (2.258 g, 99.6%). Step Ie. Into a mixture of the compound from step Ic (4.48 g, 9.80 mmol) in CH ₂ Cl ₂ (20.0 mL) is added Et ₃ N (4.24 mL, 29.4 mmol) and the compound from step Id (2.66 g, 11.8 mmol). The resulted mixture is stirred at room temperature for 16 hours before being diluted with EtOAc. The organics are washed with saturated NaHCO ₃ , water, brine, dried (Na ₂ SO ₄ ), and evaporated. The residue is chromatographed (silica, hexanes-EtOAc) to give the desired compound (5.21 g, 82%). ESIMS m/z = 647.42 [M+H] ⁺ .

Step If. Into a mixture of the compound from step Ie (100 mg, 0.154 mmol) in methanol (8.0 mL) is added Ba(OH) ₂ 8H ₂ O (488 mg, 1.54 mmol). The resulted mixture is stirred at room temperature for 12 hours before being acidified with 2M aq H ₂ SO ₄ . The precipitate is filted and the filtrate is concentrated and chromatographed (silica, hexanes-EtOAc) to give the desired compound (51.5 mg, 53%).

ESIMS m/z = 633.68 [M+H] ⁺ .

Step Ig. Into a mixture of compound from step If (51 mg, 80.6 μmol) in anhydrous tetrahydrofuran (8 mL) are added triethylamine (0.07 mL, 0.483 mmol) and ethyl chloroformate (23 μL, 0.242 mmol) at 0 ⁰ C. The resultant white cloudy mixture is gradually warmed up to ambient temperature and is the reaction is monitored by mass spectrometry before being delivered to the next step Ih. ESIMS m/z = 705.36 [M+H] ⁺ . Step Ih. Into a mixture of crude compound from step Ig (at most 80.6 μmol) in anhydrous tetrahydrofuran (8 mL) at -78 ⁰ C are added sodium borohydride (30.5 mg, 0.806 mmol) and ethanol (0.5 mL, 4.03 mmol) slowly. The resultant mixture is gradually warmed up to 0 ⁰ C before being quenched with saturated aqueous ammonium chloride and partitioned between ethyl acetate and water. The organics are washed with brine, dried over sodium sulfate and evaporated. The residue is

chromatographed (silica, hexanes-EtOAc) to give the desired compound (37.8 mg, 2 steps 76%) as a colorless oil. ESIMS m/z = 619.38 [M+H] ⁺ .

Step Ii. Into a mixture of compound from step Ih (37.8 mg, 61.1 μmol) in methyl iodide (1.5 mL) are added tetrabutylammonium iodide (4.5 mg, 12.2 μmol) and 50% NaOH aqueous solution (6 mL). The resultant white cloudy mixture is stirred for 2.5 h before being diluted with water. The mixture is partitioned between ethyl acetate and water and the organics are washed with brine, dried over sodium sulfate and evaporated. The residue is chromatographed (silica, hexanes-EtOAc) to give the desired compound (33.2 mg, 86%) as a colorless oil with epimerization at 2 position.

ESIMS m/z = 633.42 [M+H] ⁺ .

Step Ij. Into a mixture of compound from step Ii (33.2 mg, 52.5 μmol) in THF (8.0 mL) is added p-toluenesulfonic acid (8.0 mg, 42.0 μmol) and tetrabutylammonium fluoride (IM in THF, 0.08 mL, 78.7 μmol). The resultant solution is stirred for 2 hours before being quenched with aq. NH ₄ Cl. The mixture is partitioned between EtOAc and water, and the organics are washed with brine, dried over sodium sulfate and evaporated. The residue is chromatographed (silica, hexanes-EtOAc) to give the desired compound (27.1 mg, 100%) as a colorless oil. ESIMS m/z = 519.34 [M+H] ⁺ .

Step Ik. Into a mixture of compound from step Ij (27.1 mg, 52.5 μmol) in anhydrous dichloromethane (6.0 mL) are added triphenylphosphine (82.6 mg, 0.315 mmol) and JV-bromosuccinimide (56.1 mg, 0.315 mmol) at 0 ⁰ C. The resultant mixture is warmed up to ambient temperature and stirred for 12 hours before being quenched with saturated aqueous sodium bicarbonate and partitioned between dichrolomethane and water. The organics are washed with brine, dried over sodium sulfate and evaporated. The residue is chromatographed (silica, hexanes-EtOAc) to give the desired compound (28.2 mg , 92%) as a white solid. ESIMS m/z = 581.24, 583.24 [M+H] ⁺ . Step 11. Into a mixture of compound from step Ik (28.2 mg, 48.5 μmol) in anhydrous tetrahydrofuran (8.0 mL) at 0 ⁰ C is added sodium hydride (60% in mineral oil, 9.7 mg, 0.243 mmol). The mixture is stirred at ambient temperature for 2 hours before being quenched with saturated aqueous ammonium chloride and partitioned between ethyl acetate and water. The organics are washed with brine,

dried over sodium sulfate and evaporated. The residue is chromatographed (silica, hexanes-EtOAc) to give the title compound (23.8 mg, 98%) as a colorless oil.

ESIMS m/z = 501.36 [M+H] ⁺ .

Example 2. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl- 3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, W = hydrogen, J = methylene.

Step 2a. Into a mixture of compound from step 11 (7.0 mg, 16.0 μmol) in anhydrous dichloromethane (1.5 mL) is added trifluoroacetic acid (2.0 mL). The resultant mixture is stirred at room temperature for 6 hours and the volatiles were removed by N ₂ flow. The residue was purified by flash column chromatography

(silica, CH ₂ Cl2-methanol) to give the title compound (5.3 mg, 85%) as a white solid.

ESIMS m/z = 445.27 [M+H] ⁺ .

Example 3. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{- 3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, W = ethoxy, J = methylene.

Example 4. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-

3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, W = methyl, J = methylene. Example 5. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl-

3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, W = hydrogen, J = difluoromethylene.

Example 6. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty{-

3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, W = fluoro, J = tetrafluoroethylene.

Example 7. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\-

3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = cyano, Y = cyano, W = phenyl, J = methylene.

Example 8. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl- 3-methoxybenzoyl, Z = thiophen-2-yl, X = hydrogen, Y = methoxymethyl, W = hydrogen, J = methylene.

Example 9. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyi-

3-methoxybenzoyl, Z = thiophen-3-yl, X = hydrogen, Y = methoxymethyl, W = hydrogen, J = methylene.

Example 10. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl-

3-methoxybenzoyl, Z = isopropyl, X = hydrogen, Y = methoxymethyl, W = hydrogen, J = methylene.

Example 11. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl- 3-methoxybenzoyl, Z = oxazol-2-yl, X = hydrogen, Y = methoxymethyl, W = hydrogen, J = methylene.

Example 12. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl-

3-methoxybenzoyl, Z = 5-methyl-isoxazol-3-yl, X = hydrogen, Y = methoxymethyl, W = hydrogen, J = methylene.

Example 13. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl-

3-methoxybenzoyl, Z = furan-2-yl, X = hydrogen, Y = methoxymethyl, W = hydrogen, J = methylene.

Example 14. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butγ\- 3-methoxybenzoyl, Z = furan-3-yl, X = hydrogen, Y = methoxymethyl, W = hydrogen, J = methylene.

Example 15. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl-

3-methoxybenzoyl, Z = pyridin-2-yl, X = hydrogen, Y = methoxymethyl, W = hydrogen, J = methylene. Example 16. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl-

3-methoxybenzoyl, Z = pyridin-3-yl, X = hydrogen, Y = methoxymethyl, W = hydrogen, J = methylene.

Example 17. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butγ\-

3-methoxybenzoyl, Z = pyridin-4-yl, X = hydrogen, Y = methoxymethyl, W = hydrogen, J = methylene.

Example 18. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl-

3-methoxybenzoyl, Z = phenyl. X = hydrogen, Y = methoxymethyl, W = hydrogen, J = methylene.

Example 19. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl- 3-methoxybenzoyl, Z = thiazol-2-ylmethyl, X = hydrogen, Y = methoxymethyl, W

= hydrogen, J = methylene.

Example 20. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert- butylbenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, W = hydrogen, J = methylene.

Example 21. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butγ\-

3-vinylbenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, W = hydrogen, J = methylene.

Example 22. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl- 2-fluoro-5-vinylbenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl,

W = fluoro, U = hydrogen, J = lH-pyrazol-1-ylmethyl.

Example 23. Compound of Formula (Ia), wherein M = hydroxy, Q = 3-bromo-4- ferf-butylbenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, W = fluoro, U = hydrogen, J = lH-pyrazol-1-ylmethyl. Example 24. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl- benzenesulfonyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, W = fluoro, U = hydrogen, J = lH-pyrazol-l-ylmethyl.

Example 25. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-Butyl- phenylcarbamoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, W = fluoro, U = hydrogen, J = lH-pyrazol-l-ylmethyl.

Example 26. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyi-

3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, W =

/S hydrogen, J = ^■ < ^"* !*.

Example 27. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-buty\- 3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, W =

Example 28. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl-

3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, W = o U

O' "NH hydrogen, J = f * Example 29. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyi- 3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = hydrogen, Y = methoxymethyl, W = o hydrogen

Example 30. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butγ\- 3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoride, Y = methoxymethyl, W =

hydrogen, J = < /"N>.

Example 31. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl- 3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoride. Y = -CH=NOMe. W =

hydrogen, J = "* /?S T".

Example 32. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-tert-butyl-

3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoride, Y = fluoromethyl, W =

/\ hydrogen, J = "^ T*. Example 33. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-ferf-butyl- 3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X = fluoride, Y = azide, W = hydrogen, J

Example 34. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-ferf-butyl- 3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

atom to which they are attached JL W = hydrogen, J = A

Example 35. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-ferf-butyl- 3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

^o atom to which they are attached is N , W = hydrogen, J = **?" ^* ?". Example 36. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-ferf-butyl- 3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

atom to which they are attached is ^** *»• ^0Me , W = hydrogen, J = -"r "P".

Example 37. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-ferf-butyl-

3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

atom to which they are attached is ^" ^ '"° , W = hydrogen, J = *? T*. Example 38. Compound of Formula (Ia), wherein M = hydroxy, Q = 4-ferf-butyl- 3-methoxybenzoyl, Z = l,3-thiazol-2-yl, X and Y taken together with the carbon

atom to which they are attached i iss >> ,, WW == hhyyddrrooggeenn,, JJ == A **? "T*.. All references cited herein, whether in print, electronic, computer readable storage media or other

form, are expressly incorporated by reference in their entirety, including but not limited to, abstracts, articles, journals, publications, texts, treatises, internet web sites, databases, patents, and patent publications.

The compounds of the present invention exhibit potent inhibitory properties against the HCV NS5B polymerase. The following examples describe assays in which the compounds of the present invention can be tested for anti-HCV effects. NS5B Polymerase Enzyme Assay

NS5B polymerase from the genotype Ib-BK strain was purified as a recombinant form from E. coli. The purified protein contains a hexahistidine tag that replaces the 21 amino acids normally found at the carboxy-terminal end. In the assay, NS5B polymerase (an RNA-dependent RNA polymerase "RdRp") is briefly pre-incubated with test compounds dissolved in DMSO. The substrate in the reaction consists of poly-cytidylic acid template and a biotinylated poly- guanosine primer. The substrate mix contains H-labeled GTP; following the reaction radioactive incorporation into products is determined using scintillation proximity assay. Materials and Reagents:

96-well polypropylene plates Matrix # 4918

Streptavidin PVT SPA Scintillation Beads, 50 mg GE # RPNQ0006 (resuspend in 5 mL PBS just before use)

96-well Flexible PET Microplate Perkin Elmer #1450-401

Plate seals (reusable) Perkin Elmer #1450-462

DMSO Alfa Aesar # 22914

RNase-free dH ₂ O (DEPC-treated) biotinylated-rGrGrG Prepared as a 200 DM stock in RNase-free dH ₂ O

(custom ordered from Dharmacon/Thermo Fisher) 5X Reaction Buffer (generated using RNase-free dH ₂ O): 100 mM Hepes, pH 7.5 15O mM NaCl RNasin Plus RNase Inhibitor Promega # N2615

BSA (50 mg/mL, purified) Ambion # 2616

Poly-cytidylic acid Amersham #27-4220-02

Prepare as 5 mg/mL stock in RNase-free TE. IM MgCl ₂

[8- ³ H] Guanosine 5 '-triphosphate GE # TRK314 ammonium salt, 37 MBq, 1 mCi. 0.5 M EDTA solution prepared in RNAse-free dH ₂ O. 4 M CsCl solution prepared in RNase-free dH ₂ O. Incorporation of ³ H-GTP into RNA was measured using absorption of biotinylated RNA reaction products to streptavidin-coated SPA beads. The template was generated by mixing biotinylated 3mer-rG with poly-rC.

Final reaction conditions were as follows: 2OmM Hepes, pH 7.5, 3OmM NaCl, 8mM MgCl ₂ , 2mM DTT, 0.1 U/μl RNase inhibitor, 0.5 μM biotin-G3, 2.5 μg/ml poly-rC, 0.05 mg/ml BSA, 2.0 nM NS5B protein.

Concentrated NS5B Master Mix was prepared by mixing the following (in order): 561.7 μl dH ₂ O, 800 μl 5X Buffer (100 mM Hepes, 150 mM NaCl, pH 7.5), 32 μl IM MgCl ₂ , 80 μl 0.1 M DTT, 10 μl 40 U/μl RNase inhibitor, 10 μl 200 μM biotinylated-rG3, 2 μl 5 mg/ml poly-rC, 4 μl 50 mg/ml BSA, and 0.3 μl 26.3 μM purified NS5B.

Concentrated Negative Control Mix was prepared by mixing the following (in order): 56.2 μl dH ₂ O, 80 μl 5X Buffer (100 mM Hepes, 150 mM NaCl, pH 7.5), 3.2 μl IM MgCl ₂ , 8.0 μl 0.1 M DTT, 1.0 μl 40 U/μl RNase inhibitor, 1.0 μl 200 μM biotinylated-rG3, 0.2 μl 5 mg/ml poly-rC, and 0.4 μl 50 mg/ml BSA, Substrate Mix was prepared by mixing 100 μl [8- H] Guanosine 5'- triphosphate and 400 μl RNase-free dH ₂ O.

Reactions were set up in clear PET microplates with additions as follows (in order): 18 μl RNase-free dH ₂ O; 2 μl of test compounds in DMSO; 15 μl NS5B Master Mix or Negative Control Mix; 5 μl Substrate Mix. Total Reaction volume of 40 μl.

Reactions were performed in clear 96-well U-bottom PET plates. After enzyme additions were made (prior to adding substrates), plates were mixed on a plate-shaker for 10 minutes at 21 ⁰ C. Reactions were initiated by adding substrate mix, mixing for another 2 minutes, then placing at 37°C for 3 hours. Reactions were terminated by the addition of 30 μl Termination Mix (made by mixing 504 μl PBS, pH 7.4, 720 μl 0.5 M EDTA, and 936 μl streptavidin- coated SPA beads at 10 mg/ml in PBS). Plates were then mixed on a plate-shaker for 30 minutes at 21 ⁰ C.

30 μl of 4M CsCl was then added to each well. Following a brief mixing period, plates were left at 21 ⁰ C for one hour then counted using a TriLux Microbeta Counter.

Results were determined by subtracting background level (reactions done with Negative Control Mix) from all other reactions. Ten concentrations of each compound were tested (2.5-fold serial dilutions) in quadruplicate. Results (CPM) from each well were fitted to a 4-Parameter Logistical Model (XLFit v4.21, model # 205) to obtain an IC50 value for each test compound.

Cell-Based Replicon Assay

Quantification of HCV replicon RNA (HCV Cell Based Assay) is accomplished using the Huh 11-7 cell line (Lohmann, et al Science 285:110-113, 1999). Cells are seeded at 4x10 ³ cells/well in 96 well plates and fed media containing DMEM (high glucose), 10% fetal calf serum, penicillin-streptomycin and non-essential amino acids. Cells are incubated in a 7.5% CO ₂ incubator at 37 ⁰ C. At the end of the incubation period, total RNA is extracted and purified from cells using Ambion RNAqueous 96 Kit (Catalog No. AMI 812). To amplify the HCV RNA so that sufficient material can be detected by an HCV specific probe (below), primers designed within a specific region of HCV genome sequence mediate both the reverse transcription of the HCV RNA and the amplification of the cDNA by polymerase chain reaction (PCR) using the TaqMan One-Step RT- PCR Master Mix Kit (Applied Biosystems catalog no. 4309169).

Detection of the RT-PCR product is accomplished using the Applied Biosystems (ABI) Prism 7500 Sequence Detection System (SDS) that detects the fluorescence that is emitted when the probe, which is labeled with a fluorescence reporter dye and a quencher dye, is degraded during the PCR reaction. The increase in the amount of fluorescence is measured during each cycle of PCR and reflects the increasing amount of RT-PCR product. Specifically, quantification is based on the threshold cycle, where the amplification plot crosses a defined fluorescence threshold. Comparison of the threshold cycles of the sample with a known standard provides a highly sensitive measure of relative template concentration in different samples (ABI User Bulletin #2 December 11, 1997). The data is analyzed using the ABI SDS program version 1.7. The relative template

concentration can be converted to RNA copy numbers by employing a standard curve of HCV RNA standards with known copy number (ABI User Bulletin #2 December 11, 1997).

The RT-PCR product was detected using a labeled probe designed within a specific region of HCV genome sequence.

The RT reaction is performed at 48 ⁰ C for 30 minutes followed by PCR. Thermal cycler parameters used for the PCR reaction on the ABI Prism 7500 Sequence Detection System are: one cycle at 95 ⁰ C, 10 minutes followed by 40 cycles each of which include one incubation at 95 ⁰ C for 15 seconds and a second incubation for 60 ⁰ C for 1 minute.

To normalize the data to an internal control molecule within the cellular RNA, RT-PCR is performed on the cellular messenger RNA glyceraldehyde-3- phosphate dehydrogenase (GAPDH). The GAPDH copy number is very stable in the cell lines used. GAPDH RT-PCR is performed on the same RNA sample from which the HCV copy number is determined. The GAPDH primers and probesare contained in the ABI Pre-Developed TaqMan Assay Kit (catalog no. 4310884E). The ratio of HCV/GAPDH RNA is used to calculate the activity of compounds evaluated for inhibition of HCV RNA replication.

Activity of compounds as inhibitors of HCV replication (Cell based Assay) in replicon containing Huh-7 cell lines.

The effect of a specific anti-viral compound on HCV replicon RNA levels in Huh-1 l-7cells is determined by comparing the amount of HCV RNA normalized to GAPDH (e.g. the ratio of HCV/GAPDH) in the cells exposed to compound versus cells exposed to the DMSO vehicle (negative control). Specifically, cells are seeded at 4x 10 ³ cells/well in a 96 well plate and are incubated either with: 1) media containing 1% DMSO (0% inhibition control), or 2) media/1 %DMSO containing a fixed concentration of compound. 96 well plates as described above are then incubated at 37 ⁰ C for 4 days (EC50 determination). Percent inhibition is defined as:

% Inhibition= 100-100*S/Cl, where

S= the ratio of HCV RNA copy number/GAPDH RNA copy number in the sample;

Cl= the ratio of HCV RNA copy number/GAPDH RNA copy number in the 0% inhibition control (media/1 %DMSO).

The dose-response curve of the inhibitor is generated by adding compound in serial, three-fold dilutions over three logs to wells starting with the highest concentration of a specific compound at 1.5 uM and ending with the lowest concentration of 0.23 nM. Further dilution series (500 nM to 0.08 nM for example) is performed if the EC50 value is not positioned well on the curve. EC50 is determined with the IDBS Activity Base program "XL Fit" using a 4-paramater, non-linear regression fit (model # 205 in version 4.2.1, build 16) . In the above assays, representative compounds of the present invention were found to have HCV replication inhibitory activity and HCV NS3 protease inhibitory activity. These compounds were also effective in inhibiting HCV NS3 proteases of different HCV genotypes including genotypes 1, 2, 3 and 4.

Representative compounds were tested in the above assays (Examples 3, 5, 7, 18-21, 42-48, 50-55, 58, 91-96, 98, 112-118, 121, 129, 135-136 of the first principle embodiment, Examples of 2, 4 of the second principle embodiment, Examples of 55 of the third principle embodiment, and Example 8 of the fifth priciple embodiment). These compounds were found to have activities in the ranges of <= 10 nM-500 nM in the NS5B Polymerase Enzyme Assay and/or <= 10 nM-2000 nM in the Cell-Based Replicon Assay.

Although the invention has been described with respect to various preferred embodiments, it is not intended to be limited thereto, but rather those skilled in the art will recognize that variations and modifications may be made therein which are within the spirit of the invention and the scope of the appended claims.