WO2023118267A1

WO2023118267A1 - Novel galactoside inhibitor of galectins

Info

Publication number: WO2023118267A1
Application number: PCT/EP2022/087188
Authority: WO
Inventors: Fredrik Zetterberg; Kristoffer Peterson; Ulf Nilsson
Original assignee: Galecto Biotech Ab
Priority date: 2021-12-22
Filing date: 2022-12-21
Publication date: 2023-06-29

Abstract

The present invention relates to a is β-D-galactopyranose compound of formula (1) wherein these compounds are high affinity galectin-3 and 9 inhibitors for use in treatment of a disease or disorder, such as but not limited to inflammation,; fibrosis, acute transplantation rejection of the kidney, heart, lung, liver, and pancreas, acute post explosion /improvised explosive devices, acute post toxic dust, acute chemical exposure, chronic lung fibrosis, interstitial lung fibrosis (IPF), Interstitial Lung Disease (ILD), Childhood ILD (ChILD), such as non specific interstitial pneumonia (NSIP), Crytogenic organising pneumonia (COP), Desquamative interstital pneumonia (DIP), Sarcoidosis; dermatomyositis; chronic liver fibrosis; chronic alcohol fibrosis, chronic viral fibrosis, chronic diabetic fibrosis, diabetic nephropathy, chronic glomerulonephritis, renal artery stenosis, endometriosis; scarring; keloid formation; aberrant scar formation; surgical adhesions; scleroderma; systemic sclerosis; septic shock; cancers; metastasising cancers; autoimmune diseases; chronic scarring; asthma and other interstitial lung diseases, pulmonary arterial hypertension, Rheumatoid disease associated interstitial lung disease RA-ILD, Systemic Sclerosis SSc-ILD, lung disease with fibrosis; Otosclerosis, mesothelioma; post-surgery disorders; toxin exposure disorders; Tissue injury; congenital hepatic fibrosis; hereditary fibrosing poikiloderma with tendon contractures, myopathy, and pulmonary fibrosis; liver disorders, liver cirrhosis of various origins, autoimmune cirrhosis and sclerosing cholangitis, virally induced cirrhosis, cirrhosis induced by genetic disease, moderate hepatic impairment; Liver cancer, cholangiocarcinoma, biliary tract cancer; neurodegenerative disorders, cerebrovascular diseases.

Description

NOVEL GALACTOSIDE INHIBITOR OF GALECTINS

Technical field

The present invention relates to novel compounds, the use of said compounds as medicament and for the manufacture of a medicament for the treatment of diseases or disorders such as but not limited to inflammation, such as acute post myocardial infarctions (MI), acute coronary syndrome, acute stent occlusion, acute myocardial reperfusion injury, acute pneumonitidies, acute lung injury (ALI), acute kidney injury (AKI), acute hepatitis, acute on chronic liver failure, acute alcohol hepatitis, acute pancreatitis, acute uveitis, acute pancreatitis related liponecrosis, acute retinitis, acute nephritis, acute myocarditis, autoimmune or autoreactive myocarditis, giant cell myocarditis, chronic autoimmune diseases in all organs, (e.g. lung, liver, kidney, heart, skin, muscle, gut), chronic bacterial infections, chronic viral related inflammation; fibrosis, such as pulmonary fibrosis, liver fibrosis, kidney fibrosis, ophthalmological fibrosis and fibrosis of the skin and heart, acute post-surgical ocular fibrosis, acute transplantation rejection of the kidney, heart, lung, liver, and pancreas, acute post explosion /improvised explosive devices, acute post toxic dust (such as dust from terror attack known as 9/11), acute chemical exposure, chronic lung fibrosis, interstitial lung fibrosis (IPF), Interstitial Lung Disease (ILD), Childhood ILD (ChILD), such as nonspecific interstitial pneumonia (NSIP), Crytogenic organising pneumonia (COP), Desquamative interstital pneumonia (DIP), Sarcoidosis; dermatomyositis; chronic liver fibrosis; chronic alcohol fibrosis, chronic viral fibrosis, chronic diabetic fibrosis, diabetic nephropathy, chronic glomerulonephritis, renal artery stenosis, endometriosis; scarring; keloid formation; aberrant scar formation; surgical adhesions; scleroderma; systemic sclerosis; septic shock; cancers, such as carcinomas, sarcomas, leukemias and lymphomas, such as T- cell lymphomas; metastasising cancers; autoimmune diseases, such as psoriasis, rheumatoid arthritis, Crohn’s disease, ulcerative colitis, intestinal fibrosis, ankylosing spondylitis, systemic lupus erythematosus; metabolic disorders; coagulopathies, such as thrombosis proneness idiopathic (thrombophilia), autoimmune based thrombophilia, microthrombosis at multiorgan failure, COVID-19 related coagulopathy, thrombophilia in cancer disease; cardiovascular disorders, such as cardiac fibrosis, cardiac failure, left and right atrial fibrillation, atheromatosis, arterial inflammation, arterial calcification aortic stenosis; heart disease; heart failure; aortic stenosis, atherosclerosis, pathological angiogenesis, such as ocular angiogenesis or a disease or condition associated with ocular angiogenesis, e.g. neovascularization related to cancer; and eye diseases, such as age-related macular degeneration and corneal neovascularization; atherosclerosis; endocrine disorders, such as Addison, autoimmune hypophysitis; metabolic diseases such as diabetes; type 2 diabetes; insulin resistance; obesity; Diastolic HF; atrophic diseases in the brain, such as Alzheimer’s and Parkinson’s, atrophic diseases in the cerebellum, such as cerebellar atrophy, atrophic spinal diseases such as ALS; disorders related to transplantation in organs, such as anti -rejection prophylaxis, anti-acute rejection, anti-chronic rejection; acute burn; acute inflammatory reaction; chronic acute skin graft rejection; chronic scarring; asthma and other interstitial lung diseases, including Hermansky-Pudlak syndrome, pulmonary arterial hypertension, Rheumatoid disease associated interstitial lung disease RA-ILD, Systemic Sclerosis SSc-ILD, lung disease with fibrosis such as COPD (Chronic Obstructive Pulmonary Disease) and asthma; Otosclerosis, mesothelioma; post-surgery disorders, such as anti-keloid, anti-stricture, antiadhesion, anti-thrombosis, fibrosis/scar reduction following cosmetic procedures; toxin exposure disorders, such as toxic hepatitis, cholera toxin related, mushroom toxin based acute renal failure, pertussis toxin, aeromonas hydrophila enterotoxin, cadmium induced cardiac toxicity, helicobacter O-antigen related toxicity, LPS based toxicity, Streptozotocin toxicity, asbestos exposure, Nephrogenic Systemic Fibrosis (Post Contrast Agents); Tissue injury, such as Spinal cord injury, Peripheral nerve repair; congenital hepatic fibrosis; hereditary fibrosing poikiloderma with tendon contractures, myopathy, and pulmonary fibrosis; liver disorders, such as non-alcoholic steatohepatitis (NASH) or non-alcoholic fatty liver disease, liver cirrhosis of various origins, such as alcoholic and non-alcoholic, autoimmune cirrhosis such as primary biliary cirrhosis and sclerosing cholangitis, virally induced cirrhosis, cirrhosis induced by genetic disease, moderate hepatic impairment; Liver cancer, cholangiocarcinoma, biliary tract cancer; neurodegenerative disorders such as Parkinsons disease, Alzheimers disease, cognitive impairment, cerebrovascular diseases such as stroke, traumatic brain injury, Huntington's disease, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), peripheral nephropathy. The invention also relates to pharmaceutical compositions comprising said novel compounds. Background Art

Galectins are proteins with a characteristic carbohydrate recognition domain (CRD). This is a tightly folded P-sandwich of about 130 amino acids (about 15 kDa) with the two defining features 1) a P -galactose binding site and 2) sufficient similarity in a sequence motif of about seven amino acids, most of which (about six residues) make up the P-galactose binding site. Galectins are synthesized as cytosolic proteins from where they can be targeted to the nucleus, specific cytososlic sites, or secreted to engage in mechanisms effecting physiological functions such as inflammation, immune responses, cell-migration and autophagy. (Johannes et. al 2018) There are now over 9319 publications on galectins in PubMed, with most, as mentioned above, about galectins-1 (>1989) and -3 (>4791). Evidence from literature suggests roles for galectins in e.g. fibrosis, inflammation and cancer (Dings et. al., Dube-Delarosbil et. al 2017).

Galectin-3 is widely expressed in many cell types and tissues (www.proteinatlas.org) being involved in mechanisms such as apoptosis, adhesion and migration, cell transformation, invasion and metastasis immune escape and angiogenesis. Upregulation of galectin 3 has also been associated with cancer, inflammation, neurodegenerative disease, fibrotic disease and diabetes (Dings et. al. 2018, Slack et. al. 2020, Li et. al. 2016) Example of small molecule ligands including P-D-galactopyranoside were recently reviewed and examplified in Blanchard et. al 2014 and Sethi et. al 2021.

Galectin-9 is widely expressed in many cell types and tissue, including T-cells, small intestine, liver, uterine epithelial cells, and skin epidermis (www.proteinatlas.org). Galectin-9 has been found to be involved in e.g. cancer, (Yang, Sun et al. 2021) inflammation, and fibrosis. (Hsu, Chang et al. 2020) Key molecular mechanism involves galectin-9 binding TIM-3(Wolf, Anderson et al. 2020) and PD-l,(Yang, Sun et al. 2021) checkpoint inhibitory receptors suppressing T-cell activity, as well as Dectin-1, (Daley, Mani et al. 2017) an innate immune system protein on macrophages that upon galectin-9-binding attenuates CD4⁺ and CD8⁺ T- cell activities. Summary of the invention

The compounds of the present invention are novel P-D-galactopyranose compounds that unexpectedly have shown combined high affinity for galectin-3 and galectin-9 and are considered novel potent drug candidates. A combined galectin-3 and galectin-9 inhibitor has the advantage of influencing different biological mechanisms connected to the respective galectin resulting in a combined stronger effect compared to only inhibiting one individual galectin. One example is that galectin-3 and -9 are involved in the interaction with different immune checkpoints and the combined inhibition would enhance the immunological response compared to inhibiting only one of the two respective galectins. In addition, it is seen that with these compounds the advantage is that the pyrazole moiety linked to C3 of P-D- galactopyranose results in an improved uptake over CACO-2 cells predicting high oral bioavailability after oral administration. Further compared to compounds where the moiety linked to C3 of P-D-galactopyranose is a triazole moiety this improvement is significant.

In a broad aspect the present invention concerns a P-D-galactopyranose compound of formula (1)

wherein the pyranose ring is P-D-galactopyranose,

A¹ is selected from a) a phenyl substituted in one ortho carbon atom of the phenyl ring in relation to the covalent bond to the pyrazol ring with one group selected from one of F, Cl, Br, I, CN, C1-3 alkyl optionally substituted with one to three F, or OC1-3 alkyl, optionally substituted with one to three F; and optionally substituted on one to four of the additional carbon atoms of the phenyl with a group independently selected from halogen; CN; OH; C2-4 alkenyl; an ethynyl; a spiro heterocycle; -COOH; -CONR^2aR^3a, wherein R^2aandR^3a are independently selected from hydrogen, C1-3 alkyl, and cyclopropyl, or R^2aandR^3a together with the nitrogen may form a heterocycloalkyl; C1-3 alkyl, optionally substituted with a F; C1-3 alkyl, optionally substituted with an ethynyl; cyclopropyl, optionally substituted with a F; OC1-3 alkyl, optionally substituted with a F; O-cyclopropyl, optionally substituted with a F; NR^4aR^5a, wherein R^4a and R^5a are independently selected from hydrogen, Ci- 3 alkyl and cyclopropyl; C(=O)-R^{l la}, wherein R^{l la} is selected from hydrogen and C1-3 alkyl; and R^6a-CONH- wherein R^6a is selected from C1-3 alkyl and cyclopropyl; b) a benzothiazolyl substituted with a group selected from a halogen; CN; OH; C2-4 alkenyl; an ethynyl; a spiro heterocycle; -COOH; -CONR^7aR^8a, wherein R^7aandR^8a are independently selected from H, C1-3 alkyl, and cyclopropyl, or R^7aandR^8a together with the nitrogen may form a heterocycloalkyl; C1-3 alkyl, optionally substituted with a F; C1-3 alkyl, optionally substituted with an ethynyl; cyclopropyl, optionally substituted with a F; OC1-3 alkyl, optionally substituted with a F; O-cyclopropyl, optionally substituted with a F; NR^9aR^10a, wherein R^9a and R^10a are independently selected from H, C1-3 alkyl, and cyclopropyl; C(=O)-R^{l lb}, wherein R^{l lb} is selected from H and C1-3 alkyl; and R^12a-CONH- wherein R^12a is selected from C1-3 alkyl and cyclopropyl; c) a pyridinyl substituted in one ortho carbon atom of the pyridinyl ring in relation to the covalent bond to the pyrazol ring with one group selected from one of F, Cl, Br, I, CN, C1-3 alkyl optionally substituted with one to three F, or OC1-3 alkyl, optionally substituted with one to three F; and optionally substituted on one to three of the additional carbon atoms of the pyridinyl ring with a group independently selected from halogen; CN; OH; C2-4 alkenyl; an ethynyl; a spiro heterocycle; - COOH; -CONR^13aR^14a, wherein R^13aandR^14a are independently selected from H, C1-3 alkyl, and cyclopropyl, or R^13aandR^14a together with the nitrogen may form a heterocycloalkyl; C1-3 alkyl, optionally substituted with a F; C1-3 alkyl, optionally substituted with an ethynyl; cyclopropyl, optionally substituted with a F; OC1-3 alkyl, optionally substituted with a F; O-cyclopropyl, optionally substituted with a F; NR^15aR^16a, wherein R^15a and R^16a are independently selected from H, C1-3 alkyl and cyclopropyl; C(=O)-R^17a, wherein R^17a is selected from H and C1-3 alkyl; and R^18a- CONH- wherein R^18a is selected from C1-3 alkyl and cyclopropyl;

B¹ is selected from the group consisting of a) phenyl, naphthalinyl, biphenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, quinoxainyl, indolyl, indazolyl, benzimidazolyl, benzisoxazolyl, benzisothiazolyl, benzoxazolyl, benzothiazolyl, benzodi oxolyl, dihydrobenzodioxinyl, dihydroquinolinonyl, dihydrobenzothiophene-2,2-dioxide, pyrrolyl, furanyl, thiazolo[4,5-b]pyridinyl, thienyl, pyrazolyl, isoxazolyl, isothiazolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, or thiadiazolyl; optionally substituted with one or more substituents independently selected from the group consisting of cyano, nitro, OH, C₂-alkynyl, halogen, C_1-6 alkyl, halo-C_1-6 alkyl, branched C_3-6 alkyl, C_3-6 cycloalkyl optionally substituted with a methyl, C3-6 cycloalkyl, C3-6 cycloalkyl substituted with a methyl, C1-6 alkoxy, halo-C1-6 alkoxy, C1-6 alkylthio, carboxy, C1-6 alkylsulfonyl, C1-6 alkoxycarbonyl, CONH₂, COR21aR22a wherein R21aand R22a are independently selected from H and C1-3 alkyl, and (R19a)(R20a)N wherein R19a is selected from hydrogen, C 6 alkyl, C1-6 alkylcarbon 20a 1- yl, or C1-6 alkylsulfonyl and R is selected from hydrogen or C_1-6 alkyl, or (R19a)(R20a)N taken together is any one of azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, optionally substituted with one or more substituents selected from halogen, C1-6 alkyl, and C1-6 alkylcarbonyl; or b) (C_1-6 alkyl-SO₂)phenyl, (C_1-6 alkyl SO₂)(halo)phenyl, (aminoSO₂)phenyl, (di-C_1-6 alkylaminoSO₂)phenyl, ((C_1-6 alkyl-NHSO₂)-C_1-6 alkyl )phenyl, (pyrrolyl)phenyl, (imidazolyl)phenyl, (oxazolyl)phenyl, (tetrazolyl)phenyl, ((pyridinyl)methyl)phenyl, phenoxyphenyl, (benzyloxy)phenyl, ((methyl)thiazolyl)-phenyl, (thiazolyl)- benzenesulfamido, ((methyl)thiadiazolyl)benzenesulfamido, (methyl)- benzothiazolonyl, or fluoropyrazolopyrimidinyl; R1 is selected from H, C1-3 alkyl, CN, halogen, C2-4 alkenyl, and C1-3 alkyl substituted with one to three halogen; or a pharmaceutically acceptable salt or solvate thereof. In an embodiment A1 is selected from a) a phenyl substituted in one ortho carbon atom of the phenyl ring in relation to the covalent bond to the pyrazol ring with one group selected from one of F, Cl, Br, I, CN, C1-3 alkyl substituted with one to three F, or OC1-3 alkyl substituted with one to three F; and optionally substituted on one to four of the additional carbon atoms of the phenyl with a group independently selected from halogen; CN; OH; C_2-4 alkenyl; an ethynyl; a spiro heterocycle; - COOH; -CONR2aR3a, wherein R2a and R3a are independently selected from hydrogen, C1-3 alkyl, and cyclopropyl, or R2a and R3a together with the nitrogen may form a heterocycloalkyl; C_1-3 alkyl, optionally substituted with a F; C_1-3 alkyl, optionally substituted with an ethynyl; cyclopropyl, optionally substituted with a F; OC1-3 alkyl, optionally substituted with a F; O-cyclopropyl, optionally substituted with a F; NR4aR5a, wherein R4a and R5a are independently selected from hydrogen, C1-3 alkyl and cyclopropyl; C(=O)-R11a, wherein R11a is selected from hydrogen and C_1-3 alkyl; and R6a-CONH- wherein R6a is selected from C1-3 alkyl and cyclopropyl. In a still further embodiment A1 is selected from c) a pyridinyl substituted in one ortho carbon atom of the pyridinyl ring in relation to the covalent bond to the pyrazol ring with one group selected from one of F, Cl, Br, I, CN, C1-3 alkyl substituted with one to three F, or OC1-3 alkyl, optionally substituted with one to three F; and optionally substituted on one to three of the additional carbon atoms of the pyridinyl ring with a group independently selected from halogen; CN; OH; C2-4 alkenyl; an ethynyl; a spiro heterocycle; -COOH; -CONR13aR14a, wherein R13a and R14a are independently selected from H, C_1-3 alkyl, and cyclopropyl, or R13a and R14a together with the nitrogen may form a heterocycloalkyl; C_1-3 alkyl, optionally substituted with a F; C1-3 alkyl, optionally substituted with an ethynyl; cyclopropyl, optionally substituted with a F; OC_1-3 alkyl, optionally substituted with a F; O- cyclopropyl, optionally substituted with a F; NR15aR16a, wherein R15a and R16a are independently selected from H, C 17a 17a 1-3 alkyl and cyclopropyl; C(=O)-R , wherein R is selected from H and C alkyl; and R18a-CONH- wherein R18a 1-3 is selected from C1-3 alkyl and cyclopropyl. In a further embodiment A1 is

wherein the asterix * indicates the carbon atom of the phenyl ring that is covalently attached to the pyrazole; wherein R2 is selected from F, Cl, Br, I, CN, C_1-3 alkyl substituted with one to three F, and OC_1-3 alkyl, optionally substituted with one to three F; R3 is selected from H, halogen; C_1-3 alkyl, optionally substituted with a F; C_2-4 alkenyl; OC_1-3 alkyl, optionally substituted with a F; R4 is selected from H, halogen; C_1-3 alkyl, optionally substituted with a F; C_2-4 alkenyl; OC_1-3 alkyl, optionally substituted with a F; R5 is selected from H and halogen; and R6 is H. In a further embodiment A1 is

wherein the asterix * indicates the carbon atom of the phenyl ring that is covalently attached to the pyrazole; wherein R² is selected from F, Cl, Br, I, CN, C1-3 alkyl substituted with one to three F, and OC1-3 alkyl, optionally substituted with one to three F;

R³ is selected from H, halogen; C1-3 alkyl, optionally substituted with a F; C2-4 alkenyl; OC1-3 alkyl, optionally substituted with a F;

R⁴ is selected from H, halogen; C1-3 alkyl, optionally substituted with a F; C2-4 alkenyl; OC1-3 alkyl, optionally substituted with a F;

R⁵ is selected from H, halogen and OC1-3 alkyl, optionally substituted with a F; and R⁶ is H.

In another embodiment A¹ is

wherein the asterix * indicates the carbon atom of the pyridinyl ring that is covalently attached to the pyrazole; wherein R⁷ is selected from F, Cl, Br, I, CN, C1-3 alkyl substituted with one to three F, and OC1-3 alkyl, optionally substituted with one to three F;

R⁸ is selected from H or halogen;

R⁹ is selected from H or halogen; and

R¹⁰ is H.

In a further embodiment A¹ is

wherein the asterix * indicates the carbon atom of the pyridinyl ring that is covalently attached to the pyrazole; wherein R¹¹ is selected from F, Cl, Br, I, CN, C1-3 alkyl substituted with one to three F, and OC1-3 alkyl, optionally substituted with one to three F; R¹² is selected from H or halogen;

R¹³ is selected from H or halogen; and

R¹⁴ is H.

In a still further embodiment A¹ is

wherein the asterix * indicates the carbon atom of the benzothiazol ring that is covalently attached to the pyrazole; wherein R¹⁵ is selected from H or halogen, such as H or F;

R¹⁶ is selected from H or halogen, such as H, F or Cl;

R¹⁷ is selected from H and C1-3 alkyl, such as H or methyl; and

R¹⁸ is H.

In a further embodiment A¹ is

wherein the asterix * indicates the carbon atom of the benzothiazol ring that is covalently attached to the pyrazole; wherein R¹⁹ is selected from H or halogen, such as H or F;

R²⁰ is selected from H or halogen, such as H or F;

R²¹ is selected from H and C1-3 alkyl, such as H; and

R²² is H.

In a still further embodiment A¹ is

wherein the asterix * indicates the carbon atom of the benzothiazol ring that is covalently attached to the pyrazole; wherein R²³ is selected from H or halogen, such as H or F; R²⁴ is selected from H or halogen, such as H or F; R²⁵ is selected from H or halogen, such as H; and R²⁶ is H or methyl, such as H.

In a further embodiment A¹ is

wherein the asterix * indicates the carbon atom of the benzothiazol ring that is covalently attached to the pyrazole; wherein R²⁷ is selected from H or halogen, such as H or F;

R²⁸ is selected from H or halogen, such as H or F; R²⁹ is selected from H or halogen, such as H; and R³⁰ is H or methyl, such as H.

In a still further embodiment B¹ is selected from the group consisting of a) phenyl, naphthalinyl, biphenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, quinoxainyl, indolyl, indazolyl, benzimidazolyl, benzisoxazolyl, benzisothiazolyl, benzoxazolyl, benzothiazolyl, benzodi oxolyl, dihydrobenzodioxinyl, dihydroquinolinonyl, dihydrobenzothiophene-2,2-di oxide, pyrrolyl, furanyl, thiazolo[4,5-b]pyridinyl, thienyl, pyrazolyl, isoxazolyl, isothiazolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, or thiadiazolyl; optionally substituted with one or more substituents independently selected from the group consisting of cyano, nitro, OH, C2-alkynyl, halogen, Ci-6 alkyl, halo-Ci-6 alkyl, branched C3-6 alkyl, C3-6 cycloalkyl optionally substituted with a methyl, C3-6 cycloalkyl, C3-6 cycloalkyl substituted with a methyl, C1-6 alkoxy, halo-Ci-6 alkoxy, C1-6 alkylthio, carboxy, C1-6 alkoxycarbonyl, CONH2, and (R^19a)(R^20a)N wherein R^19a is selected from hydrogen, C1-6 alkyl, C1-6 alkylcarbonyl, or C1-6 alkylsulfonyl and R^20a is selected from hydrogen or C1-6 alkyl, or (R^19a)(R^20a)N taken together is any one of azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, optionally substituted with one or more substituents selected from halogen, C1-6 alkyl, and C1-6 alkylcarbonyl; or b) (C1-6 alkyl-SO2)phenyl, (C1-6 alkyl SO2)(halo)phenyl, (aminoSO2)phenyl, (di-Ci-6 alkylaminoSO2)phenyl, ((C1-6 alkyl-NHSO2)-Ci-6 alkyl )phenyl, (pyrrolyl)phenyl, (imidazolyl)phenyl, (oxazolyl)phenyl, (tetrazolyl)phenyl, ((pyridinyl)methyl)phenyl, phenoxy phenyl, (benzyl oxy )phenyl, ((methyl)thiazolyl)- phenyl, (thiazolyl)-benzenesulfamido, ((methyl)thiadiazolyl)benzenesulfamido, (methyl)-benzothiazolonyl, or fluoropyrazolopyrimidinyl.

In a still further embodiment B¹ is selected from the group consisting of a) phenyl, naphthalinyl, biphenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, quinoxainyl, indolyl, indazolyl, benzimidazolyl, benzisoxazolyl, benzisothiazolyl, benzoxazolyl, benzothiazolyl, benzodi oxolyl, dihydrobenzodioxinyl, dihydroquinolinonyl, dihydrobenzothiophene-2,2-di oxide, pyrrolyl, furanyl, thiazolo[4,5-b]pyridinyl, thienyl, pyrazolyl, isoxazolyl, isothiazolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, or thiadiazolyl; optionally substituted with one or more substituents independently selected from the group consisting of cyano, nitro, OH, C2-alkynyl, halogen, Ci-6 alkyl, halo-Ci-6 alkyl, C3-6 cycloalkyl, C3-6 cycloalkyl substituted with a methyl, C1-6 alkoxy, halo-Ci-6 alkoxy, C1-6 alkylthio, carboxy, C1-6 alkoxycarbonyl, CONH2, and (R^19a)(R^20a)N wherein R^19a is selected from hydrogen, C1-6 alkyl, C1-6 alkylcarbonyl, or C1-6 alkylsulfonyl and R^20a is selected from hydrogen or C1-6 alkyl, or (R^19a)(R^20a)N taken together is any one of azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, optionally substituted with one or more substituents selected from halogen, C1-6 alkyl, and C1-6 alkylcarbonyl; or b) (C1-6 alkyl-SO2)phenyl, (C1-6 alkyl SO2)(halo)phenyl, (aminoSO2)phenyl, (di-Ci-6 alkylaminoSO2)phenyl, ((C1-6 alkyl-NHSO2)-Ci-6 alkyl )phenyl, (pyrrolyl)phenyl, (imidazolyl)phenyl, (oxazolyl)phenyl, (tetrazolyl)phenyl, ((pyridinyl)methyl)phenyl, phenoxy phenyl, (benzyl oxy )phenyl, ((methyl)thiazolyl)- phenyl, (thiazolyl)-benzenesulfamido, ((methyl)thiadiazolyl)benzenesulfamido, (methyl)-benzothiazolonyl, or fluoropyrazolopyrimidinyl;

In a still further embodiment B¹ is selected from the group consisting of phenyl, pyridinyl, and benzothiazolyl; optionally substituted with one or more substituents independently selected from the group consisting of halogen, C1-6 alkyl, and halo-Ci-6 alkyl. Typically, B¹ is selected from the group consisting of phenyl substituted with one or two substituents selected from the group consisting of halogen and CF3; pyridinyl substituted with one or two substituents selected from the group consisting of halogen and CF3; and benzothiazolyl substituted with one C1-6 alkyl, such as methyl. In a further embodiment B¹ is phenyl substituted with one or two substituents selected from the group consisting of C1-3 alkyl, C3-6 cycloalkyl, C3-6 cycloalkyl substituted with a methyl and CF3.

In a still further embodiment B¹ is selected from the group consisting of phenyl, pyridinyl, and benzothiazolyl; optionally substituted with one or more substituents selected from the group consisting of halogen, CN, C1-6 alkylthio, C1-6 alkoxy optionally substituted with a halogen, C1-6 alkyl, branched C3-6 alkyl, C3-6 cycloalkyl optionally substituted with a methyl, C3-6 cycloalkyl, and halo-Ci-6 alkyl. Typically, B¹ is phenyl substituted with one, two or three substituents selected from the group consisting of Cl, F, Br, cyclopropyl, C3-6 cycloalkyl optionally substituted with a methyl, C1-3 alkyl, SCH3, OCF3, CN, and CF3. Typically, B¹ is pyridinyl substituted with one or two substituents selected from the group consisting of halogen, eg. F, Br and Cl, C3-6 cycloalkyl, OCF3, C1-3 alkyl and CF3. Typically, B¹ is benzothiazolyl substituted with one or two substituents selected from the group consisting of methyl, F, Br, CN, OCH3 and CF3.

In a particular preferred embodiment when B¹ is a benzothiazolyl, the covalent bond from B¹ to the nitrogen of the triazolyl ring is between one of the carbon atoms of the benzo ring of the benzothiazolyl and the nitrogen of the triazolyl ring.

In a further embodiment R¹ is selected from H or C1-3 alkyl. Typically, R¹ is methyl. In another embodiment R¹ is H. In a further embodiment R¹ is CN. In a further embodiment R¹ is selected from F, Cl, and Br. Typically, R¹ is Cl or R¹ is Br. In a further embodiment R¹ is selected from C1-3 alkyl, such as methyl, ethyl or isopropyl. In a further embodiment R¹ is selected from ethyl or isopropyl.

In a still further aspect the present invention concerns a P-D-galactopyranose compound of formula (1) selected from any one of the group consisting of: 6-{5-{3-Deoxy-3-[4-(2,3-difluoro-4-methylphenyl)-lH-l,2-pyrazol-l-yl]-P-D- galactopyranosyl}-3-methyl-lH-l,2,4-triazol-l-yl}-2 -methylbenzothiazole, 5-Chl oro-1 -{5-{3-deoxy-3 -[4-(2, 3 -difluoro-4-m ethylphenyl)- 1H-1, 2-pyrazol-l -yl]-P- D-galactopyranosyl } -3 -methyl- 1H- 1 ,2,4-triazol- 1 -yl } -2-(trifluoromethyl)benzene, 5-Chl oro-1 -{5-{3-deoxy-3-[4-(7-fluorobenzothiazol-5-yl)-lH-l, 2-pyrazol-l -yl]-P-D- galactopyranosyl}-3-methyl-lH-l,2,4-triazol-l-yl}-2-(trifluoromethyl)benzene, 5-Chl oro-1 -{5-{3-deoxy-3-[4-(7-fluoro-2-methylbenzothiazol-5-yl)-lH-l,2-pyrazol- 1 -yl] -P-D-galactopyranosyl } -3 -methyl - 1H- 1 ,2,4-triazol - 1 -yl } -2- (trifluoromethyl)benzene,

5-Chl oro-1 -{5-{3-deoxy-3-[4-(4-fluorobenzothiazol-6-yl)-lH-l, 2-pyrazol-l -yl]-P-D- galactopyranosyl}-3-methyl-lH-l,2,4-triazol-l-yl}-2-(trifluoromethyl)benzene, 5-Chl oro-1 -{5-{3-deoxy-3-[4-(5-fluorobenzothiazol-7-yl)-lH-l,2-pyrazol-l-yl]-P-D- galactopyranosyl}-3-methyl-lH-l,2,4-triazol-l-yl}-2-(trifluoromethyl)benzene, 5-Chl oro-1 -{5-{3-deoxy-3-[4-(6,7-difluorobenzothiazol-5-yl)-lH-l, 2-pyrazol-l -yl]- P-D-galactopyranosyl } -3 -methyl- 1H- 1 ,2,4-triazol- 1 -yl } -2-(trifluoromethyl)benzene, 1 -{5-{3-[4-(4-Chl oro-2, 3 -difluorophenyl)- 1H-1, 2-pyrazol-l -yl]-3 -deoxy -P-D- galactopyranosyl } -3 -methyl- 1H- 1 ,2,4-triazol- 1 -yl } -5-chloro-2- (trifluoromethyl)benzene, 5-Chloro-l-{5-{3-deoxy-3-[4-(2,3,4-trifluorophenyl)-lH-l,2-pyrazol-l-yl]-P-D- galactopyranosyl}-3-methyl-lH-l,2,4-triazol-l-yl}-2-(trifluoromethyl)benzene, 1 -{5-{3-[4-(2-Chl oro-3 -fluorophenyl)- 1H-1, 2-pyrazol-l -yl]-3-deoxy-P-D- galactopyranosyl } -3 -methyl- 1H- 1 ,2,4-triazol- 1 -yl } -5-chloro-2- (trifluoromethyl)benzene,

1 -{5-{3 -[4-(4-Bromo-2,3-difluorophenyl)-lH-l, 2-pyrazol-l -yl] -3 -deoxy -P-D- galactopyranosyl } -3 -methyl- 1H- 1 ,2,4-triazol- 1 -yl } -5-chloro-2- (trifluoromethyl)benzene,

5-Chl oro- 1 - { 5 - { 3 -deoxy -3 - [4-(2, 3 -difluoropheny 1)- 1 H- 1 , 2 -py razol - 1 -y 1 ] -P-D- galactopyranosyl}-3-methyl-lH-l,2,4-triazol-l-yl}-2-(trifluoromethyl)benzene, 5-Chl oro-1 -{5-{3-deoxy-3-[4-(2, 3-difluoro-4-methoxyphenyl)-lH-l, 2-pyrazol-l -yl]- P-D-galactopyranosyl } -3 -methyl- 1H- 1 ,2,4-triazol- 1 -yl } -2-(trifluoromethyl)benzene, 5-Chloro-l-{5-{3-deoxy-3-{4-[2,3-difluoro-4-(trifluoromethyl)phenyl]-lH-l,2- pyrazol-l-yl}-P-D-galactopyranosyl}-3-methyl-lH-l,2,4-triazol-l-yl}-2- (trifluoromethyl)benzene,

5-Chl oro-1 -{5-{3-deoxy-3-{4-[2,3-difluoro-4-(l-methylethenyl)phenyl]-lH-l, 2- pyrazol-l-yl}-P-D-galactopyranosyl}-3-methyl-lH-l,2,4-triazol-l-yl}-2- (trifluoromethyl)benzene,

5-Chl oro-1 -{5-{3-deoxy-3-[4-(4,5-difluorobenzothiazol-6-yl)-lH-l, 2-pyrazol-l -yl]- P-D-galactopyranosyl } -3 -methyl- 1H- 1 ,2,4-triazol- 1 -yl } -2-(trifluoromethyl)benzene, 5-Chl oro-3 -{5-{3-deoxy-3-[4-(4,5-difluorobenzothiazol-6-yl)-lH-l, 2-pyrazol-l -yl]- P-D-galactopyranosyl } -3 -methyl- 1H- 1 2 4-triazol- 1 -yl } -2-(trifluoromethyl)pyridine, 5-Bromo-3 -{5-{3-deoxy-3 -[4-(4,5-difluorobenzothiazol-6-yl)-lH-l, 2-pyrazol-l -yl]- P-D-galactopyranosyl } -3 -methyl- 1H- 1 ,2,4-triazol- 1 -yl } -2-(trifluoromethyl)pyridine, 5-Bromo-l -{5-{3-deoxy-3 -[4-(4,5-difluorobenzothiazol-6-yl)-lH-l, 2-pyrazol-l -yl]- P-D-galactopyranosyl } -3 -methyl- 1H- 1 ,2,4-triazol- 1 -yl } -2-(trifluoromethyl)benzene, 5-Bromo-l -{5-{3-[4-(4-chl oro-2, 3 -difluorophenyl)- 1H-1, 2-pyrazol-l -yl]-3-deoxy-P- D-galactopyranosyl } -3 -methyl- 1H- 1 ,2,4-triazol- 1 -yl } -2-(trifluoromethyl)benzene, 3-{ 5-{3-[4-(4-Chl oro-2, 3 -difluorophenyl)- 1H-1, 2-pyrazol-l -yl]-3 -deoxy -P-D- galactopyranosyl } -3 -methyl- 1H- 1 ,2,4-triazol- 1 -yl } -5-chloro-2- (trifluoromethyl)pyridine,

5-Bromo-3 -{5-{3-[4-(4-chl oro-2, 3 -difluorophenyl)- 1H-1, 2-pyrazol-l -yl]-3-deoxy-P- D-galactopyranosyl } -3 -methyl- 1H- 1 ,2,4-triazol- 1 -yl } -2-(trifluoromethyl)pyridine, 3-{5-{3-[4-(4-Chloro-2,3-difluorophenyl)-lH-l,2-pyrazol-l-yl]-3-deoxy-P-D- galactopyranosyl}-3-methyl-lH-l,2,4-triazol-l-yl}-5-chloro-2-cyclopropylpyridine, l-{5-{3-[4-(4-Chloro-2,3-difluorophenyl)-lH-l,2-pyrazol-l-yl]-3-deoxy-P-D- galactopyranosyl}-3-methyl-lH-l,2,4-triazol-l-yl}-5-chloro-2-cyclopropylbenzene,

5-Bromo-l -{5-{3-[4-(4-chl oro-2, 3 -difluorophenyl)- 1H-1, 2-pyrazol-l -yl]-3-deoxy-P- D-galactopyranosyl } -3 -methyl- 1H- 1 ,2,4-triazol- 1 -yl } -2-cy anobenzene,

6-{5-{3-[4-(4-Chloro-2,3-difluorophenyl)-lH-l,2-pyrazol-l-yl]-3-deoxy-P-D- galactopyranosyl}-3-methyl-lH-l,2,4-triazol-l-yl}-2 -methylbenzothiazole,

1 -{5-{3-[4-(4-Chl oro-2, 3 -difluorophenyl)- 1H-1, 2-pyrazol-l -yl]-3 -deoxy -P-D- galactopyranosyl } -3 -methyl- 1H- 1 ,2,4-triazol- 1 -yl } -5-chloro-2- (trifluoromethoxy)benzene,

3-{ 5-{3-[4-(4-Chl oro-2, 3 -difluorophenyl)- 1H-1, 2-pyrazol-l -yl]-3 -deoxy -P-D- galactopyranosyl } -3 -methyl- 1H- 1 ,2,4-triazol- 1 -yl } -5-chloro-2- (trifluoromethoxy)pyridine, 5-Chloro-l-{5-{3-[4-(4-cyano-2,3-difluorophenyl)-lH-l, 2-pyrazol-l -yl]-3-deoxy-P- D-galactopyranosyl } -3 -methyl- 1H- 1 ,2,4-triazol- 1 -yl } -2-(trifluoromethyl)benzene, 1 -{5-{3-[4-(4-Chl oro-2, 5 -difluorophenyl)- 1H-1, 2-pyrazol-l -yl]-3 -deoxy -P-D- galactopyranosyl } -3 -methyl- 1H- 1 ,2,4-triazol- 1 -yl } -5-chloro-2- (trifluoromethyl)benzene,

1 -{5-{3-[4-(4-Chl oro-5 -fluoro-2 -methoxyphenyl)- 1H-1, 2-pyrazol-l -yl]-3 -deoxy -P-D- galactopyranosyl } -3 -methyl- 1H- 1 ,2,4-triazol- 1 -yl } -5-chloro-2- (trifluoromethyl)benzene, l-{5-{3-{4-[4-Chloro-5-fluoro-2-(trifluoromethyl)phenyl]-lH-l,2-pyrazol-l-yl}-3- deoxy-P-D-galactopyranosyl } -3 -methyl- 1H- 1 ,2,4-triazol- 1 -yl } -5-chloro-2- (trifluoromethyl)benzene, and

1 -{5-{3-{4-[4-Chl oro-5-fluoro-2-(tri fluoromethoxy )phenyl]-lH-l, 2-pyrazol-l-yl} -3- deoxy-P-D-galactopyranosyl } -3 -methyl- 1H- 1 ,2,4-triazol- 1 -yl } -5-chloro-2- (trifluoromethyl)benzene; or a pharmaceutically acceptable salt or solvat thereof.

In a further aspect the present invention concerns a P-D-galactopyranose compound of formula (1) selected from any one of the group consisting of: l-{5-{3-[4-(4-Chloro-2,3-difhrorophenyl)-lH-l,2-pyrazol-l-yl]-3-deoxy-P-D- galactopyranosyl}-3-methyl-lH-l,2,4-triazol-l-yl}-5-chloro-4-fluoro-2- (trifluoromethyl)benzene,

5-Chl oro-1 -{5-{3-deoxy-3-[4-(4,5-difluorobenzothiazol-6-yl)-lH-l,2-pyrazol- 1 -yl]-P-D-galactopyranosyl } -3 -methyl- 1H- 1 ,2,4-triazol- 1 -yl } -4-fluoro-2- (trifluoromethyl)benzene, l-{5-{3-[4-(4-Chloro-2,3-difhrorophenyl)-lH-l,2-pyrazol-l-yl]-3-deoxy-P-D- galactopyranosyl}-3-methyl-lH-l,2,4-triazol-l-yl}-4,5-dichloro-2- (trifluoromethyl)benzene,

4,5-Dichloro-l-{5-{3-deoxy-3-[4-(4,5-difluorobenzothiazol-6-yl)-lH-l,2- pyrazol-l-yl]-P-D-galactopyranosyl}-3-methyl-lH-l,2,4-triazol-l-yl}-2- (trifluoromethyl)benzene,

6-{5-{3-Deoxy-3-[4-(4,5-difluorobenzothiazol-6-yl)-lH-l,2-pyrazol-l-yl]-P- D-galactopyranosyl } -3 -methyl- 1H- 1 ,2,4-triazol- 1 -yl } -2 -methylbenzothiazole,

6-{5-{3-Deoxy-3-[4-(2,3,4-trifhrorophenyl)-lH-l,2-pyrazol-l-yl]-P-D- galactopyranosyl}-3-methyl-lH-l,2,4-triazol-l-yl}-2 -methylbenzothiazole,

6-{5-{3-[4-(4-Chloro-2,3-difluorophenyl)-lH-l,2-pyrazol-l-yl]-3-deoxy-P-D- galactopyranosyl}-3-methyl-lH-l,2,4-triazol-l-yl}-5-fluoro-2 -methylbenzothiazole,

5-Bromo-6-{ 5-{3-[4-(4-chl oro-2, 3 -difluorophenyl)- 1H-1, 2-pyrazol-l -yl]-3- deoxy-P-D-galactopyranosyl } -3 -methyl- 1H- 1 ,2,4-triazol- 1 -yl } -2- methy lb enzothi azol e,

6-{5-{3-[4-(4-Chloro-2,3-difluorophenyl)-lH-l,2-pyrazol-l-yl]-3-deoxy-P-D- galactopyranosyl}-3-methyl-lH-l,2,4-triazol-l-yl}-5-cyano-2 -methylbenzothiazole,

6-{5-{3-[4-(4-Chloro-2,3-difluorophenyl)-lH-l,2-pyrazol-l-yl]-3-deoxy-P-D- galactopyranosyl}-3-methyl-lH-l,2,4-triazol-l-yl}-5-(trifluoromethyl)-2- methy lb enzothi azol e, 6-{ 5-{3-Deoxy-3-[4-(4,5-difluorobenzothiazol-6-yl)-lH-l, 2-pyrazol-l -yl]-P- D-galactopyranosyl } -3 -methyl- 1H- 1 ,2,4-triazol- 1 -yl } -5-fluoro-2- methy lb enzothi azol e,

1 -{5-{3-[4-(4-Chl oro-2, 3 -difluorophenyl)- 1H-1, 2-pyrazol-l -yl]-3 -deoxy -P-D- galactopyranosyl } -3 -methyl- 1H- 1 ,2,4-triazol- 1 -yl } -5-cy ano-2- (trifluoromethyl)benzene, l-{5-{3-[4-(4-Chloro-2,3-difluorophenyl)-lH-l,2-pyrazol-l-yl]-3-deoxy-P-D- galactopyranosyl}-3-methyl-lH-l,2,4-triazol-l-yl}-5-cyclopropyl-2- (trifluoromethyl)benzene, l-{5-{3-[4-(4-Chloro-2,3-difluorophenyl)-lH-l,2-pyrazol-l-yl]-3-deoxy-P-D- galactopyranosyl}-3-methyl-lH-l,2,4-triazol-l-yl}-2-(trifluoromethyl)-5- methylbenzene, l-{5-{3-[4-(4-Chloro-2,3-difluorophenyl)-lH-l,2-pyrazol-l-yl]-3-deoxy-P-D- galactopyranosyl}-3-methyl-lH-l,2,4-triazol-l-yl}-2-(trifluoromethyl)-5-(l- methylcyclopropyl)benzene, l-{5-{3-[4-(4-Chloro-2,3-difluorophenyl)-lH-l,2-pyrazol-l-yl]-3-deoxy-P-D- galactopyranosyl}-3-methyl-lH-l,2,4-triazol-l-yl}-2-(trifluoromethyl)-5-

(methy Ithi o)b enzene,

5-Bromo-l -{5-{3-[4-(4-chl oro-2, 3 -difluorophenyl)- 1H-1, 2-pyrazol-l -yl]-3- deoxy-P-D-galactopyranosyl } -3 -methyl- 1H- 1 ,2,4-triazol- 1 -yl } -4-fluoro-2- (trifluoromethyl)benzene,

3-{5-{3-[4-(4-Chloro-2,3-difluorophenyl)-lH-l,2-pyrazol-l-yl]-3-deoxy-P-D- galactopyranosyl}-3-methyl-lH-l,2,4-triazol-l-yl}-2-(trifluoromethyl)-5- methylpyridine,

5 -Chloro- 1 - { 5 - { 3 -deoxy-3 - [4 -(2 , 3 -difluoro-4-i sopropy Iphenyl)- 1H-1,2- pyrazol-l-yl]-P-D-galactopyranosyl}-3-methyl-lH-l,2,4-triazol-l-yl}-2- (trifluoromethyl)benzene,

5 -Chloro- 1 - { 5 - { 3 -deoxy-3 - [4 -(2 , 3 -difluoro-4-ethenylphenyl)- 1 H- 1 ,2-pyrazol - 1 -yl]-P-D-galactopyranosyl } -3 -methyl - 1H- 1 ,2,4-triazol - 1 -yl } -2- (trifluoromethyl)benzene,

5 -Chloro- 1 - { 5 - { 3 -deoxy-3 - [4 -(2 , 3 -difluoro-4-ethylphenyl)- 1 H- 1 ,2-pyrazol - 1 - yl]-P-D-galactopyranosyl } -3 -methyl- 1H- 1 ,2,4-triazol- 1 -yl } -2- (trifluoromethyl)benzene, 5 -Bromo-3 - { 5 - { 3 -deoxy-3 - [4 -(2 , 3 -difluoro-4-methoxyphenyl)- 1H-1,2- pyrazol-l-yl]-P-D-galactopyranosyl}-3-methyl-lH-l,2,4-triazol-l-yl}-2- (trifluoromethyl)pyridine,

5 -Chi oro-3 - { 5 - { 3 -deoxy-3 - { 4 - [2 , 3 -difluoro-4-(trifluorom ethoxy )phenyl] - 1 H-

1.2-pyrazol-l-yl}-P-D-galactopyranosyl}-3-methyl-lH-l,2,4-triazol-l-yl}-2- (trifluoromethyl)pyridine,

1 -{5-{3-[4-(4-Chl oro-2, 3-difluoro-5-methoxyphenyl)-lH-l, 2-pyrazol-l-yl]-3 - deoxy-P-D-galactopyranosyl } -3 -methyl- 1H- 1 ,2,4-triazol- 1 -yl } -5-chloro-2- (trifluoromethyl)benzene,

5-Chloro-l-{5-{3-deoxy-3-[4-(6,7-difluoro-2-methylbenzothiazol-5-yl)-lH-

1.2-pyrazol-l-yl]-P-D-galactopyranosyl}-3-methyl-lH-l,2,4-triazol-l-yl}-2- (trifluoromethyl)benzene,

5-Chl oro-1 -{ 5-{3 -deoxy-3 -[4-(5,6-difluorobenzothi azol -4-yl)-lH-l, 2-pyrazol- 1 -yl]-P-D-galactopyranosyl } -3 -methyl - 1H- 1 ,2,4-triazol - 1 -yl } -2- (trifluoromethyl)benzene,

6-{5-{3-[4-(4-Chloro-2,3-difluorophenyl)-lH-l,2-pyrazol-l-yl]-3-deoxy-P-D- galactopyranosyl}-3-methyl-lH-l,2,4-triazol-l-yl}-2,5-dimethylbenzothiazole, and

6-{ 5-{3-[4-(4-Chl oro-2, 3-difluorophenyl)-lH-l,2-pyrazol-l-yl]-3 -deoxy-P-D- galactopyranosyl } -3 -methyl- 1H- 1 ,2,4-triazol- 1 -yl } -5-m ethoxy -2- methylbenzothiazole; or a pharmaceutically acceptable salt or solvat thereof.

In a still further aspect the present invention concerns a P-D-galactopyranose compound of formula (1) selected from any one of the group consisting of:

6-{ 5-{3-[4-(4-Chl oro-2, 3-difluorophenyl)-lH-l,2-pyrazol-l-yl]-3 -deoxy-P-D- galactopyranosyl } -3 -methyl- 1H- 1 ,2,4-triazol- 1 -yl } -2-methyl-5-

(methy Ithi o)b enzothi azol e,

6-{ 5-{3-[4-(4-Chl oro-2, 3-difluorophenyl)-lH-l,2-pyrazol-l-yl]-3 -deoxy-P-D- galactopyranosyl } -3 -methyl- 1H- 1 ,2,4-triazol- 1 -yl } -2-methyl-5- (methylsulfonyl)benzothi azole,

6-{5-{3-[4-(4-Chloro-2,3-difluorophenyl)-lH-l,2-pyrazol-l-yl]-3-deoxy-P-D- galactopyranosyl}-3-methyl-lH-l,2,4-triazol-l-yl}-4-fluoro-2 -methylbenzothiazole,

4-Bromo-6-{ 5-{3-[4-(4-chl oro-2, 3 -difluorophenyl)- 1H-1, 2-pyrazol-l -yl]-3- deoxy-P-D-galactopyranosyl } -3 -methyl- 1H- 1 ,2,4-triazol- 1 -yl } -2- methy lb enzothi azol e, 6-{5-{3-[4-(4-Chloro-2,3-difluorophenyl)-lH-l,2-pyrazol-l-yl]-3-deoxy-P-D- galactopyranosyl}-3-methyl-lH-l,2,4-triazol-l-yl}-4-(trifluoromethyl)-2- methy lb enzothi azol e,

1 -{5-{3-[4-(4-Chl oro-5, 6-difluorobenzothi azol-7-yl)-lH-l, 2-pyrazol-l -yl]-3- deoxy-P-D-galactopyranosyl } -3 -methyl- 1H- 1 ,2,4-triazol- 1 -yl } -5-chloro-2- (trifluoromethyl)benzene,

1 -{5-{3-[4-(7-Chl oro-5, 6-difluorobenzothi azol -4-yl)-lH-l, 2-pyrazol-l-yl]-3 - deoxy-P-D-galactopyranosyl } -3 -methyl- 1H- 1 ,2,4-triazol- 1 -yl } -5-chloro-2- (trifluoromethyl)benzene,

1 -{5-{3-[4-(4-Chl oro-5, 6-difluorobenzothi azol-7-yl)-lH-l, 2-pyrazol-l-yl]-3 - deoxy-P-D-galactopyranosyl } -3 -methyl- 1H- 1 ,2,4-triazol- 1 -yl } -5-chloro-4-fluoro2- (trifluoromethyl)benzene,

3-{ 5-{3-[4-(3, 4-Dichl oro-2 -fluorophenyl)-lH-l,2-pyrazol-l-yl]-3 -deoxy-P-D- galactopyranosyl } -3 -methyl- 1H- 1 ,2,4-triazol- 1 -yl } -5-chloro-2- (trifluoromethyl)pyridine,

3-{5-{3-[4-(4-Chloro-2,3-difluorophenyl)-lH-l,2-pyrazol-l-yl]-3-deoxy-P-D- galactopyranosyl}-3-methyl-lH-l,2,4-triazol-l-yl}-2-(trifluoromethyl)-5- (methylthio)pyridine,

3-{5-{3-[4-(4-Chloro-2,3-difluorophenyl)-lH-l,2-pyrazol-l-yl]-3-deoxy-P-D- galactopyranosyl}-3-methyl-lH-l,2,4-triazol-l-yl}-2-(trifluoromethyl)-5- ethylpyridine,

5-Bromo-3 -{5-{3-[4-(4-chl oro-2, 3 -difluorophenyl)- 1H-1, 2-pyrazol-l -yl]-3- deoxy-P-D-galactopyranosyl } -3 -methyl- 1H- 1 ,2,4-triazol- 1 -yl } -2-(trifluoromethyl)-6- methylpyridine, l-{5-{3-[4-(4-Chloro-2,3-difluorophenyl)-lH-l,2-pyrazol-l-yl]-3-deoxy-P-D- galactopyranosyl}-3-methyl-lH-l,2,4-triazol-l-yl}-5-chloro-3-fluoro-2- (trifluoromethyl)benzene,

1 -{5-{3-[4-(4-Chl oro-2, 3 -difluorophenyl)- 1H-1, 2-pyrazol-l -y 1 ] -3 -deoxy -P Algal actopy ranosy 1 } -3 -methyl - 1 H- 1 , 2, 4 -tri azol - 1 -yl } -3 , 5 -di chi oro-2 - (trifluoromethyl)benzene,

1 -{5-{3-[4-(4-Chl oro-2, 3 -difluorophenyl)- 1H-1, 2-pyrazol-l -yl]-3 -deoxy-P-D- galactopyranosyl }-3-methyl-lH-l, 2, 4-triazol-l-yl}-5-chloro-2-(trifluoromethyl)-3- methylbenzene, 3-{ 5-{3-[4-(4-Chl oro-2, 3 -difluorophenyl)- 1H-1, 2-pyrazol-l -yl]-3 -deoxy -P-D- galactopyranosyl } -3 -methyl- 1H- 1 ,2,4-triazol- 1 -yl } -5-chloro-2-(N- methylcarbamoyl)pyridine,

3-{5-{3-[4-(4-Chloro-2,3-difluorophenyl)-lH-l,2-pyrazol-l-yl]-3-deoxy-P-D- galactopyranosyl}-3-methyl-lH-l,2,4-triazol-l-yl}-5-chloro-2-(N,N- dimethylcarbamoyl)pyridine, l-{5-{3-[4-(4-Chloro-2,3-difluorophenyl)-lH-l,2-pyrazol-l-yl]-3-deoxy-P-D- galactopyranosyl}-3-methyl-lH-l,2,4-triazol-l-yl}-5-chloro-3-cyano-2- (trifluoromethyl)benzene,

1 -{5-{3-[4-(2, 4-Dichl oro-3 -fluorophenyl)- 1H-1, 2-pyrazol-l -yl]-3 -deoxy -P-D- galactopyranosyl } -3 -methyl- 1H- 1 ,2,4-triazol- 1 -yl } -5-chloro-2- (trifluoromethyl)benzene,

3-{ 5-{3-[4-(2, 4-Dichl oro-3 -fluorophenyl)- 1H-1, 2-pyrazol-l -yl]-3 -deoxy -P-D- galactopyranosyl } -3 -methyl- 1H- 1 ,2,4-triazol- 1 -yl } -5-chloro-2- (trifluoromethyl)pyridine,

6-{5-{3-[4-(4-Chloro-2,3-difluorophenyl)-lH-l,2-pyrazol-l-yl]-3-deoxy-P-D- galactopyranosyl}-3-methyl-lH-l,2,4-triazol-l-yl}-4-chloro-7-(trifluoromethyl) benzothiazole, l-{5-{3-[4-(4-Chloro-2,3-difluorophenyl)-lH-l,2-pyrazol-l-yl]-3-deoxy-P-D- galactopyranosyl }-3-methyl-lH-l, 2, 4-triazol-l-yl}-5-chl oro-2 -methylbenzene,

1 -{5-{3-[4-(4-Chl oro-2, 3-difluoro-6-methoxyphenyl)-lH-l, 2-pyrazol-l -yl]-3- deoxy-P-D-galactopyranosyl } -3 -methyl- 1H- 1 ,2,4-triazol- 1 -yl } -5-chloro-2- (trifluoromethyl)benzene,

1 -{5-{3 -Deoxy-3-[4-(2, 3-difluoro-5-methoxyphenyl)-lH-l, 2-pyrazol-l -yl]-P- D-galactopyranosyl } -3 -methyl- 1H- 1 ,2,4-triazol- 1 -yl } -5-chloro-2- (trifluoromethyl)benzene,

3-{ 5-{3-[4-(4-Chl oro-2, 3-difluoro-6-methoxyphenyl)-lH-l, 2-pyrazol-l -yl]-3- deoxy-P-D-galactopyranosyl } -3 -methyl- 1H- 1 ,2,4-triazol- 1 -yl } -5-chloro-2- (trifluoromethyl)pyridine,

3-{ 5-{3-[4-(4-Chl oro-5 -cyano-2, 3 -difluorophenyl)- 1H-1, 2-pyrazol-l -yl]-3- deoxy-P-D-galactopyranosyl } -3 -methyl- 1H- 1 ,2,4-triazol- 1 -yl } -5-chloro-2- (trifluoromethyl)pyridine, 3-{ 5-{3-[4-(4-Chl oro-2, 3 -difluoro-5 -methylphenyl)- 1H-1, 2-pyrazol-l -yl]-3- deoxy-P-D-galactopyranosyl } -3 -methyl- 1H- 1 ,2,4-triazol- 1 -yl } -5-chloro-2- (trifluoromethyl)pyridine,

3-{5-{3-[4-(4-Chloro-2,3-difluorophenyl)-lH-l,2-pyrazol-l-yl]-3-deoxy-P-D- galactopyranosyl}-lH-l,2,4-triazol-l-yl}-5-chloro-2-(trifluoromethyl)pyridine,

3-{5-{3-Deoxy-3-[4-(2,3-difluoro-4-methylphenyl)-lH-l,2-pyrazol-l-yl]-P-D- galactopyranosyl}-3-methyl-lH-l,2,4-triazol-l-yl}-2-(trifluoromethyl)-5- methylpyridine,

6-{5-{3-Deoxy-3-[4-(2,3,4-trifluorophenyl)-lH-l,2-pyrazol-l-yl]-P-D- galactopyranosyl}-3-methyl-lH-l,2,4-triazol-l-yl}-5-fluoro-2 -methylbenzothiazole,

3-{ 5-{3-[4-(4-Chl oro-2, 3 -difluorophenyl)- 1H-1, 2-pyrazol-l -yl]-3 -deoxy -P-D- galactopyranosyl } -3 -cyano- 1H- 1 ,2,4-triazol- 1 -yl } -5-chloro-2- (trifluoromethyl)pyridine,

3-{3-Bromo-5-{3-[4-(4-chloro-2,3-difluorophenyl)-lH-l,2-pyrazol-l-yl]-3- deoxy-P-D-galactopyranosyl}-lH-l,2,4-triazol-l-yl}-5-chloro-2- (trifluoromethyl)pyridine,

3-{5-{3-[4-(4-Chloro-2,3-difluorophenyl)-lH-l,2-pyrazol-l-yl]-3-deoxy-P-D- galactopyranosyl}-3-chloro-lH-l,2,4-triazol-l-yl}-5-chloro-2- (trifluoromethyl)pyridine,

3-{ 5-{3-[4-(4-Chl oro-2, 3 -difluorophenyl)- 1H-1, 2-pyrazol-l -yl]-3 -deoxy -P-D- gal actopy ranosy 1 } -3 -ethyl - 1 H- 1 , 2, 4 -tri azol - 1 -yl } - 5 -chi oro-2 - (trifluoromethyl)pyridine,

5 -Chi oro-3 - { 5 - { 3 -deoxy-3 - [4 -(2 , 3 -difluoro-4-m ethylphenyl)- \H- 1 ,2-pyrazol - l-yl]-P-D-galactopyranosyl}-3-methyl-lJ7-l,2,4-triazol-l-yl}-2- (trifluoromethyl)pyridin,

3-{3-Bromo-5-{3-deoxy-3-[4-(2,3,4-trifluorophenyl)-lH-l,2-pyrazol-l-yl]-P- D-galactopyranosyl } - 1H- 1 ,2,4-triazol- 1 -yl } -5-chloro-2-(trifluoromethyl)pyridine, and

5-Chloro-3-{5-{3-deoxy-3-[4-(2,3,4-trifluorophenyl)-lH-l,2-pyrazol-l-yl]-P- D-galactopyranosyl}-3-ethyl-lH-l,2,4-triazol-l-yl}-2-(trifluoromethyl)pyridine; or a pharmaceutically acceptable salt or solvat thereof.

In a further aspect the present invention relates to a compound of formula (1) for use as a medicine.

In a still further aspect, the present invention relates to a pharmaceutical composition comprising the compound of any one of the previous aspects and/or embodiments and optionally a pharmaceutically acceptable additive, such as a carrier and/or excipient.

In a further aspect the present invention relates to a compound of formula (1) of the present invention for use in a method for treating a disorder relating to the binding of a galectin-3 and galectin-9 to a ligand in a mammal, such as a human. In a further embodiment the disease or disorder is selected from the group consisting of inflammation, such as acute post myocardial infarctions (MI), acute coronary syndrome, acute stent occlusion, acute myocardial reperfusion injury, acute pneumonitidies, acute lung injury (ALI), acute kidney injury (AKI), acute hepatitis, acute on chronic liver failure, acute alcohol hepatitis, acute pancreatitis, acute uveitis, acute pancreatitis related liponecrosis, acute retinitis, acute nephritis, acute myocarditis, autoimmune or autoreactive myocarditis, giant cell myocarditis, chronic autoimmune diseases in all organs, (e.g. lung, liver, kidney, heart, skin, muscle, gut), chronic bacterial infections, chronic viral related inflammation; fibrosis, such as pulmonary fibrosis, liver fibrosis, kidney fibrosis, ophthalmological fibrosis and fibrosis of the skin and heart, acute post-surgical ocular fibrosis, acute transplantation rejection of the kidney, heart, lung, liver, and pancreas, acute post explosion /improvised explosive devices, acute post toxic dust (such as dust from terror attack known as 9/11), acute chemical exposure, chronic lung fibrosis, interstitial lung fibrosis (IPF), Interstitial Lung Disease (ILD), Childhood ILD (ChILD), such as nonspecific interstitial pneumonia (NSIP), Crytogenic organising pneumonia (COP), Desquamative interstital pneumonia (DIP), Sarcoidosis; dermatomyositis; chronic liver fibrosis; chronic alcohol fibrosis, chronic viral fibrosis, chronic diabetic fibrosis, diabetic nephropathy, chronic glomerulonephritis, renal artery stenosis, endometriosis; scarring; keloid formation; aberrant scar formation; surgical adhesions; scleroderma; systemic sclerosis; septic shock; cancers, such as carcinomas, sarcomas, leukemias and lymphomas, such as T-cell lymphomas; metastasising cancers; autoimmune diseases, such as psoriasis, rheumatoid arthritis, Crohn’s disease, ulcerative colitis, intestinal fibrosis, ankylosing spondylitis, systemic lupus erythematosus; metabolic disorders; coagulopathies, such as thrombosis proneness idiopathic (thrombophilia), autoimmune based thrombophilia, microthrombosis at multiorgan failure, COVID-19 related coagulopathy, thrombophilia in cancer disease; cardiovascular disorders, such as cardiac fibrosis, cardiac failure, left and right atrial fibrillation, atheromatosis, arterial inflammation arterial calcification, aortic stenosis; heart disease; heart failure; aortic stenosis, atherosclerosis, pathological angiogenesis, such as ocular angiogenesis or a disease or condition associated with ocular angiogenesis, e.g. neovascularization related to cancer; and eye diseases, such as age- related macular degeneration and corneal neovascularization; atherosclerosis; endocrine disorders, such as Addison, autoimmune hypophysitis; metabolic diseases such as diabetes; type 2 diabetes; insulin resistance; obesity; Diastolic HF; atrophic diseases in the brain, such as Alzheimer’s and Parkinson’s, atrophic diseases in the cerebellum, such as cerebellar atrophy, atrophic spinal diseases such as ALS; disorders related to transplantation in organs, such as anti -rejection prophylaxis, antiacute rejection, anti-chronic rejection; acute bum; acute inflammatory reaction; chronic acute skin graft rejection; chronic scarring; asthma and other interstitial lung diseases, including Hermansky-Pudlak syndrome, pulmonary arterial hypertension, Rheumatoid disease associated interstitial lung disease RA-ILD, Systemic Sclerosis SSc-ILD, lung disease with fibrosis such as COPD (Chronic Obstructive Pulmonary Disease) and asthma; Otosclerosis, mesothelioma; post-surgery disorders, such as anti-keloid, anti-stricture, anti-adhesion, anti-thrombosis, fibrosis/scar reduction following cosmetic procedures; toxin exposure disorders, such as toxic hepatitis, cholera toxin related, mushroom toxin based acute renal failure, pertussis toxin, aeromonas hydrophila enterotoxin, cadmium induced cardiac toxicity, helicobacter O- antigen related toxicity, LPS based toxicity, Streptozotocin toxicity, asbestos exposure, Nephrogenic Systemic Fibrosis (Post Contrast Agents); Tissue injury, such as Spinal cord injury, Peripheral nerve repair; congenital hepatic fibrosis; hereditary fibrosing poikiloderma with tendon contractures, myopathy, and pulmonary fibrosis; liver disorders, such as non-alcoholic steatohepatitis (NASH) or non-alcoholic fatty liver disease, liver cirrhosis of various origins, such as alcoholic and non-alcoholic, autoimmune cirrhosis such as primary biliary cirrhosis and sclerosing cholangitis, virally induced cirrhosis, cirrhosis induced by genetic disease, moderate hepatic impairment; fibrotic disorders such as advanced liver fibrosis and cirrhosis due to different aetiology (such as non-alcoholic steatohepatitis, alcoholic steatohepatitis, viral hepatitis and autoimmune liver diseases); Liver cancer, cholangiocarcinoma, biliary tract cancer; neurodegenerative disorders such as Parkinsons disease, Alzheimers disease, cognitive impairment, cerebrovascular diseases such as stroke, traumatic brain injury, Huntington’s disease, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS) peripheral nephropathy. In a still further aspect the present invention relates to a method for treatment of a disease or disorder relating to the binding of a galectin-3 and galectin-9 to a ligand in a mammal, such as a human, wherein a therapeutically effective amount of at least one compound of formula (1) of the present invention is administered to a mammal in need of said treatment.

In a further embodiment the disease or disorder is selected from the group consisting of inflammation, such as acute post myocardial infarctions (MI), acute coronary syndrome, acute stent occlusion, acute myocardial reperfusion injury, acute pneumonitidies, acute lung injury (ALI), acute kidney injury (AKI), acute hepatitis, acute on chronic liver failure, acute alcohol hepatitis, acute pancreatitis, acute uveitis, acute pancreatitis related liponecrosis, acute retinitis, acute nephritis, acute myocarditis, autoimmune or autoreactive myocarditis, giant cell myocarditis, chronic autoimmune diseases in all organs, (e.g. lung, liver, kidney, heart, skin, muscle, gut), chronic bacterial infections, chronic viral related inflammation; fibrosis, such as pulmonary fibrosis, liver fibrosis, kidney fibrosis, ophthalmological fibrosis and fibrosis of the skin and heart, acute post-surgical ocular fibrosis, acute transplantation rejection of the kidney, heart, lung, liver, and pancreas, acute post explosion /improvised explosive devices, acute post toxic dust (such as dust from terror attack known as 9/11), acute chemical exposure, chronic lung fibrosis, interstitial lung fibrosis (IPF), Interstitial Lung Disease (ILD), Childhood ILD (ChILD), such as nonspecific interstitial pneumonia (NSIP), Crytogenic organising pneumonia (COP), Desquamative interstital pneumonia (DIP), Sarcoidosis; dermatomyositis; chronic liver fibrosis; chronic alcohol fibrosis, chronic viral fibrosis, chronic diabetic fibrosis, diabetic nephropathy, chronic glomerulonephritis, renal artery stenosis, endometriosis; scarring; keloid formation; aberrant scar formation; surgical adhesions; scleroderma; systemic sclerosis; septic shock; cancers, such as carcinomas, sarcomas, leukemias and lymphomas, such as T-cell lymphomas; metastasising cancers; autoimmune diseases, such as psoriasis, rheumatoid arthritis, Crohn’s disease, ulcerative colitis, intestinal fibrosis, ankylosing spondylitis, systemic lupus erythematosus; metabolic disorders; coagulopathies, such as thrombosis proneness idiopathic (thrombophilia), autoimmune based thrombophilia, microthrombosis at multiorgan failure, COVID-19 related coagulopathy, thrombophilia in cancer disease; cardiovascular disorders, such as cardiac fibrosis, cardiac failure, left and right atrial fibrillation, atheromatosis, arterial inflammation, arterial calcification, aortic stenosis; heart disease; heart failure; aortic stenosis, atherosclerosis, pathological angiogenesis, such as ocular angiogenesis or a disease or condition associated with ocular angiogenesis, e.g. neovascularization related to cancer; and eye diseases, such as age- related macular degeneration and corneal neovascularization; atherosclerosis; endocrine disorders, such as Addison, autoimmune hypophysitis; metabolic diseases such as diabetes; type 2 diabetes; insulin resistance; obesity; Diastolic HF; atrophic diseases in the brain, such as Alzheimer’s and Parkinson’s, atrophic diseases in the cerebellum, such as cerebellar atrophy, atrophic spinal diseases such as ALS; disorders related to transplantation in organs, such as anti -rejection prophylaxis, antiacute rejection, anti-chronic rejection; acute bum; acute inflammatory reaction; chronic acute skin graft rejection; chronic scarring; asthma and other interstitial lung diseases, including Hermansky-Pudlak syndrome, pulmonary arterial hypertension, Rheumatoid disease associated interstitial lung disease RA-ILD, Systemic Sclerosis SSc-ILD, lung disease with fibrosis such as COPD (Chronic Obstructive Pulmonary Disease) and asthma; Otosclerosis, mesothelioma; post-surgery disorders, such as anti-keloid, anti-stricture, anti-adhesion, anti-thrombosis, fibrosis/scar reduction following cosmetic procedures; toxin exposure disorders, such as toxic hepatitis, cholera toxin related, mushroom toxin based acute renal failure, pertussis toxin, aeromonas hydrophila enterotoxin, cadmium induced cardiac toxicity, helicobacter O- antigen related toxicity, LPS based toxicity, Streptozotocin toxicity, asbestos exposure, Nephrogenic Systemic Fibrosis (Post Contrast Agents); Tissue injury, such as Spinal cord injury, Peripheral nerve repair; congenital hepatic fibrosis; hereditary fibrosing poikiloderma with tendon contractures, myopathy, and pulmonary fibrosis; liver disorders, such as non-alcoholic steatohepatitis (NASH) or non-alcoholic fatty liver disease, liver cirrhosis of various origins, such as alcoholic and non-alcoholic, autoimmune cirrhosis such as primary biliary cirrhosis and sclerosing cholangitis, virally induced cirrhosis, cirrhosis induced by genetic disease, moderate hepatic impairment; fibrotic disorders such as advanced liver fibrosis and cirrhosis due to different aetiology (such as non-alcoholic steatohepatitis, alcoholic steatohepatitis, viral hepatitis and autoimmune liver diseases); Liver cancer, cholangiocarcinoma, biliary tract cancer; neurodegenerative disorders such as Parkinsons disease, Alzheimers disease, cognitive impairment, cerebrovascular diseases such as stroke, traumatic brain injury Huntington’s disease, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), peripheral nephropathy, in a mammal, such as a human, comprising administering a therapeutically effective amount of a composition of the present invention.

Another aspect of the present invention concerns combination therapy involving administering a compound of formula (1) of the present invention together with a therapeutically active compound different from the compound of formula (1) (interchangeable with “a different therapeutically active compound”). In one embodiment the present invention relates to a combination of a compound of formula (1) and a different therapeutically active compound for use in treatment of a disorder relating to the binding of a galectin-3/9 to a ligand in a mammal. Such disorders are disclosed below.

In an embodiment of the present invention, a therapeutically effective amount of at least one compound of formula (1) of the present invention is administered to a mammal in need thereof in combination with a different therapeutically active compound. In a further embodiment, said combination of a compound of formula (1) together with a different therapeutically active compound is administered to a mammal suffering from a disorder selected from the group consisting of further embodiment the disease or disorder is selected from the group consisting of inflammation, such as acute post myocardial infarctions (MI), acute coronary syndrome, acute stent occlusion, acute myocardial reperfusion injury, acute pneumonitidies, acute lung injury (ALI), acute kidney injury (AKI), acute hepatitis, acute on chronic liver failure, acute alcohol hepatitis, acute pancreatitis, acute uveitis, acute pancreatitis related liponecrosis, acute retinitis, acute nephritis, acute myocarditis, autoimmune or autoreactive myocarditis, giant cell myocarditis, chronic autoimmune diseases in all organs, (e.g. lung, liver, kidney, heart, skin, muscle, gut), chronic bacterial infections, chronic viral related inflammation; fibrosis, such as pulmonary fibrosis, liver fibrosis, kidney fibrosis, ophthalmological fibrosis and fibrosis of the skin and heart, acute post-surgical ocular fibrosis, acute transplantation rejection of the kidney, heart, lung, liver, and pancreas, acute post explosion /improvised explosive devices, acute post toxic dust (such as dust from terror attack known as 9/11), acute chemical exposure, chronic lung fibrosis, interstitial lung fibrosis (IPF), Interstitial Lung Disease (ILD), Childhood ILD (ChILD), such as nonspecific interstitial pneumonia (NSIP), Crytogenic organising pneumonia (COP), Desquamative interstital pneumonia (DIP), Sarcoidosis; dermatomyositis; chronic liver fibrosis; chronic alcohol fibrosis, chronic viral fibrosis, chronic diabetic fibrosis, diabetic nephropathy, chronic glomerulonephritis, renal artery stenosis, endometriosis; scarring; keloid formation; aberrant scar formation; surgical adhesions; scleroderma; systemic sclerosis; septic shock; cancers, such as carcinomas, sarcomas, leukemias and lymphomas, such as T-cell lymphomas; metastasising cancers; autoimmune diseases, such as psoriasis, rheumatoid arthritis, Crohn’s disease, ulcerative colitis, intestinal fibrosis, ankylosing spondylitis, systemic lupus erythematosus; metabolic disorders; coagulopathies, such as thrombosis proneness idiopathic (thrombophilia), autoimmune based thrombophilia, microthrombosis at multiorgan failure, COVID-19 related coagulopathy, thrombophilia in cancer disease; cardiovascular disorders, such as cardiac fibrosis, cardiac failure, left and right atrial fibrillation, atheromatosis, arterial inflammation, arterial calcification, aortic stenosis; heart disease; heart failure; aortic stenosis, atherosclerosis, pathological angiogenesis, such as ocular angiogenesis or a disease or condition associated with ocular angiogenesis, e.g. neovascularization related to cancer; and eye diseases, such as age- related macular degeneration and corneal neovascularization; atherosclerosis; endocrine disorders, such as Addison, autoimmune hypophysitis; metabolic diseases such as diabetes; type 2 diabetes; insulin resistance; obesity; Diastolic HF; atrophic diseases in the brain, such as Alzheimer’s and Parkinson’s, atrophic diseases in the cerebellum, such as cerebellar atrophy, atrophic spinal diseases such as ALS; disorders related to transplantation in organs, such as anti -rejection prophylaxis, antiacute rejection, anti-chronic rejection; acute burn; acute inflammatory reaction; chronic acute skin graft rejection; chronic scarring; asthma and other interstitial lung diseases, including Hermansky-Pudlak syndrome, pulmonary arterial hypertension, Rheumatoid disease associated interstitial lung disease RA-ILD, Systemic Sclerosis SSc-ILD, lung disease with fibrosis such as COPD (Chronic Obstructive Pulmonary Disease) and asthma; Otosclerosis, mesothelioma; post-surgery disorders, such as anti-keloid, anti-stricture, anti-adhesion, anti-thrombosis, fibrosis/scar reduction following cosmetic procedures; toxin exposure disorders, such as toxic hepatitis, cholera toxin related, mushroom toxin based acute renal failure, pertussis toxin, aeromonas hydrophila enterotoxin, cadmium induced cardiac toxicity, helicobacter O- antigen related toxicity, LPS based toxicity, Streptozotocin toxicity, asbestos exposure, Nephrogenic Systemic Fibrosis (Post Contrast Agents); Tissue injury, such as Spinal cord injury, Peripheral nerve repair; congenital hepatic fibrosis; hereditary fibrosing poikiloderma with tendon contractures, myopathy, and pulmonary fibrosis; liver disorders, such as non-alcoholic steatohepatitis (NASH) or non-alcoholic fatty liver disease, liver cirrhosis of various origins, such as alcoholic and non-alcoholic, autoimmune cirrhosis such as primary biliary cirrhosis and sclerosing cholangitis, virally induced cirrhosis, cirrhosis induced by genetic disease, moderate hepatic impairment; Liver cancer, cholangiocarcinoma, biliary tract cancer; neurodegenerative disorders such as Parkinsons disease, Alzheimers disease, cognitive impairment, cerebrovascular diseases such as stroke, traumatic brain injury, Huntington’s disease, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), peripheral nephropathy.

A non-limiting group of cancers given as examples of cancers, including both solid and liquid cancers, that may be treated, managed and/or prevented by administration of a compound of formula (I) in combination with a different therapeutically active compound is selected from: colon carcinoma, breast cancer, head and neck cancer, testis cancer, urothelial cancer, pancreatic cancer, ovarian cancer, prostate cancer, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangeosarcoma, lymphangeoendothelia sarcoma, synovioma, mesothelioma, Ewing’s sarcoma, leiomyosarcoma, rhabdomyosarcoma, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystandeocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms’ tumor, cervical cancer, testicular tumor, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioblastomas, neuronomas, craniopharingiomas, schwannomas, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroama, oligodendroglioma, meningioma, melanoma, neuroblastoma, retinoblastoma, leukemias and lymphomas, acute lymphocytic leukemia and acute myelocytic polycythemia vera, multiple myeloma, Waldenstrom’s macroglobulinemia, and heavy chain disease, acute nonlymphocytic leukemias, chronic lymphocytic leukemia, chronic myelogenous leukemia, Hodgkin’s Disease, non-Hodgkin’s lymphomas, rectum cancer, urinary cancers, uterine cancers, oral cancers, skin cancers, stomach cancer, brain tumors, liver cancer, laryngeal cancer, esophageal cancer, mammary tumors, childhood-null acute lymphoid leukemia (ALL), thymic ALL, B-cell ALL, acute myeloid leukemia, myelomonocytoid leukemia, acute megakaryocytoid leukemia, Burkitt’s lymphoma, acute myeloid leukemia, chronic myeloid leukemia, and T cell leukemia, small and large non-small cell lung carcinoma, acute granulocytic leukemia, germ cell tumors, endometrial cancer, gastric cancer, cancer of the head and neck, chronic lymphoid leukemia, hairy cell leukemia and thyroid cancer.

In some aspects of the present invention, the administration of at least one compound of formula (1) of the present invention and at least one additional therapeutic agent demonstrates therapeutic synergy. In some aspects of the methods of the present invention, a measurement of response to treatment observed after administering both at least one compound of formula (1) of the present invention and the additional therapeutic agent is improved over the same measurement of response to treatment observed after administering either the at least one compound of formula (1) of the present invention or the additional therapeutic agent alone.

A further aspect of the present invention concerns combination therapy involving administering a compound of formula (1) of the present invention together with an anti-fibrotic compound different from the compound of formula (1) to a mammal in need thereof. In a further embodiment, such anti-fibrotic compound may be selected from the following non-limiting group of anti-fibrotic compounds: pirfenidone, nintedanib, simtuzumab (GS-6624, AB0024), BG00011 (STX100), PRM-151, PRM-167, PEG-FGF21, BMS-986020, FG-3019, MN-001, IW001, SAR156597, GSK2126458, PAT-1251 and PBI-4050.

A further aspect of the present invention concerns combination therapy involving administering a compound of formula (1) of the present invention together with an anti-cardiovascular compound different from the compound of formula (1) to a mammal in need thereof.

A still further aspect of the present invention concerns combination therapy involving administering a compound of formula (1) in combination with a further conventional cancer treatment such as chemotherapy and/or radiotherapy, and/or treatment with immunostimulating substances, and/or gene therapy, and/or treatment with antibodies and/or treatment using dendritic cells to a mammal in need thereof. In an embodiment the compound of formula (1) is administered together with at least one additional therapeutic agent selected from an antineoplastic chemotherapy agent. In a further embodiment, the antineoplastic chemotherapeutic agent is selected from: all-trans retinoic acid, Actimide, Azacitidine, Azathioprine, Bleomycin, Carboplatin, Capecitabine, Cisplatin, Chlorambucil, Cyclophosphamide, Cytarabine, Daunorubicin, Docetaxel, Doxifluridine, Doxorubicin, Epirubicin, Etoposide, Fludarabine, Fluorouracil, Gemcitabine, Hydroxyurea, Idarubicin, Irinotecan, Lenalidomide, Leucovorin, Mechlorethamine, Melphalan, Mercaptopurine, Methotrexate, Mitoxantrone, Oxaliplatin, Paclitaxel, Pemetrexed, Revlimid, Temozolomide, Teniposide, Thioguanine, Valrubicin, Vinblastine, Vincristine, Vindesine and Vinorelbine. In one embodiment, a chemotherapeutic agent for use in the combination of the present agent may, itself, be a combination of different chemotherapeutic agents. Suitable combinations include FOLFOX and IFL. FOLFOX is a combination which includes 5 -fluorouracil (5-FU), leucovorin, and oxaliplatin. IFL treatment includes irinotecan, 5-FU, and leucovorin.

In a further embodiment of the present invention, the further conventional cancer treatment includes radiation therapy. In some embodiments, radiation therapy includes localized radiation therapy delivered to the tumor. In some embodiments, radiation therapy includes total body irradiation.

In other embodiments of the present invention the further cancer treatment is selected from the group of immunostimulating substances e.g. cytokines and antibodies. Such cytokines may be selected from the group consisting of, but not limited to: GM-CSF, type I IFN, interleukin 21, interleukin 2, interleukin 12 and interleukin 15. The antibody is preferably an immunostimulating antibody such as anti-CD40 or anti-CTLA-4 antibodies. The immunostimulatory substance may also be a substance capable of depletion of immune inhibitory cells (e.g. regulatory T-cells) or factors, said substance may for example be E3 ubiquitin ligases. E3 ubiquitin ligases (the ELECT, RING and U-box proteins) have emerged as key molecular regulators of immune cell function, and each may be involved in the regulation of immune responses during infection by targeting specific inhibitory molecules for proteolytic destruction. Several ELECT and RING E3 proteins have now also been linked to the induction and maintenance of immune self-tol erance: c-Cbl, Cbl-b, GRAIL, Itch and Nedd4 each negatively regulate T cell growth factor production and proliferation. In some embodiments of the present invention the compound of formula (1) is administered together with at least one additional therapeutic agent selected from a checkpoint inhibitor. In some embodiments of the invention, the checkpoint inhibitor is acting on one or more of the following, non-limiting group of targets: CEACAM1, galectin-9, TIM3, CD80, CTLA4, PD-1, PD-L1, HVEM, BTLA, CD 160, VISTA, B7- H4, B7-2, CD155, CD226, TIGIT, CD96, LAG3, GITF, 0X40, CD137, CD40, IDO, and TDO. These are known targets and some of these targets are described in Melero et al., Nature Reviews Cancer (2015). Examples of check point inhibitors administered together with the compound of formula (1) are Anti-PD-1 : Nivolumab, Pembrolizumab, Cemiplimab. Anti-PD-Ll : Atezolizumab, Avelumab, Durvalumab and one Anti-CTLA-4: Ipilimumab. Each one of these check point inhibitors can be made the subject of an embodiment in combination with any one of the compounds of formula (1).

In some embodiments of the present invention the compound of formula (1) is administered together with at least one additional therapeutic agent selected from an inhibitor of indoleamine-2,3-dioxygenase (IDO).

In some embodiments of the present invention the compound of formula (1) is administered together with at least one additional therapeutic agent selected from one or more inhibitors of the CTLA4 pathway. In some embodiments, the inhibitor of the CTLA4 pathway is selected from one or more antibodies against CTLA4.

In some embodiments of the present invention the compound of formula (1) is administered together with at least one additional therapeutic agent selected from one or more inhibitors of the PD-l/PD-L pathway. In some embodiments, the one or more inhibitors of the PD-l/PD-L pathway are selected from one or more antibodies or antibody fragments against PD-1, PD-L1, and/or PD-L2, or other ways by which an anti-PDl antibodies can be induced, such as mRNA-based introduction of genetic material which sets forth in-body production of anti-PDl or anti-PDLl antibodies or fragments of such antibodies.

In further embodiment of the present invention a compound of formula (1) is administered in combination with an Angiotensin Converting Enzyme inhibitor (ACE), a beta blocker, a statin, and an aspirin to a mammal suffering from post MI for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with an Angiotensin II-receptor blocker (ARB), a beta blocker, a statin, and an aspirin to a mammal suffering from post MI for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with an ACE, a beta blocker, a statin, and clopidogrel to a mammal suffering from post MI for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with an ARB, a beta blocker, a statin, and clopidogrel to a mammal suffering from post MI for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with an ACE, eplenerenone, a beta blocker, a statin, and clopidogrel to a mammal suffering from post MI, (in particular post MI with reduced, e.g. <40%, LVF, no renal impairment and have normal blood potassium levels (< 5 mEq/L)) for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with clopidogrel and/or ticagrelor and/or prasugrel to a mammal suffering from acute coronary syndrome for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with clopidogrel and an aspirin to a mammal suffering from acute coronary syndrome for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with ticagrelor and an aspirin to a mammal suffering from acute coronary syndrome for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with ticagrelor to a mammal suffering from stent occlusion for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with ticagrelor and an aspirin to a mammal suffering from stent occlusion for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with prasugrel to a mammal suffering from stent occlusion for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with prasugrel and an aspirin to a mammal suffering from stent occlusion for the treatment hereof In further embodiment of the present invention a compound of formula (1) is administered in combination with azathioprine (AZT) and/or mycophenolate to a mammal suffering from Pneumonitis for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with nindetanib to a mammal suffering from pneumonitis for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with pirfenidone to a mammal suffering from pneumonitis for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with adenosine to a mammal suffering from myocardial reperfusion injury for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with carperitide to a mammal suffering from myocardial reperfusion injury for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with cyclosporin A (CsA) to a mammal suffering from myocardial reperfusion injury for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with delcasertib to a mammal suffering from myocardial reperfusion injury for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with exenatide to a mammal suffering from myocardial reperfusion injury for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with sodium nitrite to a mammal suffering from myocardial reperfusion injury for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with 3,5-Seco-4-nor-cholestan-5-one oxime-3-ol (TR040303) to a mammal suffering from myocardial reperfusion injury for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with a neuromuscular blocking agent to a mammal suffering from ALI or ARDS for the treatment hereof In further embodiment of the present invention a compound of formula (1) is administered in combination with formoterol and/or budesonide to a mammal suffering from ALI or ARDS for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with a PDE inhibitor to a mammal suffering from ALI or ARDS for the treatment hereof. Preferred PDE inhibitors are selective and non- selective, such as aminophylline, paraxanthine, pentoxifylline, or theophylline. More examples are PDE-3 inhibitors, such as inamrinone, milrinone, enoximone; or PDE-4 inhibitors, such as ibudilast, piclamilast, roflumilast; or PDE-5 inhibitors, such as dipyridamole.

In further embodiment of the present invention a compound of formula (1) is administered in combination with an interferon (IFN), such as PEG-IFN alfa-2b PEG- Intron, to a mammal suffering from acute hepatitis C for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with ledipasvir and sofosbuvir to a mammal suffering from acute hepatitis C for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with glecaprevir and/or pibrentasvir to a mammal suffering from acute hepatitis C for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with sofosbuvir and/or velpatasvir to a mammal suffering from acute hepatitis C for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with N-acetylcystein (NAC) to a mammal suffering from alcohol hepatitis for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with granulocyte colony-stimulating factor (G-CSF) to a mammal suffering from alcohol hepatitis for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with Norfloxacin or with Norfloxacin and G-CSF to a mammal suffering from acute on chronic liver failure for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with lexipafant to a mammal suffering from acute pancreatitis for the treatment hereof In further embodiment of the present invention a compound of formula (1) is administered in combination with imipenem to a mammal suffering from acute pancreatitis for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with adalimumab to a mammal suffering from acute uveitis for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with infliximab to a mammal suffering from acute uveitis for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with AZT and/or CsA and/or mycopenolate and/or cyclophosphamide and/or tacrolimus and/or chlorambucil to a mammal suffering from acute uveitis for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with foscarnet to a mammal suffering from acute retinitis (acute retinal necrosis (ARN)) for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with ganciclovir to a mammal suffering from acute retinitis (acute retinal necrosis- ARN) for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with valacyclovir and/or acyclovir to a mammal suffering from acute retinitis (acute retinal necrosis- ARN) for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with methylprednisolone to a mammal suffering from acute myocarditis for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with alemtuzumab to a mammal suffering from acute myocarditis for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with anti-thymocyte globulin to a mammal suffering from acute myocarditis for the treatment hereof. In further embodiment of the present invention a compound of formula (1) is administered in combination with abatacept to a mammal suffering from acute myocarditis for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with rituximab to a mammal suffering from acute myocarditis for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with AZT to a mammal suffering from autoimmune hepatitis for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in an induction setting optionally with budesonide to a mammal suffering from autoimmune hepatitis for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with mycophenolate mofetil to a mammal suffering from autoimmune hepatitis for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with CsA to a mammal suffering from autoimmune hepatitis for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with tacrolimus to a mammal suffering from autoimmune hepatitis for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with rituximab to a mammal suffering from autoimmune hepatitis for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with infliximab to a mammal suffering from autoimmune hepatitis for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with ACE and prednisolone to a mammal suffering from a liver disease, such as IgA nephropathy for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with ARB and prednisolone to a mammal suffering from a liver disease, such as IgA nephropathy for the treatment hereof. In further embodiment of the present invention a compound of formula (1) is administered in combination with ACE and/or ARB to a mammal suffering from a liver disease, such as IgA nephropathy for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with ACE and/or ARB and cyclophosphamide to a mammal suffering from a liver disease, such as IgA nephropathy for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with AZT to a mammal suffering from a heart disease, such as autoimmune or autoreactive myocarditis or giant cell myocarditis for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with CsA to a mammal suffering from a heart disease, such as autoimmune or autoreactive myocarditis or giant cell myocarditis for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with dapsone to a mammal suffering from dermatitis herpetiformis for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with rituximab to a mammal suffering from dermatitis herpetiformis for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with colchicine to a mammal suffering from dermatitis herpetiformis for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with hydroxychloroquine to a mammal suffering from dermatomyositis for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with methotrexate to a mammal suffering from dermatomyositis for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with octagam (intravenous Immunoglobulin) to a mammal suffering from dermatomyositis for the treatment hereof. In further embodiment of the present invention a compound of formula (1) is administered in combination with etanercept to a mammal suffering from dermatomyositis for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with hydroxychloroquine to a mammal suffering from lupus of the skin (SLE) for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with methotrexate to a mammal suffering from lupus of the skin (SLE) for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with AZT to a mammal suffering from lupus of the skin (SLE) for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with mycophenolate to a mammal suffering from lupus of the skin (SLE) for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with cyclophosphamide to a mammal suffering from lupus of the skin (SLE) for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with anifrolumab to a mammal suffering from lupus of the skin (SLE) for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with methotrexate to a mammal suffering from scleroderma for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with rituximab to a mammal suffering from scleroderma for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with intravenous immunoglobulin to a mammal suffering from scleroderma for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with abatacept to a mammal suffering from scleroderma for the treatment hereof. In further embodiment of the present invention a compound of formula (1) is administered in combination with tocilizumab to a mammal suffering from scleroderma for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with dapsone to a mammal suffering from pemphigoid for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with AZT to a mammal suffering from pemphigoid for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with methotrexate to a mammal suffering from pemphigoid for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with mycophenolate to a mammal suffering from pemphigoid for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with cyclophosphamide to a mammal suffering from pemphigoid for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with omalizumab to a mammal suffering from pemphigoid for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with dupilumab to a mammal suffering from pemphigoid for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with AZT to a mammal suffering from pemphigus for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with mycophenolate mofetil to a mammal suffering from pemphigus for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with dapsone to a mammal suffering from pemphigus for the treatment hereof. In further embodiment of the present invention a compound of formula (1) is administered in combination with rituximab optionally together with AZT to a mammal suffering from pemphigus for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with cyclophosphamide to a mammal suffering from pemphigus for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with rituximab to a mammal suffering from vasculitis for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with methotrexate to a mammal suffering from vasculitis for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with azathioprine to a mammal suffering from vasculitis for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with mycophenolate mofetil to a mammal suffering from vasculitis for the treatment hereof.

Herein vasculitis means cytoplasmic antibody-associated vasculitis (AAV), including granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA), PAN, Giant cell arteritis and Takayasu Arteritis.

In further embodiment of the present invention a compound of formula (1) is administered in combination with cyclophosphamide to a mammal suffering from eosinophilic granulomatosis with polyangiitis for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with rituximab to a mammal suffering from eosinophilic granulomatosis with polyangiitis for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with methotrexate to a mammal suffering from eosinophilic granulomatosis with polyangiitis for the treatment hereof. In further embodiment of the present invention a compound of formula (1) is administered in combination with azathioprine to a mammal suffering from eosinophilic granulomatosis with polyangiitis for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with mycophenolate mofetil to a mammal suffering from eosinophilic granulomatosis with polyangiitis for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with mepolizumab to a mammal suffering from eosinophilic granulomatosis with polyangiitis for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with azathioprine to a mammal suffering from polyarteritis nodosa for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with methotrexate to a mammal suffering from polyarteritis nodosa for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with cyclophosphamide to a mammal suffering from polyarteritis nodosa for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with tocilizumab to a mammal suffering from giant cell arteritis for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with methotrexate to a mammal suffering from giant cell arteritis for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with abatecept to a mammal suffering from giant cell arteritis for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with methotrexate to a mammal suffering from Takayasu arteritis for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with azathioprine to a mammal suffering from takayasu arteritis for the treatment hereof. In further embodiment of the present invention a compound of formula (1) is administered in combination with a TNF inhibitor to a mammal suffering from takayasu arteritis for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with tocilizumab to a mammal suffering from takayasu arteritis for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with methotrexate to a mammal suffering from myositis or polymyositis for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with azathioprine to a mammal suffering from myositis or polymyositis for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with methotrexate and azathioprine to a mammal suffering from myositis or polymyositis for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with mycophenolate mofetil to a mammal suffering from myositis or polymyositis for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with tacrolimus to a mammal suffering from myositis or polymyositis for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with rituximab to a mammal suffering from myositis or polymyositis for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with cyclophosphamide to a mammal suffering from myositis or polymyositis for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with tocilizumab to a mammal suffering from myositis or polymyositis for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with abatecept to a mammal suffering from myositis or polymyositis for the treatment hereof. In further embodiment of the present invention a compound of formula (1) is administered in combination with anakinra to a mammal suffering from myositis or polymyositis for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with certolizumab to a mammal suffering from crohn’s disease for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with methotrexate to a mammal suffering from crohn’s disease for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with infliximab to a mammal suffering from crohn’s disease for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with adalimumab to a mammal suffering from crohn’s disease for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with ustekinumab to a mammal suffering from crohn’s disease for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with vedolizumab to a mammal suffering from crohn’s disease for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with infliximab to a mammal suffering from ulcerative colitis for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with adalimumab to a mammal suffering from ulcerative colitis for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with golimumab to a mammal suffering from ulcerative colitis for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with vedolizumab to a mammal suffering from ulcerative colitis for the treatment hereof. In further embodiment of the present invention a compound of formula (1) is administered in combination with tofacitinib to a mammal suffering from ulcerative colitis for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with azathioprine to a mammal suffering from ulcerative colitis for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with 6-mercaptopurine to a mammal suffering from ulcerative colitis for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with CsA to a mammal suffering from ulcerative colitis for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with an interferon to a mammal suffering from a chronic viral related inflammation, such as chronic viral hepatitis (A, B, or C) for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with lamivudine to a mammal suffering from a chronic viral related inflammation, such as chronic viral hepatitis (A, B, or C) for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with adefovir to a mammal suffering from a chronic viral related inflammation, such as chronic viral hepatitis (A, B, or C) for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with entecavir to a mammal suffering from a chronic viral related inflammation, such as chronic viral hepatitis (A, B, or C) for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with tenofovir to a mammal suffering from a chronic viral related inflammation, such as chronic viral hepatitis (A, B, or C) for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with PEG-interferon and ribavirin to a mammal suffering from a chronic viral related inflammation, such as chronic viral hepatitis (A, B, or C) for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with famciclovir and/or boceprevir to a mammal suffering from a chronic viral related inflammation, such as chronic viral hepatitis (A, B, or C) for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with antiretroviral therapy to a mammal suffering from HIV for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with azathioprine to a mammal suffering from ocular fibrosis, such as acute post-surgical ocular fibrosis for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with methotrexate to a mammal suffering from ocular fibrosis, such as acute post-surgical ocular fibrosis for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with cyclophosphamide to a mammal suffering from ocular fibrosis, such as acute post-surgical ocular fibrosis for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with mycophenolate to a mammal suffering from ocular fibrosis, such as acute post-surgical ocular fibrosis for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with bevacizumab to a mammal suffering from ocular fibrosis, such as acute post-surgical ocular fibrosis for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with ranibizumab to a mammal suffering from ocular fibrosis, such as acute post-surgical ocular fibrosis for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with ciclosporin to a mammal suffering from transplantation rejection, such as kidney, heart, lung, liver, or pancreas rejection, for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with tacrolimus to a mammal suffering from transplantation rejection, such as kidney, heart, lung, liver, or pancreas rejection, for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with azathioprine to a mammal suffering from transplantation rejection, such as kidney, heart, lung, liver, or pancreas rejection, for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with mycophenolic acid to a mammal suffering from transplantation rejection, such as kidney, heart, lung, liver, or pancreas rejection, for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with sirolimus to a mammal suffering from transplantation rejection, such as kidney, heart, lung, liver, or pancreas rejection, for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with everolimus to a mammal suffering from transplantation rejection, such as kidney, heart, lung, liver, or pancreas rejection, for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with basiliximab to a mammal suffering from transplantation rejection, such as kidney, heart, lung, liver, or pancreas rejection, for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with daclizumab to a mammal suffering from transplantation rejection, such as kidney, heart, lung, liver, or pancreas rejection, for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with tocilizumab to a mammal suffering from transplantation rejection, such as kidney, heart, lung, liver, or pancreas rejection, for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with rituximab to a mammal suffering from transplantation rejection, such as kidney, heart, lung, liver, or pancreas rejection, for the treatment hereof. In further embodiment of the present invention a compound of formula (1) is administered in combination with anti -thymocyte globulin and/or anti -lymphocyte globulin to a mammal suffering from transplantation rejection, such as kidney, heart, lung, liver, or pancreas rejection, for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with cyclophosphamide to a mammal suffering from COP for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with cyclosporin to a mammal suffering from COP for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with azathioprine to a mammal suffering from COP for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with mycophenolate to a mammal suffering from COP for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with azathioprine to a mammal suffering from DIP for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with cyclophosphamide to a mammal suffering from DIP for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with nindetanib to a mammal suffering from DIP for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with an aminoglycoside to a mammal suffering from acute interstitial pneumonia for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with a carbepenem to a mammal suffering from acute interstitial pneumonia for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with a piperacillin and/or tazobactam to a mammal suffering from acute interstitial pneumonia for the treatment hereof. In further embodiment of the present invention a compound of formula (1) is administered in combination with a quinolone to a mammal suffering from acute interstitial pneumonia for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with a methotrexate to a mammal suffering from sarcoidosis for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with azathioprine to a mammal suffering from sarcoidosis for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with leflunomide to a mammal suffering from sarcoidosis for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with ACE and/or ARB and a dipeptidyl peptidase IV (DPP4) inhibitor to a mammal suffering from a diabetic nephropathy for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with ACE and/or ARB and a glucagon-like peptide 1 receptor (GLP-1) agonist to a mammal suffering from a diabetic nephropathy for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with ACE and/or ARB and a sodium-glucose cotransporter-2 inhibitor to a mammal suffering from a diabetic nephropathy for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with obethicolic acid to a mammal suffering from NASH for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with a peroxisome proliferator-activated receptor (PPAR) agonist, e.g. elafibranor, to a mammal suffering from NASH for the treatment hereof. In further embodiment of the present invention a compound of formula (1) is administered in combination with a sodium-glucose co-transporter-2 inhibitor to a mammal suffering from NASH for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with a GLP-1 agonist to a mammal suffering from NASH for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with ACE and/or ARB and/or a diuretic to a mammal suffering from chronic glomerulonephritis for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with pirfenidone to a mammal suffering from chronic glomerulonephritis for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with a loxl2 inhibitor, such as (R,R)-trans-(3-((4- (aminomethyl)-6-(tri fluoromethyl)pyri din-2 -yl)oxy )phenyl)(3-fluoro-4- hydroxypyrrolidin-l-yl)methanone, and optionally pirfenidone to a mammal suffering from chronic glomerulonephritis for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with eplerenone to a mammal suffering from heart fibrosis for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with VEGF and/or IGF-1 and/or HGF and/or NRG-1 and/or EGF and/or FGF agents to a mammal suffering from heart fibrosis for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with rivaroxaban to a mammal suffering from thrombosis proneness idiopathic (thrombophilia) or autoimmune based thrombophilia for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with apixaban to a mammal suffering from thrombosis proneness idiopathic (thrombophilia) or autoimmune based thrombophilia for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with edoxaban to a mammal suffering from thrombosis proneness idiopathic (thrombophilia) or autoimmune based thrombophilia for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with dabigatran to a mammal suffering from thrombosis proneness idiopathic (thrombophilia) or autoimmune based thrombophilia for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with fondaparinux to a mammal with heparin induced thrombocytopenia and suffering from microthrombosis at multiorgan failure for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with argatroban to a mammal with heparin induced thrombocytopenia and suffering from microthrombosis at multiorgan failure for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with unfractionated heparin to a mammal suffering from COVID-19 related coagulopathy for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with a factor XII inhibitor to a mammal suffering from COVID-19 related coagulopathy for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with aspirin to a mammal suffering from COVID-19 related coagulopathy for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with nafamostat to a mammal suffering from COVID-19 related coagulopathy for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with a tissue plasminogen activator (tPA) to a mammal suffering from COVID-19 related coagulopathy for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with a low-molecular-weight heparin (LMWH) to a mammal suffering from cancer-associated thrombosis therapy for the treatment hereof. In further embodiment of the present invention a compound of formula (1) is administered in combination with edoxaban to a mammal suffering from cancer- associated thrombosis therapy for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with rivaroxaban to a mammal suffering from cancer- associated thrombosis therapy for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with a short acting insulin, such as Humalog or NovoRapid, to a mammal suffering from diabetes type 1 for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with a long-acting insulin, such as Lantus, Levemir or Tresiba, to a mammal suffering from diabetes type 1 for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with metformin to a mammal suffering from diabetes type 2 for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with a DPP4 inhibitor to a mammal suffering from diabetes type 2 for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with a GLP-1 agonist to a mammal suffering from diabetes type 2 for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with a sodium-glucose co-transporter-2 inhibitor to a mammal suffering from diabetes type 2 for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with methylprednisolone to a mammal suffering from autoimmune hypophysitis for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with dexamethasone to a mammal suffering from autoimmune hypophysitis for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with AZT to a mammal suffering from autoimmune hypophysitis for the treatment hereof. In further embodiment of the present invention a compound of formula (1) is administered in combination with cabergoline and/or bromocriptine to a mammal having hyperprolactinaemic and suffering from autoimmune hypophysitis for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with donepezil to a mammal suffering from alzheimer’s disease for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with rivastigmine to a mammal suffering from alzheimer’s disease for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with galantamine to a mammal suffering from alzheimer’s disease for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with memantine to a mammal suffering from alzheimer’s disease for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with aducanumab to a mammal suffering from alzheimer’s disease for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with carbidopa and/or levodopa to a mammal suffering from parkinson’s disease for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with entacapone and/or tolcapone and with carbidopa and/or levodopa to a mammal suffering from parkinson’s disease for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with bromocriptine to a mammal suffering from parkinson’s disease for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with pergolide to a mammal suffering from parkinson’s disease for the treatment hereof. In further embodiment of the present invention a compound of formula (1) is administered in combination with pramipexole to a mammal suffering from parkinson’s disease for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with selegeline to a mammal suffering from parkinson’s disease for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with rasagaline to a mammal suffering from parkinson’s disease for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with amantadine to a mammal suffering from parkinson’s disease for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with riluzole optionally with non-invasive ventilation to a mammal suffering from ALS for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with edanvarone to a mammal suffering from ALS for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with riluzole and amitriptyline and/or trihexyphenidyl (for Sialorrhoea) to a mammal suffering from ALS for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with riluzole and nuedexta (for pseudobulbar effect) to a mammal suffering from ALS for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with tacrolimus to a mammal to prevent an organ rejection.

In further embodiment of the present invention a compound of formula (1) is administered in combination with sirolimus to a mammal to prevent an organ rejection.

In further embodiment of the present invention a compound of formula (1) is administered in combination with everolimus to a mammal to prevent an organ rejection. In further embodiment of the present invention a compound of formula (1) is administered in combination with mycophenolate acid to a mammal to prevent an organ rejection.

In further embodiment of the present invention a compound of formula (1) is administered in combination with antithymocyte globulin to a mammal to prevent an organ rejection.

In further embodiment of the present invention a compound of formula (1) is administered in combination with alemtuzumab to a mammal to prevent an organ rejection.

In further embodiment of the present invention a compound of formula (1) is administered in combination with basiliximab to a mammal to prevent an organ rejection.

In further embodiment of the present invention a compound of formula (1) is administered in combination with muromonab-CD3 to a mammal to prevent an organ rejection.

In further embodiment of the present invention a compound of formula (1) is administered in combination with anti-thymocyte globulin to a mammal to prevent an acute organ rejection.

In further embodiment of the present invention a compound of formula (1) is administered in combination with muromonab-CD3 to a mammal to prevent an acute organ rejection.

In further embodiment of the present invention a compound of formula (1) is administered in combination with sirolimus and/or to mycophenolate mofetil a mammal to prevent a chronic organ rejection.

In further embodiment of the present invention a compound of formula (1) is administered in combination with triamcinolone acetonide to a mammal suffering from keloids for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with intralesional IFN to a mammal suffering from keloids for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with 5-FU to a mammal suffering from keloids for the treatment hereof. In further embodiment of the present invention a compound of formula (1) is administered in combination with doxorubicin to a mammal suffering from keloids for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with bleomycin to a mammal suffering from keloids for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with verapamil to a mammal suffering from keloids for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with retinoic acid to a mammal suffering from keloids for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with tacrolimus to a mammal suffering from keloids for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with etanercept to a mammal suffering from keloids for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with pantoprazole and/or esomeprazole and with trimethoprim-sulfamethoxazole to a mammal suffering from tracheal stenosis or idiopathic subglottic stenosis for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with LMWH to a mammal suffering from deep vein thrombosis for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with unfractionated heparin to a mammal suffering from deep vein thrombosis and renal insufficiency for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with fondaparinux to a mammal suffering from deep vein thrombosis, such as heparin induced thrombocytopenia, for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with rivaroxaban to a mammal suffering from deep vein thrombosis for the treatment hereof In further embodiment of the present invention a compound of formula (1) is administered in combination with vasopressin optionally with an antibiotic provided there is acute or recurrent cholangitis to a mammal suffering from congenital hepatic fibrosis for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with somatostatin optionally with an antibiotic provided there is acute or recurrent cholangitis to a mammal suffering from congenital hepatic fibrosis for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with a diuretic, such as frusemide, to a mammal suffering from cardiac failure for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with ACE and/or ARB to a mammal suffering from cardiac failure for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with hydralazine optionally with ACE and/or ARB to a mammal suffering from cardiac failure for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with a soluble guanylate cyclase (sGC) stimulator and standard of care to a mammal suffering from cardiac failure for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with eplerenone and/or spironolactone to a mammal suffering from cardiac failure for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with ivabradine to a mammal suffering from cardiac failure for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with a statin and an ACE, such as captopril, enalapril, fosinopril or lisonopril, and with aspirin to a mammal suffering from atherosclerosis for the treatment hereof.

In further embodiment of the present invention a compound of formula (1) is administered in combination with a statin and a beta blocker, such as atenolol, bisoprolol, metoprolol or carvedilol, and with aspirin to a mammal suffering from atherosclerosis for the treatment hereof In further embodiment of the present invention a compound of formula (1) is administered in combination with ACE and/or ARB to a mammal suffering from aortic stenosis for the treatment hereof. In further embodiment of the present invention a compound of formula (1) is administered in combination with a beta blocker to a mammal suffering from aortic stenosis for the treatment hereof. In further embodiment of the present invention a compound of formula (1) is administered in combination with digoxin to a mammal suffering from aortic stenosis for the treatment hereof. In a still further aspect the present invention relates to a process of preparing a compound of formula II or a pharmaceutically acceptable salt or solvate thereof comprising the step a1 where A1, R1 and B1 are defined as above under formula 1;

a1) Reacting a compound of the formula I wherein L1 is a halide such as bromine or iodine with a compound of the formula A1-X1, wherein X1 is defined as a boronic acid, borinatester, tinalkyl or zincalkyl suitable for cross-coupling reactions such as Suzuki, Stille or Negishi couplings in the presence of a catalyst such as Pd(PPh3)4 or Pd(dppf)Cl₂ in a suitable solvent such as 1,4-dioxane/water optionally in the presence of a base such as K2CO3, optionally at elevated temperature to give a compound of formula II; alternatively reacting a compound of formula I wherein L1 is defined as a boronic acid, borinatester, tinalkyl or zincalkyl suitable for cross-coupling reactions such as Suzuki, Stille or Negishi couplings with a compound of formula A1-X2 wherein X2 is a halide such as bromine or iodine in the presence of a catalyst such as Pd(PPh₃)₄ or Pd(dppf)Cl₂ and a base such as K₂CO₃ in a suitable solvent such as 1,4- dioxane and water optionally at elevated temperature to give a compound of formula II. In a still further aspect the present invention relates to a process of preparing a compound of formula IV or a pharmaceutically acceptable salt or solvate thereof comprising the step a2 where A1, R1 and B1 are defined as above under formula 1;

a2) Reacting a compound of the formula III wherein X³ is a protective group such as a boc-group, X⁴ and X⁵ together form a protective group such as benzylidene and X⁶ is either a hydrogen or a protective group such as methoxymethyl with a compound of the formula V

V in the presence of an acid such as HC1 in a suitable solvent such as EtOH, optionally at elevated temperature to give a compound of formula IV.

In a still further aspect the present invention relates to a process of preparing a compound of formula VII or a pharmaceutically acceptable salt or solvate thereof comprising the step a3 where R¹ and B¹ are defined as above under formula 1, Z¹ is an aryl or a heteroaryl selected under formula 1 under A¹, L³ is an alkyl group;

a3) Reacting a compound of the formula VI wherein L² is an alkenyl group with hydrogen in the presence of a suitable catalyst such as platinum(IV) oxide in an inert solvent such as THF to give a compound of formula VII.

In a still further aspect the present invention relates to a process of preparing a compound of formula IX or a pharmaceutically acceptable salt or solvate thereof comprising the step a4 where R¹ and B¹ are defined as above under formula 1, Z² is an aryl or a heteroaryl selected under formula 1 under A¹, L⁵ is a cyano group;

a4) Reacting a compound of the formula VIII wherein L⁴ is a halide such as bromine with a cyanide reagent such as zinc cyanide in the presence of zinc, Pd2(dba)s and l,l’-bis(diphenylphosphino)ferrocene in an inert solvent such as DMF optionally at elevated temperature to give a compound of formula IX.

In a still further aspect the present invention relates to a process of preparing a compound of formula XI or a pharmaceutically acceptable salt or solvate thereof comprising the step a5 where R¹ and A¹ are defined as above under formula 1, Z³ is an aryl or a heteroaryl selected under formula 1 under B¹, L⁷ is a cyano group;

a5) Reacting a compound of the formula X wherein L⁶ is a halide such as bromine with a cyanide reagent such as copper cyanide in an inert solvent such as DMSO at elevated temperature to give a compound of formula XI; alternatively reacting a compound of formula X wherein L⁶ is a halide such as bromine with a cyanide reagent such as zinc cyanide in the presence of zinc, Pd2(dba)s and 1,1’- bis(diphenylphosphino)ferrocene in an inert solvent such as DMF optionally at elevated temperature to give a compound of formula XI.

In a still further aspect the present invention relates to a process of preparing a compound of formula XIII or a pharmaceutically acceptable salt or solvate thereof comprising the step a6 where R¹ and A¹ are defined as above under formula 1, Z⁴ is an aryl or a heteroaryl selected under formula 1 under B¹, L⁹ is a Ci-6 alkyl or C3-6 cycloalkyl optionally with substitutents selected under formula 1;

a6) Reacting a compound of the formula XII wherein L8 is a halide such as bromine or iodine with a compound of the formula L9-X7, wherein X7 is defined as a boronic acid, borinatester, tinalkyl or zincalkyl suitable for cross-coupling reactions such as Suzuki, Stille or Negishi couplings in the presence of a catalyst such as Pd(PPh3)4 or Pd(dppf)Cl₂ in a suitable solvent such as 1,4-dioxane/water, optionally in the presence of a base such as K2CO3, optionally at elevated temperature to give a compound of formula XIII. In a still further aspect the present invention relates to a process of preparing a compound of formula XV or a pharmaceutically acceptable salt or solvate thereof comprising the step a7 where R1 and A1 are defined as above under formula 1, Z5 is an aryl or a heteroaryl selected under formula 1 under B1, L10 is a C_1-6 alkyl;

a7) Reacting a compound of the formula XIV with 3-chloroperbenzoic acid in an inert solvent such as DCM to give a compound of formula XV. In a still further aspect the present invention relates to a process of preparing a compound of formula XVII or a pharmaceutically acceptable salt or solvate thereof comprising the step a8 where R1 and A1 are defined as above under formula 1, Z6 is an aryl or a heteroaryl selected under formula 1 under B1, R21a and R22a are selected under formula 1 under B1;

a8) Reacting a compound of the formula XVI with a compound of the formula in a suitable solvent such as methanol or THF to give a compound of formula XVII. In a still further aspect the present invention relates to a process of preparing a compound of formula XIX or a pharmaceutically acceptable salt or solvate thereof comprising the step a9 where A¹ and B¹ are defined as above under formula 1;

a9) Reacting a compound of the formula XVIII with trifluoroacetic anhydride in the presence of pyridine in a suitable solvent such as THF to give a compound of formula XIX.

In a still further aspect the present invention relates to a process of preparing a compound of formula XXV or a pharmaceutically acceptable salt or solvate thereof comprising the steps al0-al4 wherein R¹ and B¹ are defined as above under formula 1, X⁸ and X⁹ together form a protective group such as benzylidene, X¹⁰ is either a hydrogen or a protective group such as methoxymethyl and X¹¹ is a protective group such as a boc-group, L¹¹ is defined as a halide such as iodine or bromine and L¹² is defined as a boronic acid or a borinate.

alO) Reacting a compound of the formula XX with a reducing agent such as triphenylphosphine in an inert solvent such as THF and water optionally at elevated temperature to give a compound of formula XXI. al 1) Reacting a compound of the formula XXI with V-/c/7-b utyl oxy carbonyl -3 -(4- cyanophenyl)oxaziridine in an inert solvent such as DCM to give a compound of formula XXII. al2) Reacting a compound of the formula XXII with a deprotecting agent such as TFA in an inert solvent such as DCM to give an intermediate which is further reacted with 1,1,3,3-tetraethoxypropane in the presence of an acid such as HC1 in a suitable solvent such as ethanol to give a compound of formula XXIII. al 3) Reacting a compound of the formula XXIII with a halogenating agent such as N- bromosuccinimide or V-iodosuccinimide in an inert solvent such as THF to give a compound of formula XXIV. al4) Reacting compound of formula XXIV with bis(pinacolato)diboron in the presence of a catalyst such as Pd(dppf)C12 and a base such as potassium acetate in an inert solvent such as DMSO optionally at elevated temperature to give a compound of formula XXV.

In a still further aspect the present invention relates to a process of preparing a compound of formula XXX or a pharmaceutically acceptable salt or solvate thereof comprising the steps al 5-al 8 wherein R¹ and B¹ are defined as above under formula 1.

al 5) Reacting a compound of the formula XXVI wherein X¹²-X¹⁵ are independently selected from protective groups such as acetate, with a cyanide reagent such as trimethylsilyl cyanide in the presence of a reagent such as boron trifluoride diethyl etherate in an inert solvent such as nitromethane at 0 °C to give a compound of formula XXVII. al 6) Reacting a compound of the formula XXVII wherein X¹²-X¹⁴ are independently selected from protective groups such as acetate, with acetyl chloride in methanol optionally at elevated temperature giving a product which is further reacted with benzaldehyde dimethylacetal in the presence of D(+)-10-camphorsulfonic acid in a suitable solvent such as DMF to give a compound of formula XXVIII, wherein X¹⁶ and X¹⁷ together form a protective group such as benzylidene. al 7) Reacting a compound of the formula XXVIII with ammonia in a solvent such as methanol to give a compound of formula XXIX. al 8) Reacting a compound of the formula XXIX with a compound of the formula

XXXI

XXXI in a solvent such as 1,4-di oxane optionally at elevated temperature resulting in a product, which is further reacted with acetic acid and B¹-NHNH2 in a solvent such as acetonitrile at elevated temperature to give a compound of formula XXX.

In a still further aspect the present invention relates to a process of preparing a compound of formula V or a pharmaceutically acceptable salt or solvate thereof comprising the step al 9 where A¹ is defined as above under formula 1;

al 9) Reacting a compound of the formula XXXII with DMF and phosphoryl trichloride at elevated temperature to give a product, which is further reacted with K2CO3 in toluene at elevated temperature to give a compound of formula V.

In a still further aspect the present invention relates to a process of preparing a compound of formula XXXIV or a pharmaceutically acceptable salt or solvate thereof comprising the step a20 where B¹ is defined as above under formula 1;

a20) Reacting a compound of the formula XXXIII wherein L¹³ is a leaving group such as a halide such as bromine with methyl 2,2-difluoro-2-fluorosulfonylacetate in the presence of a copper salt such as Cui in an inert solvent such as DMF optionally at elevated temperature to give a compound of formula XXXIV. In a still further aspect the present invention relates to a process of preparing a compound of formula XXXVII or a pharmaceutically acceptable salt or solvate thereof comprising the steps a21-a22 where B¹ is defined as above under formula 1;

a21) Reacting a compound of the formula XXXV with ammonium chloride in the presence of iron in a solvent mixture such as ethanol/water at elevated temperature to give a compound of formula XXXXVI; optionally reacting a compound of the formula XXXV with acetic acid in the presence of iron at elevated temperature to give a compound of formula XXXVI. a22) Reacting a compound of the formula XXXVI with sodium nitrite in the presence of an acid such as HC1 in water to give a product that is reacted with tin(II)chloride to give a compound of formula XXXVII.

In a still further aspect the present invention relates to a process of preparing a compound of formula XXXIX or a pharmaceutically acceptable salt or solvate thereof comprising the step a23 where A¹ is defined as above under formula 1 and X¹⁹ is a boronic acid or boronic ester;

a23) Reacting a compound of the formula XXXVIII wherein X¹⁸ is a halide such as bromine or iodine with bis(pinacolato)diboron in the presence of a catalyst such as Pd(dppf)C12 and a base such as potassium acetate in a solvent such as DMSO to give a compound of formula XXXIX; alternatively reacting a compound of the formula XXXVIII wherein X¹⁸ is a hydrogen with 2 -isopropoxy -4,4,5, 5-tetramethyl-l, 3,2- dioxaborolane in the presence of a base such as lithium diisopropylamide in a suitable solvent such as THF at -78 °C to give a compound of formula XXXIX.

In a still further aspect the present invention relates to a process of preparing a compound of formula XXXXI or a pharmaceutically acceptable salt or solvate thereof comprising the step a24 where A¹ is defined as above under formula 1 and X²¹ is a halide;

a24) Reacting a compound of the formula XXXX wherein X²⁰ is a hydrogen with a halogenating agent such as 7V-bromosuccinimide or 7V-iodosuccinimide in an inert solvent such as THF or DMF to give a compound of formula XXXXI; alternatively reacting a compound of the formula XXXX wherein X²⁰ is a hydrogen with a halogenating agent such as 7V-bromosuccinimide in concentrated sulfuric acid at elevated temperature to give a compound of formula XXXXI; alternatively reacting a compound of the formula XXXX wherein X²⁰ is a hydrogen with a reagent such as iodine in the presence of w-butyllitium in a suitable solvent such as THF at temperatures ranging from -78 °C to room temperature to give a compound of formula XXXXI; alternatively reacting a compound of the formula XXXX wherein X²⁰ is a nitro group with isopentyl nitrite and CuBr2 in an inert solvent such as acetonitrile to give a compound of formula XXXXI.

In a still further aspect the present invention relates to a process of preparing a compound of formula XXXXIV or a pharmaceutically acceptable salt or solvate thereof comprising the steps a25-a26 where X²³- X²⁶ are independently selected from the group of substituents for the benzothiazolyl defined above under A¹ b) in formula 1;

a25) Reacting a compound of the formula XXXXII wherein X²² is a hydrogen with benzyltrimethylammonium tribromide and ammonium thiocyanate in an inert solvent such as acetonitrile to give a compound of formula XXXXIII; alternatively reacting a compound of the formula XXXXII wherein X²² is a hydrogen with bromine and potassium thiocyanate in a suitable solvent such as acetic acid to give a compound of formula XXXXIII; alternatively reacting a compound of the formula XXXXII wherein X²² is a nitro group with NaNCh in the presence of an acid such as sulfuric acid in water at -5 °C to give a product which is further reacted with copper(I) thiocyanate and potassium thiocyanate in water to give a compound of formula XXXXIII. a26) Reacting a compound of the formula XXXXIII with isoamyl nitrite in an inert solvent such as THF or DMF to give a compound of formula XXXXIV.

In a still further aspect the present invention relates to a process of preparing a compound of formula IL or a pharmaceutically acceptable salt or solvate thereof comprising the steps a27-a30 where X²⁸- X³² are independently selected from the group of substituents for the benzothiazolyl defined above under A¹ b) in formula 1 and X²⁷ is a halide such as fluorine or bromine;

a27) Reacting a compound of the formula XXXXV with ammonium chloride in the presence of iron in a solvent mixture such as ethanol/water at elevated temperature to give a compound of formula XXXXVI. a28) Reacting a compound of the formula XXXXVI with a compound of the formula O

using a base such as DIPEA in an inert solvent such as DCM to give a compound of formula XXXXVII. a29) Reacting a compound of the formula XXXXVII with Lawesson’s reagent in a suitable solvent such as toluene at elevated temperature to give a compound of formula XXXXVIII. a30) Reacting a compound of the formula XXXXVIII in the presence of a copper salt such as Cui and a reagent such as 1,10-phenanthroline in a suitable solvent such as 1,2-dimethoxy ethane optionally at elevated temperature to give a compound of formula IL. In a still further aspect the present invention relates to a process of preparing a compound of formula XXXII or a pharmaceutically acceptable salt or solvate thereof comprising the step a31 where A¹ is defined as above under formula 1;

a31) Reacting a compound of the formula L wherein X³³ is a hydrogen with tert-butyl ethylmal onate in the presence of a base such as sodium hydride in a solvent such as 1- methyl-2-pyrrolidinone at temperatures below 20 °C to give an intermediate which is further reacted with a base such as sodium hydroxide in a suitable solvent mixture such as methanol/water to give a compound of formula XXXII; alternatively reacting a compound of the formula L wherein X³³ is a halide such as iodine with ethyl malonate in the presence of 2-phenylphenol, a copper salt such as Cui and a base such as cesium carbonate in a suitable solvent such as THF at elevated temperature to give an intermediate which is further reacted with a base such as sodium hydroxide in a suitable solvent mixture such as ethanol/water to give a compound of formula XXXII.

In a still further aspect the present invention relates to a process of preparing a compound of formula LIV or a pharmaceutically acceptable salt or solvate thereof comprising the steps a32-a34 where A¹ is defined as above under formula 1;

a32) Reacting a compound of the formula LI wherein X³⁴ is a hydrogen with potassium nitrate in the presence of an acid such as H2SO4 at 0 °C to give a compound of formula LII. a33) Reacting a compound of the formula LII with acetic acid in the presence of iron at elevated temperature to give a compound of formula LIII. a34) Reacting a compound of the formula LIII with sodium nitrite in the presence of an acid such as HC1 in water at 0 °C to give a product that is reacted with a reagent such as potassium iodide to give a compound of formula LIV wherein X³⁵ is a halide such as iodine.

In a still further aspect the present invention relates to a process of preparing a compound of formula LVI or a pharmaceutically acceptable salt or solvate thereof comprising the step a35 where B¹ is defined as above under formula 1;

a35) Reacting a compound of the formula LV wherein X³⁶ is a hydrogen with potassium nitrate in the presence of an acid such as H2SO4 at 0 °C to give a compound of formula LVI; alternatively reacting a compound of formula LV wherein X³⁶ is a hydrogen with ammonium nitrate in the presence of trifluoroacetic anhydride in an inert solvent such as DCM to give a compound of formula LVI.

In a still further aspect the present invention relates to a process of preparing a compound of formula LX or a pharmaceutically acceptable salt or solvate thereof comprising the steps a36-a38 where B¹ is defined as above under formula 1;

a36) Reacting a compound of the formula LVII wherein X³⁷ is a halide such as bromine or iodine with bis(pinacolato)diboron in the presence of a catalyst such as Pd(dppf)C12 and a base such as potassium acetate in a solvent such as DMSO to give a compound of formula LVIII. a37) Reacting a compound of the formula LVIII with hydrogen peroxide in the presence of a base such as sodium hydroxide in a suitable solvent such as THF at 0 °C to give a compound of formula LIX. a38) Reacting a compound of the formula LIX with an alkylhalide such as iodomethane in the presence of a base such as potassium carbonate in a suitable solvent such as DMF to give a compound of formula LX wherein X³⁸ is an alkyl such as methyl.

In a still further aspect the present invention relates to a process of preparing a compound of formula LXII or a pharmaceutically acceptable salt or solvate thereof comprising the step a39 where B¹ is defined as above under formula 1;

a39) Reacting a compound of the formula LXI wherein X³⁹ is a halide such as fluorine or bromine with a sodium alkyl thiolate such as NaSMe in a suitable solvent such as DMF or 1,4-di oxane to give a compound of formula LXII wherein X⁴⁰ is an alkyl such as methyl. In a still further aspect the present invention relates to a process of preparing a compound of formula LXIV or a pharmaceutically acceptable salt or solvate thereof comprising the step a40 where A1, R1 and B1 are defined as above under formula 1;

a40) Reacting a compound of the formula LXIII wherein X41 is a protective group such as a boc-group, X42 and X43 together form a protective group such as benzylidene with a compound of the formula V

in the presence of an acid such as HCl in a suitable solvent such as EtOH, optionally at elevated temperature to give an intermediate. This intermediate is reacted with acetic anhydride in the presence of pyridine to give a compound of formula LXIV. In a still further aspect the present invention relates to a process of preparing a compound of formula LXVI or a pharmaceutically acceptable salt or solvate thereof comprising the step a41 where B1 is defined as above under formula 1;

a41) Reacting a compound of the formula LXV with a halogenating reagent such as CuBr and CuBr2 in the presence of tert-butyl nitrite in a suitable solvent such as MeCN optionally at elevated temperature to give a compound of formula LXVI wherein X44 is a halide such as bromine. In a still further aspect the present invention relates to a process of preparing a compound of formula LXVIII or a pharmaceutically acceptable salt or solvate thereof comprising the step a42 where B1 is defined as above under formula 1;

a42) Reacting a compound of the formula LXVII wherein X⁴⁵ is a halide such as bromine with a reagent such as 2,4,6-trimethyl-l,3,5,2,4,6-trioxatriborinane in the presence of a catalyst such as Pd(dppf)C12 and a base such as K2CO3 in a suitable solvent such as DMF/water optionally at elevated temperature to give a compound of formula LXVIII wherein X⁴⁶ is an alkyl such as methyl.

In a still further aspect the present invention relates to a process of preparing a compound of formula LXX or a pharmaceutically acceptable salt or solvate thereof comprising the step a43 where B¹ is defined as above under formula 1;

a43) Reacting a compound of the formula LXIX wherein X⁴⁷ is a hydrogen with a halogenating agent such as 7V-bromosuccinimide in an inert solvent such as DMF to give a compound of formula LXX wherein X⁴⁸ is a halide such as bromine.

In a still further aspect the present invention relates to a process of preparing a compound of formula LXXIV or a pharmaceutically acceptable salt or solvate thereof comprising the steps a44-a46 where X⁴⁹- X⁵² are independently selected from the group of substituents for the benzothiazolyl defined above under B¹ in formula 1;

a44) Reacting a compound of the formula LXXI with a compound of the formula

optionally using a base such as DIPEA in an inert solvent such as DMF to give a compound of formula LXXII; alternatively reacting a compound of formula

LXXI with a compound of the formula

using a base such as pyridine optionally at elevated temperature to give a compound of formula LXXII. a45) Reacting a compound of the formula LXXII with a reagent such as Lawesson's reagent P2S5 or in a suitable solvent such as toluene at elevated temperature to give a compound of formula LXXIII. a46) Reacting a compound of the formula LXXIII in the presence of a copper salt such as Cui and a reagent such as 1,10-phenanthroline in the presence of a base such as CS2CO3 in a suitable solvent such as 1,2-dimethoxy ethane optionally at elevated temperature to give a compound of formula LXXIV; alternatively reacting a compound of formula LXXIII with Pd2(dba)s and 4,5-bis(diphenylphosphino)-9,9- dimethylxanthene in the presence of a base such as CS2CO3 in a solvent such as 1,4- dioxane at elevated temperature to give a compound of formula LXXIV.

In a still further aspect the present invention relates to a process of preparing a compound of formula LXXVII or a pharmaceutically acceptable salt or solvate thereof comprising the steps a47-a48 where X⁵³- X⁵⁵ are independently selected from the group of substituents for the benzothiazolyl defined above under B¹ in formula 1;

^LXXV LXXVI LXXVII a47) Reacting a compound of the formula LXXV with benzoyl isothiocyanate in a suitable solvent such as MeCN to give a product that is reacted further with aqueous NaOH at elevated temperature to give a compound of formula LXXVI. a48) Reacting a compound of the formula LXXVI with Br2 in an inert solvent such as CHCI3 at elevated temperature to give a product that is reacted further with isoamyl nitrite in an inert solvent such as THF to give a compound of formula LXXVII.

In a still further aspect the present invention relates to a process of preparing a compound of formula LXXIX or a pharmaceutically acceptable salt or solvate thereof comprising the step a49 where A¹ is defined as above under formula 1;

a49) Reacting a compound of the formula LXXVIII wherein X⁵⁶ is a halide such as fluorine with ammonia in a suitable solvent such as MeOH to give a compound of formula LXXIX.

In a still further aspect the present invention relates to a process of preparing a compound of formula LXXXII or a pharmaceutically acceptable salt or solvate thereof comprising the steps a50-a51 where A¹ is defined as above under formula 1;

a50) Reacting a compound of the formula LXXX wherein X⁵⁷ is a halide such as bromine with potassium hydroxide in the presence of a catalyst such as Pd2(dba)s and a reagent such as 2-di-/c/7-butylphosphino-3,4,5,6-tetramethyl-2',4',6'-triisopropyl- l,l'-biphenyl in a solvent such as 1,4-dioxane/water at elevated temperature to give a compound of formula LXXXI. a51) Reacting a compound of the formula LXXXI with an alkylhalide such as iodomethane in the presence of a base such as K2CO3 in a suitable solvent such as DMF to give a compound of formula LXXXII wherein X⁵⁸ is an alkyl such as methyl.

In a still further aspect the present invention relates to a process of preparing a compound of formula LXXXIV or a pharmaceutically acceptable salt or solvate thereof comprising the step a52 where A¹ is defined as above under formula 1;

a52) Reacting a compound of the formula LXXXIII wherein X⁵⁹ is a halide such as bromine with a reagent such as methylboronic acid in the presence of a catalyst such as Pd(dppf)C12 and a base such as K2CO3 in a suitable solvent such as 1,4-dioxane/water optionally at elevated temperature to give a compound of formula LXXXIV wherein X⁶⁰ is an alkyl such as methyl.

In a still further aspect the present invention relates to a process of preparing a compound of formula LXXXVII or a pharmaceutically acceptable salt or solvate thereof comprising the steps a53-a54 where B¹ is defined as above under formula 1;

LXXXV LXXXVI LXXXVII a53) Reacting a compound of the formula LXXXV with sodium nitrite in the presence of an acid such as HC1 in water to give a product that is reacted with methyl 2-chloro- 3-oxobutanoate in the presence of sodium acetate in a suitable solvent such as ethanol to give a compound of formula LXXXVI. a54) Reacting a compound of the formula LXXXVI with ammonia in a suitable solvent such as THF or 1,4-di oxane to give a compound of formula LXXXVII. In a still further aspect the present invention relates to a process of preparing a compound of formula XVIII or a pharmaceutically acceptable salt or solvate thereof comprising the steps a55-a61 where A¹ and B¹ are defined as above under formula 1, X⁶¹ and X⁶² together form a protective group such as benzylidene and X⁶³ is a protective group such as methoxymethyl;

LXXXXIV XVIII a55) Reacting a compound of the formula LXXXVIII with bromo(m ethoxy )m ethane in the presence of a base such as sodium hydride in an inert solvent such as THF at 0 °C to give a compound of formula LXXXIX. a56) Reacting a compound of the formula LXXXIX with lithium hydroxide monohydrate in a suitable solvent such as water to give a compound of formula LXXXX. a57) Reacting a compound of the formula LXXXX with 2-chloro-l -methylpyridinium iodide in the presence of a base such as DIPEA and 4-(dimethylamino)pyridine in a solvent such as MeCN to give a product that is reacted with a compound of the formula LXXXVII

LXXXVII in the presence of an acid such as acetic acid in a solvent such as MeCN at 65 °C to give a compound of formula LXXXXI. a58) Reacting a compound of the formula LXXXXI with a reducing agent such as triphenylphosphine in an inert solvent such as THF and water optionally at elevated temperature to give a compound of formula LXXXXII. a59) Reacting a compound of the formula LXXXXII with V-Zc/V-butyl oxy carbonyl -3- (4-cyanophenyl)oxaziridine in an inert solvent such as DCM to give a compound of formula LXXXXIII. a60) Reacting a compound of the formula LXXXXIII with a compound of the formula V

V in the presence of an acid such as HC1 in a suitable solvent such as MeOH optionally at elevated temperature to give a compound of formula LXXXXIV. a61) Reacting a compound of the formula LXXXXIV with ammonia in a suitable solvent such as MeOH to give a compound of formula XVIII.

In a still further aspect the present invention relates to a process of preparing a compound of formula IC or a pharmaceutically acceptable salt or solvate thereof comprising the steps a62-a65 where B¹ is defined as above under formula 1, X⁶⁴ and X⁶⁵ together form a protective group such as benzylidene and X⁶⁶ is a protective group such as methoxymethyl;

a62) Reacting a compound of the formula LXXXXV with lithium hydroxide monohydrate in a suitable solvent such as THF and water to give a compound of formula LXXXXVI. a63) Reacting a compound of the formula LXXXXVI with diphenyl phosphoryl azide and 2-(trimethylsilyl)ethanol using a base such as DIPEA in a suitable solvent such as 1,4-di oxane optionally at elevated temperature to give a compound of formula LXXXXVII. a64) Reacting a compound of the formula LXXXXVII with TBAF in a suitable solvent such as THF optionally at elevated temperature to give a compound of formula LXXXXVIII. a65) Reacting a compound of the formula LXXXXVIII with a halogenating reagent such as CuBr/CuBr2 or diiodomethane in the presence of a reagent such as pentyl nitrite or /c/V-butyl nitrite in an inert solvent such as MeCN optionally at elevated temperature to give a compound of formula IC wherein X⁶⁶ is a halide such as bromine or iodine.

In a still further aspect the present invention relates to a process of preparing a compound of formula CII or a pharmaceutically acceptable salt or solvate thereof comprising the steps a66-a67 where B¹ is defined as above under formula 1, X⁶⁸ and X⁶⁹ together form a protective group such as benzylidene and X⁷⁰ is a protective group such as methoxymethyl;

a66) Reacting a compound of the formula C with a reagent such as 2,4,6- ethenylboroxin-pyridine complex in the presence of a catalyst such as Pd(dppf)C12 and a base such as K2CO3 in a suitable solvent such as 1,4-dioxane/water optionally at elevated temperature to give a compound of formula CI wherein X⁷¹ is an alkyl or an alkenyl such as vinyl. a67) Reacting a compound of the formula CI wherein X⁷¹ is an alkenyl such as vinyl with platinum(IV) oxide in an inert solvent such as THF to give a product that is reacted with triphenylphosphine in a suitable solvent such as THF/water optionally at elevated temperature to give a compound of formula CII wherein X⁷² is an alkyl such as ethyl.

Detailed Description of the invention

The present compounds of formula (1) differ from prior art compounds particularly in that the pyranose ring is P-D-galactopyranose and in that a pyrazole is linked to C3 carbon atom of the pyranose ring and a 1,2,4-triazole is linked to Cl carbon atom of the pyranose ring. The compounds of the present invention are novel P-D-galactopyranose compounds that unexpectedly have shown very high affinity and specificity for galectin-3 and 9 and are considered novel potent drug candidates.

In broad first aspect the present invention concerns a P-D-galactopyranose compound of formula (1)

wherein the pyranose ring is P-D-galactopyranose, and A¹, R¹ and B¹ are as defined above.

In an embodiment A¹ is selected from a phenyl substituted in one ortho carbon atom of the phenyl ring in relation to the covalent bond to the pyrazol ring with one group selected from one of F, Cl, Br, I, CN, C1-3 alkyl substituted with one to three F, or OC1-3 alkyl, optionally substituted with one to three F; and optionally substituted on one to four of the additional carbon atoms of the phenyl with a group independently selected from halogen; CN; OH; C2-4 alkenyl; an ethynyl; a spiro heterocycle; -COOH; -CONR^2aR^3a, wherein R^2aandR^3a are independently selected from hydrogen, C1-3 alkyl, and cyclopropyl, or R^2aandR^3a together with the nitrogen may form a heterocycloalkyl; C1-3 alkyl, optionally substituted with a F; C1-3 alkyl, optionally substituted with an ethynyl; cyclopropyl, optionally substituted with a F; OC1-3 alkyl, optionally substituted with a F; O-cyclopropyl, optionally substituted with a F; NR^4aR^5a, wherein R^4a and R^5a are independently selected from hydrogen, Ci- 3 alkyl and cyclopropyl; C(=O)-R^{l la}, wherein R^{l la} is selected from hydrogen and C1-3 alkyl; and R^6a-CONH- wherein R^6a is selected from C1-3 alkyl and cyclopropyl. In a further embodiment A¹ is selected from a phenyl substituted in one ortho carbon atom of the phenyl ring in relation to the covalent bond to the pyrazol ring with one group selected from one of F, Cl, Br, I, CN, CF3, OCH3 or OCF3; and optionally substituted on one or two of the additional carbon atoms of the phenyl with a group independently selected from halogen; CN; OH; C2-4 alkenyl; an ethynyl; a spiro heterocycle; -COOH; -CONR^2aR^3a, wherein R^2aandR^3a are independently selected from hydrogen, C1-3 alkyl, and cyclopropyl, or R^2aandR^3a together with the nitrogen may form a heterocycloalkyl; C1-3 alkyl, optionally substituted with a F; C1-3 alkyl, optionally substituted with an ethynyl; cyclopropyl, optionally substituted with a F; OC1-3 alkyl, optionally substituted with a F; O-cyclopropyl, optionally substituted with a F; NR^4aR^5a, wherein R^4a and R^5a are independently selected from hydrogen, Ci- 3 alkyl and cyclopropyl; C(=O)-R^{l la}, wherein R^{l la} is selected from hydrogen and C1-3 alkyl; and R^6a-CONH- wherein R^6a is selected from C1-3 alkyl and cyclopropyl. Typically, A¹ is

wherein the asterix * indicates the carbon atom of the phenyl ring that is covalently attached to the pyrazole; wherein R² is selected from F, Cl, Br, I, CN, C1-3 alkyl substituted with one to three F, or OC1-3 alkyl, optionally substituted with one to three F;

R³, R⁴, R⁵, and R⁶ are independently selected from a hydrogen; halogen; OH; CN; C2- 4 alkenyl; an ethynyl; a spiro heterocycle; -COOH; -CONR^2aR^3a, wherein R^2aandR^3a are independently selected from hydrogen, C1-3 alkyl, and cyclopropyl, or R^2aandR^3a together with the nitrogen may form a heterocycloalkyl; C1-3 alkyl, optionally substituted with a F; C1-3 alkyl, optionally substituted with an ethynyl; cyclopropyl, optionally substituted with a F; OC1-3 alkyl, optionally substituted with a F; O- cyclopropyl, optionally substituted with a F; NH2; NHCH3; N(CHs)2; and C1-3 alkyl- CONH-.

In a further embodiment R² is Cl and R³ to R⁶ are as defined above, typically, R³ is selected from H, halogen; C1-3 alkyl, optionally substituted with a F; C2-4 alkenyl; OC1-3 alkyl, optionally substituted with a F; R⁴ is selected from H, halogen; Ci-3 alkyl, optionally substituted with a F, such as methyl, ethyl, isopropoyl or CF3; C2-4 alkenyl, such as ethynyl; OC1-3 alkyl, optionally substituted with a F; R⁵ is H; and R⁶ is H.

In a still further embodiment R² is F and R³ to R⁶ are as defined above, typically, R³ is selected from H, halogen; C1-3 alkyl, optionally substituted with a F; C2-4 alkenyl; OC1-3 alkyl, optionally substituted with a F; R⁴ is selected from H, halogen; C1-3 alkyl, optionally substituted with a F, such as methyl, ethyl, isopropoyl or CF3; C2-4 alkenyl, such as ethynyl; OC1-3 alkyl, optionally substituted with a F; R⁵ is H; and R⁶ is H.

In a further embodiment R² is selected from OCH3, CF3, and F, R³ is H, R⁴ is selected from halogen, such as Cl; R⁵ is halogen, such as F; and R⁶ is H.

In a still further embodiment R² is F and R³ is F and R⁴ is selected from H, halogen; CN; C1-3 alkyl, optionally substituted with a F, such as methyl, ethyl, isopropoyl or CF3; C2-4 alkenyl, such as ethenyl, methylethenyl; OC1-3 alkyl, optionally substituted with a F; R⁵ is H; and R⁶ is H.

In a still further embodiment R² is F and R³ is F and R⁴ is selected from H, halogen, such as Cl; CN; C1-3 alkyl, optionally substituted with a F, such as methyl, ethyl, isopropyl or CF3; C2-4 alkenyl, such as ethenyl, methylethenyl; OC1-3 alkyl, optionally substituted with a F; R⁵ is selected from halogen; CN; OC1-3 alkyl, optionally substituted with a F, such as OCH3; OC1-3 alkyl, optionally substituted with a F; and R⁶ is H.

In a still further embodiment R² is F and R³ is F and R⁴ is selected from halogen, such as Cl; R⁵ is selected from OC1-3 alkyl, optionally substituted with a F, such as OCH3; and R⁶ is H.

In a still further embodiment R² is F and R³ is F and R⁴ is selected from halogen, such as Cl; R⁵ is H; and R⁶ is OC1-3 alkyl, optionally substituted with a F, such as OCH3.

In a further embodiment R² is F and R³ is F and R⁴ is selected from halogen, such as Cl; CN; C1-3 alkyl, optionally substituted with a F, such as methyl, ethyl, isopropyl or CF3; C2-4 alkenyl, such as ethenyl, methylethenyl; OC1-3 alkyl, optionally substituted with a F, such as OCH3 or OCF3; R⁵ is H; and R⁶ is H.

In a still further embodiment R² is F and R³ is selected from halogen, such as Cl and R⁴ is selected from halogen, such as Cl; R⁵ is H; and R⁶ is H. In a still further embodiment R² is Cl and R³ is selected from halogen, such as F and R⁴ is selected from halogen, such as Cl; R⁵ is H; and R⁶ is H.

In a still further embodiment R² is F and R³ is F and R⁴ is H; R⁵ is OC1-3 alkyl, optionally substituted with a F, such as OCH3; and R⁶ is H.

In a still further embodiment R² is F and R³ is F and R⁴ is selected from halogen, such as Cl; R⁵ is methyl or CN; and R⁶ is H.

In a further embodiment R² is OC1-3 alkyl, such as OCH3, and R³ to R⁶ are as defined above, typically, R³ is selected from H, halogen; C1-3 alkyl, optionally substituted with a F; C2-4 alkenyl; OC1-3 alkyl, optionally substituted with a F; R⁴ is selected from H, halogen; C1-3 alkyl, optionally substituted with a F; C2-4 alkenyl; OC1-3 alkyl, optionally substituted with a F; R⁵ is H; and R⁶ is H.

In a still further embodiment R² is C1-3 alkyl optionally substituted with a F, such as CF3, and R³ to R⁶ are as defined above, typically, R³ is selected from H, halogen; C1-3 alkyl, optionally substituted with a F; C2-4 alkenyl; OC1-3 alkyl, optionally substituted with a F; R⁴ is selected from H, halogen; C1-3 alkyl, optionally substituted with a F, such as methyl, ethyl, isopropoyl or CF3; C2-4 alkenyl, such as ethynyl; OC1-3 alkyl, optionally substituted with a F; R⁵ is H; and R⁶ is H.

In a still further embodiment R² is OC1-3 alkyl optionally substituted with a F, such as OCF3, and R³ to R⁶ are as defined above, typically, R³ is selected from H, halogen; C1-3 alkyl, optionally substituted with a F; C2-4 alkenyl; OC1-3 alkyl, optionally substituted with a F; R⁴ is selected from H, halogen; C1-3 alkyl, optionally substituted with a F, such as methyl, ethyl, isopropoyl or CF3; C2-4 alkenyl, such as ethynyl; OC1-3 alkyl, optionally substituted with a F; R⁵ is H; and R⁶ is H.

In a further embodiment A¹ is selected from a benzothiazolyl substituted with one to four groups independently selected from halogen; CN; C2-4 alkenyl; an ethynyl; a spiro heterocycle; -COOH; -CONR^2aR^3a, wherein R^2aandR^3a are independently selected from hydrogen, C1-3 alkyl, and cyclopropyl, or R^2aandR^3a together with the nitrogen may form a heterocycloalkyl; C1-3 alkyl, optionally substituted with a F; C1-3 alkyl, optionally substituted with an ethynyl; cyclopropyl, optionally substituted with a F; OC1-3 alkyl, optionally substituted with a F; O-cyclopropyl, optionally substituted with a F; NR^4aR^5a, wherein R^4a and R^5a are independently selected from hydrogen, C1-3 alkyl and cyclopropyl; C(=O)-R^{l la}, wherein R^{l la} is selected from hydrogen and C1-3 alkyl OH; and R^6a-CONH- wherein R^6a is selected from C1-3 alkyl and cyclopropyl. In a further embodiment A¹ is selected from a benzothiazolyl substituted with one to four groups independently selected from a halogen; CN; C2-4 alkenyl; an ethynyl; a spiro heterocycle; -COOH; -COOC1-3 alkyl; -CONH2; - CONHCH3; -CON(CH3)2; C1-3 alkyl, optionally substituted with a F; C1-3 alkyl, optionally substituted with an ethynyl; cyclopropyl, optionally substituted with a F; OC1-3 alkyl, optionally substituted with a F; O-cyclopropyl, optionally substituted with a F; NH₂; NHCH₃; N(CH₃)₂; and C1-3 alkyl-CONH-. Typically, A¹ is

wherein the asterix * indicates the carbon atom of the benzothiazol ring that is covalently attached to the pyrazole; wherein R¹⁵, R¹⁶, R¹⁷, and R¹⁸ are independently selected from a hydrogen; a halogen; CN; C2-4 alkenyl; an ethynyl; a spiro heterocycle; -COOH; -COOC1-3 alkyl; -CONH₂; -CONHCH3; -CON(CH₃)₂; C1-3 alkyl, optionally substituted with a F; C1-3 alkyl, optionally substituted with an ethynyl; cyclopropyl, optionally substituted with a F; OC1-3 alkyl, optionally substituted with a F; O-cyclopropyl, optionally substituted with a F; NH2; NHCH3; N(CH3)2; and C1-3 alkyl-CONH-. In a further embodiment at least one of R¹⁵ and R¹⁶ is halogen and the other is H or halogen, R¹⁷ is selected from H, NH2 and C1-3 alkyl, such as H or methyl; and R¹⁸ is H. Typically, R¹⁵ and R¹⁶ are halogen, such as F, and R¹⁷ is C1-3 alkyl, such as methyl; and R¹⁸ is H.

In a further embodiment A¹ is

wherein the asterix * indicates the carbon atom of the benzothiazol ring that is covalently attached to the pyrazole; wherein R¹⁹, R²⁰, R²¹, and R²² are independently selected from a hydrogen; a halogen; CN; C2-4 alkenyl; an ethynyl; a spiro heterocycle; -COOH; -COOC1-3 alkyl; -CONH₂; -CONHCH3; -CON(CH₃)₂; C1-3 alkyl, optionally substituted with a F; C1-3 alkyl, optionally substituted with an ethynyl; cyclopropyl, optionally substituted with a F; OC1-3 alkyl, optionally substituted with a F; O-cyclopropyl, optionally substituted with a F; NH2; NHCH3; N(CHS)2; and C1-3 alkyl-CONH-. In a further embodiment R¹⁹ is selected from H or halogen, such as H or F; R²⁰ is selected from H or halogen, such as F; R²¹ is selected from H and C1-3 alkyl, such as H; and R²² is H.

In a still further embodiment A¹ is

wherein the asterix * indicates the carbon atom of the benzothiazol ring that is covalently attached to the pyrazole; wherein R²³, R²⁴, R²⁵, and R²⁶ are independently selected from a hydrogen; a halogen; CN; C2-4 alkenyl; an ethynyl; a spiro heterocycle; -COOH; -COOC1-3 alkyl; -CONH₂; -CONHCH3; -CON(CH₃)₂; C1-3 alkyl, optionally substituted with a F; C1-3 alkyl, optionally substituted with an ethynyl; cyclopropyl, optionally substituted with a F; OC1-3 alkyl, optionally substituted with a F; O-cyclopropyl, optionally substituted with a F; NFh; NHCH3; N(CH3)2; and C1-3 alkyl-CONH-. In a further embodiment R²³ is selected from H or halogen, such as H; R²⁴ is selected from H or halogen, such as F; R²⁵ is selected from H or halogen, such as H; and R²⁶ is H or methyl, such as H. In a further embodiment R²³ is selected from halogen, such as F; R²⁴ is selected from halogen, such as F; R²⁵ is selected from H; and R²⁶ is H or methyl, such as H. In a still further embodiment R²³ is selected from halogen, such as F; R²⁴ is selected from halogen, such as F; R²⁵ is selected from halogen, such as Cl; and R²⁶ is H.

In a further embodiment A¹ is

wherein the asterix * indicates the carbon atom of the benzothiazol ring that is covalently attached to the pyrazole; wherein R²⁷, R²⁸, R²⁹, and R³⁰ are independently selected from a hydrogen; a halogen; CN; C2-4 alkenyl; an ethynyl; a spiro heterocycle; -COOH; -COOC1-3 alkyl; -CONH₂; -CONHCH3; -CON(CH₃)₂; C1-3 alkyl, optionally substituted with a F; C1-3 alkyl, optionally substituted with an ethynyl; cyclopropyl, optionally substituted with a F; OC1-3 alkyl, optionally substituted with a F; O-cyclopropyl, optionally substituted with a F; NH2; NHCH3; N(CHS)2; and C1-3 alkyl-CONH-. In a further embodiment R²⁷ is selected from H or halogen, such as H; R²⁸ is selected from H or halogen, such as F; R²⁹ is selected from H or halogen, such as H; and R³⁰ is H or methyl, such as H. In a still further embodiment R²⁷ is selected from halogen, such as F; R²⁸ is selected from halogen, such as F; R²⁹ is selected from halogen, such as Cl; and R³⁰ is H.

In a still further embodiment A¹ is selected from a pyridinyl substituted in one ortho carbon atom of the pyridinyl ring in relation to the covalent bond to the pyrazol ring with one group selected from one of F, Cl, Br, I, CN, C1-3 alkyl substituted with one to three F, or OC1-3 alkyl, optionally substituted with one to three F; and optionally substituted on one to three of the additional carbon atoms of the pyridinyl ring with a group independently selected from halogen; CN; C2-4 alkenyl; an ethynyl; a spiro heterocycle; -COOH; -CONR^13aR^14a, wherein R^13aandR^14a are independently selected from H, C1-3 alkyl, and cyclopropyl, or R^13aandR^14a together with the nitrogen may form a heterocycloalkyl; C1-3 alkyl, optionally substituted with a F; C1-3 alkyl, optionally substituted with an ethynyl; cyclopropyl, optionally substituted with a F; OC1-3 alkyl, optionally substituted with a F; O-cyclopropyl, optionally substituted with a F; NR^15aR^16a, wherein R^15a and R^16a are independently selected from H, C1-3 alkyl and cyclopropyl; C(=O)-R^17a, wherein R^17a is selected from H and C1-3 alkyl OH; and R^18a-CONH- wherein R^18a is selected from C1-3 alkyl and cyclopropyl.

Typically, A¹ is

wherein the asterix * indicates the carbon atom of the pyridinyl ring that is covalently attached to the pyrazole; wherein R⁷ is selected from F, Cl, Br, I, CN, C1-3 alkyl substituted with one to three F, or OC1-3 alkyl, optionally substituted with one to three F; and R⁸, R⁹, and R¹⁰ are as defined above for the additional groups, typically independently selected from a halogen; CN; C2-4 alkenyl; an ethynyl; a spiro heterocycle; -COOH; -COOC1-3 alkyl; - CONH2; -CONHCH3; -CON(CH3)2; C1-3 alkyl, optionally substituted with a F; C1-3 alkyl, optionally substituted with an ethynyl; cyclopropyl, optionally substituted with a F; OC1-3 alkyl, optionally substituted with a F; O-cyclopropyl, optionally substituted with a F; NH2; NHCH3; N(CHs)2; and C1-3 alkyl-CONH-.

In an embodiment R⁷ is Cl and R⁸ to R¹⁰ are as defined above, typically, R⁸ is selected from H or halogen; R⁹ is selected from H or halogen; and R¹⁰ is H. In another embodiment R⁷ is selected from F and R⁸ to R¹⁰ are as defined above, typically, R⁸ is selected from H or halogen; R⁹ is selected from H or halogen; and R¹⁰ is H.

In a further embodiment A¹ is

wherein the asterix * indicates the carbon atom of the pyridinyl ring that is covalently attached to the pyrazole; wherein R¹¹ is selected from F, Cl, Br, I, CN, C1-3 alkyl substituted with one to three F, or OC1-3 alkyl, optionally substituted with one to three F; and R¹², R¹³, and R¹⁴ are as defined above for the additional groups, typically independently selected from a halogen; CN; C2-4 alkenyl; an ethynyl; a spiro heterocycle; -COOH; -COOC1-3 alkyl; - CONH2; -CONHCH3; -CON(CH3)2; C1-3 alkyl, optionally substituted with a F; C1-3 alkyl, optionally substituted with an ethynyl; cyclopropyl, optionally substituted with a F; OC1-3 alkyl, optionally substituted with a F; O-cyclopropyl, optionally substituted with a F; NFh; NHCH3; N(CHs)2; and C1-3 alkyl-CONH-.

In an embodiment R¹¹ is Cl and R¹² to R¹⁴ are as defined above, typically, R¹² is selected from H or halogen; R¹³ is selected from H or halogen; and R¹⁴ is H. In another embodiment R¹¹ is F and R¹² to R¹⁴ are as defined above, typically, R¹² is selected from H or halogen; R¹³ is selected from H or halogen; and R¹⁴ is H.

In a further embodiment B¹ is selected from the group consisting of phenyl, naphthalinyl, biphenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, quinoxainyl, indolyl, indazolyl, benzimidazolyl, benzisoxazolyl, benzisothiazolyl, benzoxazolyl, benzothiazolyl, benzodi oxolyl, dihydrobenzodioxinyl, dihydroquinolinonyl, dihydrobenzothiophene-2,2-dioxide, pyrrolyl, furanyl, thiazolo[4,5-b]pyridinyl, thienyl, pyrazolyl, isoxazolyl, isothiazolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, or thiadiazolyl; optionally substituted with one or more substituents selected from the group consisting of cyano, nitro, OH, C2- alkynyl, halogen, Ci-6 alkyl, halo-Ci-6 alkyl, C3-6 cycloalkyl, C1-6 alkoxy, halo-Ci-6 alkoxy, C1-6 alkylthio, carboxy, C1-6 alkoxycarbonyl, CONH2, and (R^19a)(R^20a)N wherein R^19a is selected from hydrogen, C1-6 alkyl, C1-6 alkylcarbonyl, or C1-6 alkylsulfonyl and R^20a is selected from hydrogen or C1-6 alkyl, or (R^19a)(R^20a)N taken together is any one of azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, optionally substituted with one or more substituents selected from halogen, C1-6 alkyl, and C1-6 alkylcarbonyl.

In a still further embodiment B¹ is selected from the group consisting of (C1-6 alkyl-SO2)phenyl, (C1-6 alkyl SO2)(halo)phenyl, (aminoSO2)phenyl, (di-Ci-6 alkylaminoSO2)phenyl, ((C1-6 alkyl-NHSO2)-Ci-6 alkyl )phenyl, (pyrrolyl)phenyl, (imidazolyl)phenyl, (oxazolyl)phenyl, (tetrazolyl)phenyl, ((pyridinyl)methyl)phenyl, phenoxy phenyl, (benzyl oxy )phenyl, ((methyl)thiazolyl)-phenyl, (thiazolyl)- benzenesulfamido, ((methyl)thiadiazolyl)benzenesulfamido, (methyl)- benzothiazolonyl, or fluoropyrazolopyrimidinyl.

In a further embodiment B¹ is selected from phenyl optionally substituted with one to four substituents selected from the group consisting of halogen, C1-6 alkyl, and halo-Ci-6 alkyl. Typically, B¹ is selected from phenyl substituted with one or two substituents selected from the group consisting of halogen and CF3; such as phenyl substituted with two substituents selected from the group consisting of halogen and CF3; typically, phenyl substituted with one halogen, such as Cl or Br, and one CF3.

In another embodiment B¹ is selected from phenyl substituted with two substituents selected from the group consisting of halogen, CN, OCF3, C1-3 alkyl and C3-6 cycloalkyl.

In another embodiment B¹ is selected from phenyl substituted with two substituents selected from the group consisting of halogen and C1-3 alkyl, typically one halogen, such as Cl and one C1-3 alkyl such as methyl.

In another embodiment B¹ is selected from phenyl substituted with two substituents selected from the group consisting of halogen, CN, OCF3, C1-3 alkyl and C3-6 cycloalkyl optionally substituted with a methyl.

In another embodiment B¹ is selected from phenyl substituted with two substituents selected from the group consisting of halogen, CN, CF3, C1-3 alkyl and C3-6 cycloalkyl, such as one CF3, and one substituent selected from CN, C3-6 cycloalkyl (eg. cyclopropyl), C3-6 cycloalkyl substituted with one methyl (eg. 1- methylcyclopropyl) and C1-3 alkyl (eg. methyl).

In another embodiment B¹ is selected from phenyl substituted with two substituents selected from the group consisting of C1-6 alkyl, branched C3-6 alkyl, C3-6 cycloalkyl optionally substituted with a methyl, SCH3 and CF3. In one embodiment B¹ is selected from phenyl substituted with two substituents selected from one SCH3 and one CF3.

In another embodiment B¹ is selected from phenyl substituted with three substituents selected from the group consisting of halogen and CF3; such as phenyl substituted with one CF3 and two substituents selected from halogen, such as one Cl and one F, one Br and one F, or two Cl; typically, phenyl substituted with two halogens selected from F, Cl or Br, and one CF3.

In another embodiment B¹ is selected from phenyl substituted with three substituents selected from the group consisting of C1-3 alkyl, CN, halogen and CF3; such as one CF3, one halogen, such as Cl and one C1-3 alkyl such as methyl. In a further embodiment B¹ is selected from phenyl substituted with three substituents selected from the group consisting of CN, halogen eg. Cl and CF3; typically, one CN, one halogen eg. Cl and one CF3.

In a still further embodiment B¹ is selected from the group consisting of pyridinyl substituted with one to three substituents selected from the group consisting of halogen, C1-6 alkyl, C1-6 alkylthio, CONH2, CONH(CH3), CON(CH3)2, and halo-Ci- 6 alkyl. In a still further embodiment B¹ is selected from the group consisting of pyridinyl substituted with one to three substituents selected from the group consisting of halogen, C1-6 alkyl, and halo-Ci-6 alkyl. Typically, B¹ is selected from pyridinyl substituted with one or two substituents selected from the group consisting of halogen and CF3; such as pyridinyl substituted with two substituents selected from the group consisting of halogen and CF3; typically, pyridinyl substituted with one halogen, such as Cl or Br, and one CF3.

In a still further embodiment B¹ is selected from the group consisting of pyridinyl substituted with three substituents selected from the group consisting of halogen, such as Br, Ci-6 alkyl, such as methyl, Ci-6 alkylthio and halo-Ci-6 alkyl, such as CF3.

In a still further embodiment B¹ is selected from the group consisting of pyridinyl substituted with two substituents selected from the group consisting of halogen such as Cl, CONH2, CONH(CH3), and CON(CH3)2. Typically, one halogen, such as Cl, and one of CONH(CH3) and CON(CH3)2.

In another embodiment B¹ is selected from pyridinyl substituted with one or two substituents selected from the group consisting of C1-3 alkyl and CF3; such as pyridinyl substituted with two substituents selected from the group consisting of methyl and CF3; typically, pyridinyl substituted with one methyl and one CF3.

In another embodiment B¹ is selected from pyridinyl substituted with two substituents selected from the group consisting of C1-3 alkyl, SCH3 and CF3; such as pyridinyl substituted with two substituents selected from the group consisting of methyl, ethyl, SCH3 and CF3; typically, pyridinyl substituted with one methyl and one CF3, or typically, pyridinyl substituted with one ethyl and one CF3, or typically, pyridinyl substituted with one SCH3 and one CF3.

In another embodiment B¹ is selected from pyridinyl substituted with two substituents selected from the group consisting of OCF3, C3-4 cycloalkyl and halogen;

In a further embodiment B¹ is selected from the group consisting of benzothiazolyl substituted with one to four substituents selected from the group consisting of halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, CN, C1-6 alkylsulfonyl and halo-Ci-6 alkyl. Typically, B¹ is selected from the group consisting of benzothiazolyl substituted with one to four substituents selected from the group consisting of halogen, C1-6 alkyl, and halo-Ci-6 alkyl. Typically, B¹ is selected from benzothiazolyl substituted with one C1-6 alkyl, such as methyl. Typically, B¹ is selected from benzothiazolyl substituted with one C1-6 alkyl, such as methyl and one halogen, such as F or Br. In a further embodiment, B¹ is selected from benzothiazolyl substituted with one C1-6 alkyl, such as methyl and one CN. In a still further embodiment, B¹ is selected from benzothiazolyl substituted with two C1-6 alkyl, such as two methyls. In a further embodiment, B¹ is selected from benzothiazolyl substituted with one C1-6 alkyl, such as methyl, and one substituent selected from halogen, such as F or Br, C1-6 alkoxy, such as OCH3, C1-6 alkylthio, such as SCH3, Ci- 6 alkylsulfonyl, such as methylsulfonyl, and halo-Ci-6 alkyl, such as CF3. In a further embodiment B¹ is selected from the group consisting of benzothiazolyl substituted with one or two substituents selected from the group consisting of halogen, Ci-6 alkyl, CN, and halo-Ci-6 alkyl.

In a still embodiment R¹ is selected from H, C1-3 alkyl, CN, halogen, C2-4 alkenyl, and C1-3 alkyl substituted with one to three halogen. In one embodiment R¹ is H. In another embodiment R¹ is C1-3 alkyl. Typically, R¹ is methyl.

In a further aspect the present invention concerns a P-D-galactopyranose compound of formula (1) selected from any one of the exemplified compounds of examples 1-33, or a pharmaceutically acceptable salt thereof.

In a further aspect the present invention concerns a P-D-galactopyranose compound of formula (1) selected from any one of the exemplified compounds of examples 34-61, or a pharmaceutically acceptable salt thereof.

In a further aspect the present invention concerns a P-D-galactopyranose compound of formula (1) selected from any one of the exemplified compounds of examples 62-98, or a pharmaceutically acceptable salt thereof.

The skilled person will understand that it may be necessary to adjust or change the order of steps in the processes al-a67, and such change of order is encompassed by the aspects of the process as described above in the reaction schemes and accompanying description of the process steps.

Furthermore, the skilled person will understand that the processes described above and hereinafter the functional groups of intermediate compounds may need to be protected by protecting groups.

Functional groups that it is desirable to protect include hydroxy, amino and carboxylic acid. Suitable protecting groups for hydroxy include optionally substituted and/or unsaturated alkyl groups (e.g. methyl, allyl, benzyl or tert-butyl), trialkyl silyl or diarylalkylsilyl groups (e.g. t-butyldimethylsilyl, t-butyldipheylsilyl or trimethyl silyl), AcO(acetoxy), TBS(t-butyldimethylsilyl), TMS(trimethylsilyl), PMB (p-methoxybensyl), and tetrahydropyranyl. Suitable proteting groups for carboxylic acid include (Ci-e)-alkyl or benzyl esters. Suitable protecting groups for amino include t-butyloxycarbonyl, benzyloxycarbonyl, 2-(trimethylsilyl)-ethoxy-methyl or 2- trimethylsilylethoxy carbonyl (Teoc). Suitable protecting groups for S include S- C(=N)NH₂, TIPS. The protection and deprotection of functional groups may take place before or after any reaction in the above-mentioned processes.

Furthermore the skilled person will appreciate, that, in order to obtain compounds of the invention in an alternative, and on some occasions more convenient manner, the individual process steps mentioned hereinbefore may be performed in different order, and/or the individual reactions may be performed at a different stage in the overall route (i.e. substituents may be added to and/or chemical transformations performed upon, different intermediates to those mentioned hereinbefore in conjunction with a particular reaction). This may negate, or render necessary, the need for protecting groups.

In a still further embodiment the compound (1) is on free form. “On free form” as used herein means a compound of formula (1), either an acid form or base form, or as a neutral compound, depending on the substitutents. The free form does not have any acid salt or base salt in addition. In one embodiment the free form is an anhydrate. In another embodiment the free form is a solvate, such as a hydrate.

In a further embodiment the compound of formula (1) is a crystalline form. The skilled person may carry out tests in order to find polymorphs, and such polymorphs are intended to be encompassed by the term “crystalline form” as used herein.

Whenever a “compound of formula (1)” is used herein it means the compound of formula (1) in any form incl the free form or as a salt thereof, such as a pharmaceutically acceptable salt thereof, unless otherwise indicated herein or clearly contradicted by context.

When the compounds and pharmaceutical compositions herein disclosed are used for the above treatment, a therapeutically effective amount of at least one compound is administered to a mammal in need of said treatment.

The term “Ci-_X alkyl” as used herein means an alkyl group containing 1-x carbon atoms, e.g. C1-5 or C1-6, such as methyl, ethyl, propyl, butyl, pentyl or hexyl.

The term “C1-3 alkyl” as used herein means an alkyl group containing 1-3 carbon atoms, e.g. methyl, ethyl, propyl, iso-propyl. The term “C2-4 alkenyl” as used herein means an alkenyl group containing one double bond and optionally one, two or three methyl substituents, such as -CH=CH2, - C(CH₃)=CH₂, -CH=CH-CH₃, -C(CH₃)=CH-CH₃.

The term “branched C₃-6 alkyl” as used herein means a branched alkyl group containing 3-6 carbon atoms, such as isopropyl, isobutyl, tert-butyl, isopentyl, 3- methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 2,2-dimethylbutyl, 2,3- dimethylbutyl.

The term “C_3.x cycloalkyl” as used herein means a cyclic alkyl group containing 3-x carbon atoms, e.g. C₃-6 or C₃-7, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

The term “C5-7 cycloalkyl” as used herein means a cyclic alkyl group containing 5-7 carbon atoms, such as cyclopentyl, cyclohexyl, or cycloheptyl.

The term “Oxo” as used herein means an oxygen atom with double bonds, also indicated as =0.

The term “CN” as used herein means a nitril.

The term “halogen” as used herein means Cl, F, Br or I.

The term “hydrogen” or “H” as used herein covers hydrogen isotopes, such as ¹ H and ²H (also known as deuterium).

The term “halo-Ci-6 alkyl” as used herein means one or more halogens linked to a C1-6 alkyl, such as CF₃, CH(C1)CHF2.

The term “C1-6 alkoxy” as used herein means an oxygen linked to a C1-6 alkyl, such as methoxy or ethoxy.

The term “C1-6 alkylthio” as used herein means a sulphur linked to a C1-6 alkyl, such as thiomethoxy or thioethoxy.

The term “halo-Ci-6 alkoxy” as used herein means one or more halogens linked to a C1-6 alkoxy, such as CH(F2)CH(Br)O-.

The term “C1-6 alkoxycarbonyl” as used herein means a C1-6 alkoxy linked to a carbonyl, such as methoxycarbonyl (CH2OC(=O)).

The term “a five or six membered heteroaromatic ring” as used herein means one five membered heteroaromatic ring or one six membered heteroaromatic ring. The five membered heteroaromatic ring contains 5 ring atoms of which one to four are heteroatoms selected from N, O, and S. The six membered heteroaromatic ring contains 6 ring atoms of which one to five are heteroatoms selected from N, O and S. Examples include thiophene furan pyran pyrrole imidazole, pyrazole, isothiazole, isooxazole, pyridine, pyrazine, pyrimidine and pyridazine. When such heteroaromatic rings are substituents they are termed thiophenyl, furanyl, pyranyl, pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, isooxazolyl, pyridinyl, pyrazinyl, pyrimidinyl and pyridazinyl. Also included are oxazoyl, thiazoyl, thiadiazoly, oxadiazoyl, and pyridonyl.

The term “a heterocycle, such as heteroaryl or heterocycloalkyl” as used herein means a ring system consisting of one or two 3-7 membered ring systems containing one or more heteroatoms and wherein such ring systems may optionally be aromatic. The term “a heteroaryl” as used herein means a cyclic aromatic ringsystem containing one or more heteroatoms, such as 1-10, e.g. 1-6, selected from O, S, and N, including but not limited to oxazolyl, oxadiazolyl, thiophenyl, thiadiazolyl, thiazolyl, pyridyl, pyrimidinyl, pyridonyl, pyrimidonyl, quinolinyl, azaquionolyl, isoquinolinyl, azaisoquinolyl, quinazolinyl, azaquinazolinyl, bensozazoyl, azabensoxazoyl, bensothiazoyl, or azabensothiazoyl. The term “a heterocycloalkyl” as used herein means an aliphatic ring system consisting of one or two 3-7 membered alifatic heterocycle containing one or more heteroatoms, such as 1-7, e.g. 1-5, selected from O, S, and N, including but not limited to piperidinyl, tetrahydropyranyl, tetrahydrothi pyranyl, or piperidonyl.

The term “a spiro heterocycle” as used herein means a two-ring system connected by a common carbon atom, and containing from 5 to 12 ring members wherein from 2 to 11 are carbon atoms and at least one is a heteroatom, such as a hetero atom selected from one or more N, S, O; one example is N-[2-oxa)-6- azaspiro [3.3] heptanyl.

The term “treatment” and “treating” as used herein means the management and care of a patient for the purpose of combating a condition, such as a disease or a disorder. The term is intended to include the full spectrum of treatments for a given condition from which the patient is suffering, such as administration of the active compound to alleviate the symptoms or complications, to delay the progression of the disease, disorder or condition, to alleviate or relief the symptoms and complications, and/or to cure or eliminate the disease, disorder or condition as well as to prevent the condition, wherein prevention is to be understood as the management and care of a patient for the purpose of combating the disease, condition, or disorder and includes the administration of the active compounds to prevent the onset of the symptoms or complications. The treatment may either be performed in an acute or in a chronic way. The patient to be treated is preferably a mammal; in particular, a human being, but it may also include animals, such as dogs, cats, cows, sheep and pigs.

The term “a therapeutically effective amount” of a compound of formula (1) of the present invention as used herein means an amount sufficient to cure, alleviate or partially arrest the clinical manifestations of a given disease and its complications. An amount adequate to accomplish this is defined as “therapeutically effective amount”. Effective amounts for each purpose will depend on the severity of the disease or injury as well as the weight and general state of the subject. It will be understood that determining an appropriate dosage may be achieved using routine experimentation, by constructing a matrix of values and testing different points in the matrix, which is all within the ordinary skills of a trained physician or veterinary.

In a still further aspect, the present invention relates to a pharmaceutical composition comprising the compound of formula (1) and optionally a pharmaceutically acceptable additive, such as a carrier or an excipient.

As used herein “pharmaceutically acceptable additive” is intended without limitation to include carriers, excipients, diluents, adjuvant, colorings, aroma, preservatives etc. that the skilled person would consider using when formulating a compound of the present invention in order to make a pharmaceutical composition.

The adjuvants, diluents, excipients and/or carriers that may be used in the composition of the invention must be pharmaceutically acceptable in the sense of being compatible with the compound of formula (1) and the other ingredients of the pharmaceutical composition, and not deleterious to the recipient thereof. It is preferred that the compositions shall not contain any material that may cause an adverse reaction, such as an allergic reaction. The adjuvants, diluents, excipients and carriers that may be used in the pharmaceutical composition of the invention are well known to a person skilled within the art.

As mentioned above, the compositions and particularly pharmaceutical compositions as herein disclosed may, in addition to the compounds herein disclosed, further comprise at least one pharmaceutically acceptable adjuvant, diluent, excipient and/or carrier. In some embodiments, the pharmaceutical compositions comprise from 1 to 99 % by weight of said at least one pharmaceutically acceptable adjuvant, diluent, excipient and/or carrier and from 1 to 99 % by weight of a compound as herein disclosed. The combined amount of the active ingredient and of the pharmaceutically acceptable adjuvant, diluent, excipient and/or carrier may not constitute more than 100% by weight of the composition, particularly the pharmaceutical composition.

In some embodiments, only one compound as herein disclosed is used for the purposes discussed above.

In some embodiments, two or more of the compounds as herein disclosed are used in combination for the purposes discussed above.

The composition, particularly pharmaceutical composition comprising a compound set forth herein may be adapted for oral, intravenous, topical, intraperitoneal, nasal, buccal, sublingual, or subcutaneous administration, or for administration via the respiratory tract in the form of, for example, an aerosol or an air-suspended fine powder. Therefore, the pharmaceutical composition may be in the form of, for example, tablets, capsules, powders, nanoparticles, crystals, amorphous substances, solutions, transdermal patches or suppositories.

Further embodiments of the process are described in the experimental section herein, and each individual process as well as each starting material constitutes embodiments that may form part of embodiments.

The above embodiments should be seen as referring to any one of the aspects (such as ‘method for treatment’, ‘pharmaceutical composition’, ‘compound for use as a medicament’, or ‘compound for use in a method’) described herein as well as any one of the embodiments described herein unless it is specified that an embodiment relates to a certain aspect or aspects of the present invention.

All references, including publications, patent applications and patents, cited herein are hereby incorporated by reference to the same extent as if each reference was individually and specifically indicated to be incorporated by reference and was set forth in its entirety herein.

All headings and sub-headings are used herein for convenience only and should not be construed as limiting the invention in any way.

Any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.

The terms “a” and “an” and “the” and similar referents as used in the context of describing the invention are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. The term “a” and “an” can be exchanged by “at least one” or “one or more” throughout the specification.

Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. Unless otherwise stated, all exact values provided herein are representative of corresponding approximate values (e.g., all exact exemplary values provided with respect to a particular factor or measurement can be considered to also provide a corresponding approximate measurement, modified by “about,” where appropriate).

All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context.

The use of any and all examples, or exemplary language (e.g., “such as”) provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise indicated. No language in the specification should be construed as indicating any element is essential to the practice of the invention unless as much is explicitly stated.

The citation and incorporation of patent documents herein is done for convenience only and does not reflect any view of the validity, patentability and/or enforceability of such patent documents.

The term “and/or” as used herein is intended to mean both alternatives as well as each of the alternatives individually. For instance, the expression “xxx and/or yyy” means “xxx and yyy”; “xxx”; or “yyy”, all three alternatives are subject to individual embodiments.

The description herein of any aspect or embodiment of the invention using terms such as “comprising”, “having”, “including” or “containing” with reference to an element or elements is intended to provide support for a similar aspect or embodiment of the invention that “consists of’, “consists essentially of’, or “substantially comprises” that particular element or elements, unless otherwise stated or clearly contradicted by context (e.g., a composition described herein as comprising a particular element should be understood as also describing a composition consisting of that element, unless otherwise stated or clearly contradicted by context). The present invention is further illustrated by the following examples that, however, are not to be construed as limiting the scope of protection. The features disclosed in the foregoing description and in the following examples may, both separately and in any combination thereof, be material for realizing the invention indiverse forms thereof.

Experimental procedures (Evaluation of Kd values)

The affinity of Examples 1-98 for galectins were determined by a fluorescence anisotropy assay where the compound was used as an inhibitor of the interaction between galectin and a fluorescein tagged saccharide probe as described Sbrme, P., Kahl -Knuts son, B., Huflejt, M., Nilsson, U. J., and Leffler H. (2004) Fluorescence polarization as an analytical tool to evaluate galectin-ligand interactions. Anal. Biochem. 334: 36-47, (Sbrme et al., 2004) and Monovalent interactions of Galectin-1 By Salomonsson, Emma; Larumbe, Amaia; Tejler, Johan; Tullberg, Erik; Rydberg, Hanna; Sundin, Anders; Khabut, Areej; Frejd, Torbjorn; Lobsanov, Yuri D.; Rini, James M.; et al, From Biochemistry (2010), 49(44), 9518-9532, (Salomonsson et al., 2010). Galectin 9C does only contain the CRD on the C terminus of Galectin 9.

Synthesis of Examples and intermediates

General experimental:

Nuclear Magnetic Resonance (NMR) spectra were recorded on a 400 MHz Bruker AVANCE III 500 instrument or a Varian instrument at 400 MHz, at 25 °C.

Chemical shifts are reported in ppm (d) using the residual solvent as internal standard. Peak multiplicities are expressed as follow: s, singlet; d, doublet; dd, doublet of doublets; t, triplet; dt, doublet of triplet; q, quartet; m, multiplet; br s, broad singlet. LC-MS were acquired on an Agilent 1200 HPLC coupled with an Agilent MSD mass spectrometer operating in ES (+) ionization mode. Column: Xbridge Cl 8 (4.6 x 50 mm, 3.5 pm) or SunFire C18 (4.6 x 50 mm, 3.5 pm). Solvent A water + 0.1% TFA and solvent B Acetonitrile + 0.1% TFA or solvent A water (10 mM Ammonium hydrogen carbonate) and solvent B Acetonitrile. Wavelength: 254 nM. Alternatively, LC-MS were acquired on an Agilent 1100 HPLC coupled with an Agilent MSD mass spectrometer operating in ES (+) ionization mode. Column: Waters symmetry 2.1 x 30 mm C18 or Chromolith RP-18 2 x 50 mm. Solvent A water + 0.1% TFA and solvent B Acetonitrile + 0.1% TFA. Wavelength 254 nm.

Preparative HPLC was performed on a Gilson 215. Flow: 25 mL/min Column: Xbrige prep C18 10 pm OBD (19 x 250 mm) column. Wavelength: 254 nM. Solvent A water (10 mM Ammonium hydrogen carbonate) and solvent B Acetonitrile. Alternatively, preparative HPLC were acquired on a Gilson system. Flow: 15 ml/min Column: kromasil 100-5-C18 column. Wavelength: 220 nm. Solvent A water + 0.1% TFA and solvent B Acetonitrile + 0.1% TFA.

The following abbreviations are used aq: aqueous

Calcd: Calculated

MeCN: Acetonitrile

CS2CO3: cesium carbonate

Cui: Copper Iodide

DCM: Dichloromethane

DIPEA: Diisopropylethylamine

DMF : N,N-dimethylformamide

ESI-MS: Electrospray ionization mass spectrometry

EtOAc or EA: Ethylacetate

EtsN: Tri ethylamine

EE: Hydrogen gas h: hour(s)

HPLC: High performance liquid chromatography

K2CO3: potassium carbonate

LC: Liquid Chromatography

MeCN: Acetonitrile mL: milliliter

MeOH: Methanol

MeOD: Deuterated methanol mm: millimeter mM: millimolar

MS: Mass spectroscopy nm: nanometer

NaOMe: Sodium methoxide

N2: Nitrogen gas

NMR: Nuclear magnetic resonance

Pd2(dba)3: tris(dibenzylideneacetone)dipalladium(0)

Pd(dppf)C12 : [1,1’ -bis(diphenylphosphino)ferrocene]dichloropalladium(II)

Pd(PPh3)4: tetrakis(triphenylphosphine)palladium(0) PE: petroleum ether pH: acidity

Prep: preparative rt: room temperature

TBAF: tetrabutylammonium fluoride

TFA: trifluoroacetic acid

THF: Tetrahydrofuran

TMS: Trimethyl silyl

UV: Ultraviolet

A: Angstrom

Synthesis of example 1-98 from their respective intermediates 1-98.

When naming examples and intermediates with aryl groups connected directly to Cl of the galactose unit the following methodology has been used. The highest priority has been given to the aryl furthest away from the galactose Cl, regardless of IUPAC rules.

Example 1

6- {5- {3-Deoxy-3- [4-(2,3-difluoro-4-methylphenyl)- 1H- 1 ,2-pyrazol- l-yl|-|l-D- galactopyranosyl}-3-methyl-lZ/-l,2,4-triazol-l-yl}-2-methylbenzothiazole

To a solution of 6-{5-{4,6-O-benzylidene-3-[(2-te/7-butoxycarbonyl)hydrazinyl]-3- deoxy-P-D-galactopyranosyl } -3 -methyl- 1H- 1 ,2,4-triazol- 1 -yl } -2 -methylbenzothiazole (60 mg, 0.10 mmol) in EtOH (5 mL) 3-(dimethylamino)-2-(2,3-difluoro-4- methylphenyl)prop-2-enal (27.3 mg, 0.12 mmol) and concentrated HC1 (0.2 mL) were added and the mixture was stirred 2 h at 80 °C. The mixture was concentrated and purified by prep HPLC [MeCN/H2O (10 mmol/L NH4HCO3), X-Select 10 pm 19*250 mm, 20 mL/min, UV 254] to afford the title compound (26 mg, 45 %). ESI-MS m/z calcd for [C₂₇H₂₆F₂N₆O₄S] [M+H]+: 569.2; found: 568.9.1H NMR (400 MHz, DMSO- d6) δ 8.44 (d, J = 2.0 Hz, 1H), 8.19 (s, 1H), 8.06 (d, J = 8.8 Hz, 1H), 7.93 (s, 1H), 7.75 (dd, J = 8.8, 2.4 Hz, 1H), 7.48 – 7.45 (m, 1H), 7.13 – 7.09 (m, 1H), 5.38 (d, J = 6.8 Hz, 1H), 5.16 (d, J = 6.0 Hz, 1H), 4.89 (t, J = 5.6 Hz, 1H), 4.83 (dd, J = 9.6, 7.6 Hz, 1H), 4.51 (dd, J = 10.4, 2.8 Hz, 1H), 4.40 (d, J = 9.2 Hz, 1H), 3.96 (dd, J = 6.0, 3.2 Hz, 1H), 3.77 – 3.74 (m, 1H), 3.61 – 3.55 (m, 1H), 3.53 – 3.47 (m, 1H), 2.86 (s, 3H), 2.40 (s, 3H), 2.28 (d, J = 1.2 Hz, 3H). Example 2 5-Chloro-1-{5-{3-deoxy-3-[4-(2,3-difluoro-4-methylphenyl)-1H-1,2-pyrazol-1-yl]- β-D-galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-2- (trifluoromethyl)benzene

To a solution of 1-{5-{3-[(2-tert-butoxycarbonyl)hydrazinyl]-3-deoxy-β-D- galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-5-chloro-2- (trifluoromethyl)benzene (23 mg, 0.037 mmol) in EtOH (2 mL) 3-(dimethylamino)-2- (2,3-difluoro-4-methylphenyl)prop-2-enal (13.2 mg, 0.059 mmol) and concentrated HCl (0.1 mL) were added and the mixture was stirred 2 h at 80 °C. The mixture was concentrated and purified by prep HPLC [MeCN/H2O (10 mmol/L NH4HCO3), X- Select 10 µm 19*250 mm, 20 mL/min, UV 254] to afford the title compound (4.65 mg, 21 %). ESI-MS m/z calcd for [C₂₆H₂₃ClF₅N₅O₄] [M+H]+: 600.1; found: 599.8.1H NMR (400 MHz, Methanol-d4) δ 8.20 (d, J = 1.2 Hz, 1H), 7.95 (d, J = 8.8 Hz, 1H), 7.92 (s, 1H), 7.85 (d, J = 8.8 Hz, 1H), 7.77 (br s, 1H), 7.36 – 7.30 (m, 1H), 7.02 (t, J = 7.2 Hz, 1H), 4.76 (br s, 1H), 4.40 (dd, J = 10.8, 2.8 Hz, 1H), 4.29 (d, J = 9.6 Hz, 1H), 4.09 (d, J = 2.8 Hz, 1H), 3.68 – 3.63 (m, 3H) , 2.44 (s, 3H), 2.29 (d, J = 2.0 Hz, 3H). Example 3 5-Chloro-1-{5-{3-deoxy-3-[4-(7-fluorobenzothiazol-5-yl)-1H-1,2-pyrazol-1-yl]-β- D-galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-2-(trifluoromethyl)benzene

To a solution of 5-chloro-1-{5-[3-deoxy-3-(4-iodo-1H-1,2-pyrazol-1-yl)-β-^D- galactopyranosyl]-3-methyl-1H-1,2,4-triazol-1-yl}-2-(trifluoromethyl)benzene (30 mg, 0.050 mmol) and 7-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3- benzothiazole (20.9 mg, 0.075 mmol) in 1,4-dioxane/H2O (3.0 mL, 2:1) Pd(dppf)Cl2 (7.3 mg, 0.010 mmol) and K₂CO₃ (20.7 mg, 0.15 mmol) were added. The mixture was purged three times with nitrogen, and stirred 2 h at 60 °C. The mixture was filtered, and the filtrate was acidified to pH 3-4 using TFA. The mixture was concentrated and purified by prep HPLC [MeCN/H2O (10 mmol/L TFA), X-Select 10 µm 19*250 mm, 20 mL/min, UV 254] to afford the title compound (6.5 mg, 21 %). ESI-MS m/z calcd for [C₂₆H₂₁ClF₄N₆O₄S] [M+H]+: 625.1; found: 624.8.1H NMR (400 MHz, DMSO-d₆) δ 9.47 (s, 1H), 8.42 (s, 1H), 8.25 (d, J = 0.8 Hz, 1H), 8.11 (s, 1H), 8.03 (d, J = 8.8 Hz, 1H), 7.94 (dd, J = 8.4, 1.2 Hz, 1H), 7.77 (s, 1H), 7.74 (d, J = 11.2 Hz, 1H), 5.36 (d, J = 6.8 Hz, 1H), 5.08 (d, J = 6.0 Hz, 1H), 4.81 – 4.69 (m, 1H), 4.63 (t, J = 5.6 Hz, 1H), 4.43 (dd, J = 10.8, 2.4 Hz, 1H), 4.24 (d, J = 9.2 Hz, 1H), 3.96 – 3.93 (m, 1H), 3.58 (t, J = 6.4 Hz, 1H), 3.48 – 3.38 (m, 2H), 2.37 (s, 3H). Example 4 5-Chloro-1-{5-{3-deoxy-3-[4-(7-fluoro-2-methylbenzothiazol-5-yl)-1H-1,2- pyrazol-1-yl]-β-D-galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-2- (trifluoromethyl)benzene

To a solution of 5-chloro-1-{5-[3-deoxy-3-(4-iodo-1H-1,2-pyrazol-1-yl)-β-D- galactopyranosyl]-3-methyl-1H-1,2,4-triazol-1-yl}-2-(trifluoromethyl)benzene (45 mg, 0.075 mmol) and 7-fluoro-2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)-1,3-benzothiazole (33.0 mg, 0.11 mmol) in 1,4-dioxane/H2O (6 mL, 5:1) Pd(dppf)Cl₂ (11.0 mg, 0.015 mmol) and K₂CO₃ (20.7 mg, 0.15 mmol) were added. The mixture was purged three times with nitrogen, and stirred 2 h at 60 °C. The mixture was filtered, and the filtrate was acidified to pH 3-4 using TFA. The mixture was concentrated and purified by prep HPLC [MeCN/H₂O (10 mmol/L TFA), X-Select 10 µm 19*250 mm, 20 mL/min, UV 254] to afford the title compound (22.0 mg, 46 %). ESI-MS m/z calcd for [C H ClF N O S] [M+H]+: 639.1; f 1 27 23 4 6 4 ound: 639.2. H NMR (400 MHz, DMSO-d₆) δ 8.38 (s, 1H), 8.08 (s, 1H), 8.06 (d, J = 1.2 Hz, 1H), 8.02 (d, J = 8.8 Hz, 1H), 7.94 (d, J = 8.4 Hz, 1H), 7.77 (br s, 1H), 7.64 (dd, J = 11.2, 1.2 Hz, 1H), 5.35 (d, J = 6.4 Hz, 1H), 5.07 (d, J = 6.0 Hz, 1H), 4.73 – 4.70 (m, 1H), 4.63 (t, J = 5.6 Hz, 1H), 4.42 (dd, J = 10.8, 2.8 Hz, 1H), 4.23 (d, J = 9.2 Hz, 1H), 3.94 (dd, J = 5.6, 2.4 Hz, 1H), 3.59 – 3.56 (m, 1H), 3.44 – 3.37 (m, 2H), 2.90 (s, 3H), 2.37 (s, 3H). Example 5 5-Chloro-1-{5-{3-deoxy-3-[4-(4-fluorobenzothiazol-6-yl)-1H-1,2-pyrazol-1-yl]-β- D-galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-2-(trifluoromethyl)benzene

To a solution of 5-chloro-1-{5-[3-deoxy-3-(4-iodo-1H-1,2-pyrazol-1-yl)-β-D- galactopyranosyl]-3-methyl-1H-1,2,4-triazol-1-yl}-2-(trifluoromethyl)benzene (58 mg, 0.097 mmol) and 4-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3- benzothiazole (40.5 mg, 0.15 mmol) in 1,4-dioxane/H₂O (4 mL, 3:1) Pd(dppf)Cl₂ (14.2 mg, 0.019 mmol) and K2CO3 (40.1 mg, 0.29 mmol) were added. The mixture was purged three times with nitrogen, and stirred 2 h at 60 °C. The mixture was filtered, and the filtrate was acidified to pH 3-4 using TFA. The mixture was concentrated and purified by prep HPLC [MeCN/H2O (10 mmol/L TFA), X-Select 10 µm 19*250 mm, 20 mL/min, UV 254] to afford the title compound (20.0 mg, 33 %). ESI-MS m/z calcd for [C₂₆H₂₁ClF₄N₆O₄S] [M+H]+: 625.1; found: 625.2.1H NMR (400 MHz, DMSO-d₆) δ 9.34 (s, 1H), 8.37 (s, 1H), 8.26 (d, J = 1.6 Hz, 1H), 8.05 – 8.03 (m, 2H), 7.94 (dd, J = 8.8, 1.6 Hz, 1H), 7.76 (s, 1H), 7.72 (dd, J = 12.4, 1.6 Hz, 1H), 5.34 (d, J = 6.8 Hz, 1H), 5.09 (d, J = 6.0 Hz, 1H), 4.74 – 4.71 (m, 1H), 4.63 (t, J = 5.6 Hz, 1H), 4.43 (dd, J = 10.8, 2.8 Hz, 1H), 4.23 (d, J = 9.2 Hz, 1H), 3.94 (dd, J = 5.6, 2.8 Hz, 1H), 3.59 – 3.56 (m, 1H), 3.47 – 3.37 (m, 2H), 2.37 (s, 3H). Example 6 5-Chloro-1-{5-{3-deoxy-3-[4-(5-fluorobenzothiazol-7-yl)-1H-1,2-pyrazol-1-yl]-β- ^D-galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-2-(trifluoromethyl)benzene

To a solution of 5-chloro-1-{5-[3-deoxy-3-(4-iodo-1H-1,2-pyrazol-1-yl)-β-D- galactopyranosyl]-3-methyl-1H-1,2,4-triazol-1-yl}-2-(trifluoromethyl)benzene (45 mg, 0.075 mmol) and 5-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3- benzothiazole (31.4 mg, 0.11 mmol) in 1,4-dioxane/H₂O (3.0 mL, 2:1) Pd(dppf)Cl₂ (11.0 mg, 0.015 mmol) and K2CO3 (31.1 mg, 0.23 mmol) were added. The mixture was purged three times with nitrogen, and stirred 2 h at 60 °C. The mixture was filtered, and the filtrate was acidified to pH 3-4 using TFA. The mixture was concentrated and purified by prep HPLC [MeCN/H₂O (10 mmol/L TFA), X-Select 10 µm 19*250 mm, 20 mL/min, UV 254] to afford the title compound (15.8 mg, 34 %). ESI-MS m/z calcd for [C₂₆H₂₁ClF₄N₆O₄S] [M+H]+: 625.1; found: 625.2.1H NMR (400 MHz, DMSO-d₆) δ 9.57 (s, 1H), 8.37 (s, 1H), 8.12 (d, J = 0.4 Hz, 1H), 8.04 (d, J = 8.8 Hz, 1H), 7.95 (dd, J = 8.4, 1.2 Hz, 1H), 7.83 (dd, J = 9.2, 2.4 Hz, 1H), 7.77 (s, 1H), 7.74 (dd, J = 10.4, 2.4 Hz, 1H), 5.46 (d, J = 6.4 Hz, 1H), 5.16 (d, J = 6.0 Hz, 1H), 4.78 – 4.68 (m, 1H), 4.66 (t, J = 5.6 Hz, 1H), 4.53 (dd, J = 10.8, 2.8 Hz, 1H), 4.26 (d, J = 8.8 Hz, 1H), 3.99 – 3.91 (m, 1H), 3.60 (t, J = 6.4 Hz, 1H), 3.49 – 3.41 (m, 2H), 2.37 (s, 3H). Example 7 5-Chloro-1-{5-{3-deoxy-3-[4-(6,7-difluorobenzothiazol-5-yl)-1H-1,2-pyrazol-1- yl]-β-D-galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-2- (trifluoromethyl)benzene

To a solution of 5-chloro-1-{5-[3-deoxy-3-(4-iodo-1H-1,2-pyrazol-1-yl)-β-D- galactopyranosyl]-3-methyl-1H-1,2,4-triazol-1-yl}-2-(trifluoromethyl)benzene (30 mg, 0.050 mmol) and 6,7-difluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 1,3-benzothiazole (29.7 mg, 0.10 mmol) in 1,4-dioxane/H₂O (3.0 mL, 2:1) Pd(dppf)Cl₂ (7.32 mg, 0.010 mmol) and K₂CO₃ (20.7 mg, 0.15 mmol) were added. The mixture was purged three times with nitrogen, and stirred 2 h at 60 °C. The mixture was filtered, and the filtrate was acidified to pH 3-4 using TFA. The mixture was concentrated and purified by prep HPLC [MeCN/H₂O (10 mmol/L NH₄HCO₃), X-Select 10 µm 19*250 mm, 20 mL/min, UV 254] to afford the title compound (15.2 mg, 47 %). ESI-MS m/z calcd for [C26H20ClF5N6O4S] [M+H]+: 643.1; found: 643.2. 1H NMR (400 MHz, Methanol-d₄) δ 9.25 (d, J = 1.6 Hz, 1H), 8.34 (d, J = 2.0 Hz, 1H), 8.20 (dd, J = 5.6, 1.6 Hz, 1H), 8.06 (d, J = 1.2 Hz, 1H), 7.96 (d, J = 8.8 Hz, 1H), 7.85 (dd, J = 8.4, 1.2 Hz, 1H), 7.77 (br s, 1H), 4.81 – 4.78 (m, 1H), 4.45 (dd, J = 10.8, 2.8 Hz, 1H), 4.31 (d, J = 9.2 Hz, 1H), 4.12 (d, J = 2.4 Hz, 1H), 3.69 – 3.64 (m, 3H), 2.45 (s, 3H). Example 8 1-{5-{3-[4-(4-Chloro-2,3-difluorophenyl)-1H-1,2-pyrazol-1-yl]-3-deoxy-β-D- galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-5-chloro-2- (trifluoromethyl)benzene

To a solution of 5-chloro-1-{5-[3-deoxy-3-(4-iodo-1H-1,2-pyrazol-1-yl)-β-^D- galactopyranosyl]-3-methyl-1H-1,2,4-triazol-1-yl}-2-(trifluoromethyl)benzene (35 mg, 0.058 mmol) and (4-chloro-2,3-difluorophenyl)boronic acid (22.5 mg, 0.12 mmol) in 1,4-dioxane/H₂O (3.0 mL, 2:1) Pd(dppf)Cl₂ (8.54 mg, 0.012 mmol) and K₂CO₃ (40.3 mg, 0.29 mmol) were added. The mixture was purged three times with nitrogen, and stirred 1 h at 60 °C. The mixture was filtered, and the filtrate was acidified to pH 3-4 using TFA. The mixture was concentrated and purified by prep HPLC [MeCN/H2O (10 mmol/L NH₄HCO₃), X-Select 10 µm 19*250 mm, 20 mL/min, UV 254] to afford the title compound (6.35 mg, 18 %). ESI-MS m/z calcd for [C₂₅H₂₀Cl₂F₅N₅O₄] [M+H]+: 620.1; found: 620.1.1H NMR (400 MHz, Methanol-d4) δ 8.26 (s, 1H), 7.96 – 7.94 (m, 2H), 7.85 (d, J = 8.0 Hz, 1H), 7.77 (s, 1H), 7.54 – 7.44 (m, 1H), 7.35 – 7.20 (m, 1H), 4.85 – 4.74 (m, 1H), 4.43 (dd, J = 11.2, 2.8 Hz, 1H), 4.29 (d, J = 9.2 Hz, 1H), 4.10 (d, J = 2.0 Hz, 1H), 3.66 (m, 3H), 2.44 (s, 3H). Example 9 5-Chloro-1-{5-{3-deoxy-3-[4-(2,3,4-trifluorophenyl)-1H-1,2-pyrazol-1-yl]-β-D- galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-2-(trifluoromethyl)benzene

To a solution of 1-{5-{4,6-O-benzylidene-3-[(2-tert-butoxycarbonyl)hydrazinyl]-3- deoxy-β-D-galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-5-chloro-2- (trifluoromethyl)benzene (38 mg, 0.061 mmol) in EtOH (5 mL) 3-(dimethylamino)-2- (2,3,4-trifluorophenyl)prop-2-enal (27.8 mg, 0.12 mmol) and concentrated HCl (0.2 mL) were added and the mixture was stirred 2 h at 80 °C. The mixture was concentrated and purified by prep HPLC [MeCN/H2O (10 mmol/L NaHCO3), X-Select 10 µm 19*250 mm, 20 mL/min, UV 254] to afford the title compound (21.2 mg, 58 %). ESI- MS m/z calcd for [C₂₅H₂₀ClF₆N₅O₄] [M+H]+: 604.1; found: 604.2.1H NMR (400 MHz, Methanol-d₄) δ 8.21 (d, J = 1.2 Hz, 1H), 7.95 (d, J = 8.8 Hz, 1H), 7.92 (s, 1H), 7.85 (dd, J = 8.8, 1.2 Hz, 1H), 7.77 (s, 1H), 7.48 – 7.44 (m, 1H), 7.17 – 7.09 (m, 1H), 4.82 – 4.74 (m, 1H), 4.41 (dd, J = 10.8, 2.8 Hz, 1H), 4.29 (d, J = 9.2 Hz, 1H), 4.09 (d, J = 2.4 Hz, 1H), 3.69 – 3.62 (m, 3H), 2.44 (s, 3H). Example 10 1-{5-{3-[4-(2-Chloro-3-fluorophenyl)-1H-1,2-pyrazol-1-yl]-3-deoxy-β-D- galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-5-chloro-2- (trifluoromethyl)benzene

To a solution of 1-{5-{4,6-O-benzylidene-3-[(2-tert-butoxycarbonyl)hydrazinyl]-3- deoxy-β-D-galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-5-chloro-2- (trifluoromethyl)benzene (60 mg, 0.096 mmol) in EtOH (5 mL) 3-(dimethylamino)-2- (2-chloro-3-fluorophenyl)prop-2-enal (32.7 mg, 0.14 mmol) and concentrated HCl (0.2 mL) were added and the mixture was stirred 2 h at 80 °C. The mixture was cooled to rt and basified to pH = 8 using NaHCO₃. The mixture was concentrated and purified by prep HPLC [MeCN/H2O (10 mmol/L NaHCO3), X-Select 10 µm 19*250 mm, 20 mL/min, UV 254] to afford the title compound (19 mg, 33 %). ESI-MS m/z calcd for [C₂₅H₂₁Cl₂F₄N₅O₄] [M+H]+: 602.1; found: 602.2.1H NMR (400 MHz, DMSO-d₆) δ 8.26 (s, 1H), 8.03 (d, J = 8.8 Hz, 1H), 7.96 (s, 1H), 7.93 (d, J = 9.2 Hz, 1H), 7.76 (br s, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.42 – 7.37 (m, 1H), 7.30 – 7.26 (m, 1H), 5.43 (d, J = 6.8 Hz, 1H), 5.08 (d, J = 6.0 Hz, 1H), 4.69 – 4.60 (m, 2H), 4.47 (dd, J = 10.8, 2.8 Hz, 1H), 4.24 (d, J = 9.2 Hz, 1H), 3.93 (dd, J = 5.6, 2.4 Hz, 1H), 3.58 (t, J = 6.0 Hz, 1H), 3.44 – 3.36 (m, 2H), 2.36 (s, 3H). Example 11 1-{5-{3-[4-(4-Bromo-2,3-difluorophenyl)-1H-1,2-pyrazol-1-yl]-3-deoxy-β-^D- galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-5-chloro-2- (trifluoromethyl)benzene

To a solution of 1-{5-{4,6-O-benzylidene-3-[(2-tert-butoxycarbonyl)hydrazinyl]-3- deoxy-β-D-galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-5-chloro-2- (trifluoromethyl)benzene (60 mg, 0.096 mmol) in EtOH (5 mL) 2-(4-bromo-2,3- difluorophenyl)-3-(dimethylamino)prop-2-enal (33.4 mg, 0.12 mmol) and concentrated HCl (0.2 mL) were added and the mixture was stirred 2 h at 80 °C. The mixture was concentrated and purified by prep HPLC [MeCN/H2O (10 mmol/L NaHCO3), X-Select 10 µm 19*250 mm, 20 mL/min, UV 254] to afford the title compound (21 mg, 33 %). ESI-MS m/z calcd for [C + 1 25H20BrClF5N5O4] [M+H] : 664.1; found: 664.0. H NMR (400 MHz, DMSO-d6) δ 8.24 (s, 1H), 8.03 (d, J = 8.8 Hz, 1H), 8.00 (s, 1H), 7.93 (d, J = 8.4 Hz, 1H), 7.75 (s, 1H), 7.60 – 7.52 (m, 2H), 5.41 (d, J = 6.8 Hz, 1H), 5.08 (d, J = 6.0 Hz, 1H), 4.68 – 4.61 (m, 2H), 4.48 (dd, J = 10.4, 2.4 Hz, 1H), 4.23 (d, J = 9.2 Hz, 1H), 3.92 (t, J = 6.0 Hz, 1H), 3.57 (t, J = 6.4 Hz, 1H), 3.44 – 3.40 (m, 2H), 2.36 (s, 3H). Example 12 5-Chloro-1-{5-{3-deoxy-3-[4-(2,3-difluorophenyl)-1H-1,2-pyrazol-1-yl]-β-D- galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-2-(trifluoromethyl)benzene

To a solution of 1-{5-{4,6-O-benzylidene-3-[(2-tert-butoxycarbonyl)hydrazinyl]-3- deoxy-β-^D-galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-5-chloro-2- (trifluoromethyl)benzene (50 mg, 0.080 mmol) in EtOH (5 mL) 3-(dimethylamino)-2- (2,3-difluorophenyl)prop-2-enal (25.3 mg, 0.12 mmol) and concentrated HCl (0.2 mL) were added and the mixture was stirred 2 h at 80 °C. The mixture was concentrated and purified by prep HPLC [MeCN/H₂O (10 mmol/L NaHCO₃), X-Select 10 µm 19*250 mm, 20 mL/min, UV 254] to afford the title compound (12.2 mg, 26 %). ESI-MS m/z calcd for [C H ClF N O ] [ + 1 25 21 5 5 4 M+H] : 586.1; found: 586.2. H NMR (400 MHz, Methanol-d₄) δ 8.25 (d, J = 1.6 Hz, 1H), 7.98 – 7.94 (m, 2H), 7.85 (d, J = 8.8 Hz, 1H), 7.77 (br s, 1H), 7.49 – 7.44 (m, 1H), 7.17 – 7.08 (m, 2H), 4.81 – 4.73 (m, 1H), 4.42 (dd, J = 10.8, 2.8 Hz, 1H), 4.29 (d, J = 9.2 Hz, 1H), 4.10 (d, J = 2.4 Hz, 1H), 3.68 – 3.63 (m, 3H), 2.44 (s, 3H). Example 13 5-Chloro-1-{5-{3-deoxy-3-[4-(2,3-difluoro-4-methoxyphenyl)-1H-1,2-pyrazol-1- yl]-β-D-galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-2- (trifluoromethyl)benzene

To a solution of 5-chloro-1-{5-[3-deoxy-3-(4-iodo-1H-1,2-pyrazol-1-yl)-β-D- galactopyranosyl]-3-methyl-1H-1,2,4-triazol-1-yl}-2-(trifluoromethyl)benzene (45 mg, 0.075 mmol) and 2-(2,3-difluoro-4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane (135 mg, 30 % purity, 0.15 mmol) in 1,4-dioxane/H₂O (3.0 mL, 2:1) Pd(dppf)Cl₂ (11 mg, 0.015 mmol) and K₂CO₃ (51.9 mg, 0.38 mmol) were added. The mixture was purged three times with nitrogen, and stirred 1 h at 60 °C. The mixture was filtered, and the filtrate was acidified to pH 3-4 using TFA. The mixture was concentrated and purified by prep HPLC [MeCN/H₂O (10 mmol/L NH₄HCO₃), X- Select 10 µm 19*250 mm, 20 mL/min, UV 254] to afford the title compound (6.56 mg, 14 %). ESI-MS m/z calcd for [C + 1 26H23ClF5N5O5] [M+H] : 616.1; found: 616.2. H NMR (400 MHz, Methanol-d₄) δ 8.15 (s, 1H), 7.95 (d, J = 8.8 Hz, 1H), 7.90 – 7.81 (m, 2H), 7.77 (s, 1H), 7.41 – 7.33 (m, 1H), 6.98 – 6.90 (m, 1H), 4.81 – 4.69 (m, 1H), 4.39 (dd, J = 10.8, 2.8 Hz, 1H), 4.29 (d, J = 9.2 Hz, 1H), 4.09 (d, J = 2.8 Hz, 1H), 3.91 (s, 3H), 3.70 – 3.61 (m, 3H), 2.44 (s, 3H). Example 14 5-Chloro-1-{5-{3-deoxy-3-{4-[2,3-difluoro-4-(trifluoromethyl)phenyl]-1H-1,2- pyrazol-1-yl}-β-D-galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-2- (trifluoromethyl)benzene

To a solution of 5-chloro-1-{5-[3-deoxy-3-(4-iodo-1H-1,2-pyrazol-1-yl)-β-^D- galactopyranosyl]-3-methyl-1H-1,2,4-triazol-1-yl}-2-(trifluoromethyl)benzene (45 mg, 0.075 mmol) and 2-[2,3-difluoro-4-(trifluoromethyl)phenyl]-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane (46.2 mg, 0.15 mmol) in 1,4-dioxane/H2O (3.0 mL, 2:1) Pd(dppf)Cl₂ (11 mg, 0.015 mmol) and K₂CO₃ (51.9 mg, 0.38 mmol) were added. The mixture was purged three times with nitrogen, and stirred 1 h at 60 °C. The mixture was filtered, and the filtrate was acidified to pH 3-4 using TFA. The mixture was concentrated and purified by prep HPLC [MeCN/H₂O (10 mmol/L NH₄HCO₃), X- Select 10 µm 19*250 mm, 20 mL/min, UV 254] to afford the title compound (24.4 mg, 50 %). ESI-MS m/z calcd for [C H ClF N O ] [M + 1 26 20 8 5 4 +H] : 654.1; found: 654.2. H NMR (400 MHz, Methanol-d₄) δ 8.35 (s, 1H), 8.05 (s, 1H), 7.95 (d, J = 8.4 Hz, 1H), 7.85 (d, J = 8.4 Hz, 1H), 7.77 (s, 1H), 7.72 – 7.63 (m, 1H), 7.53 – 7.44 (m, 1H), 4.82 – 4.75 (m, 1H), 4.45 (dd, J = 10.4, 2.4 Hz, 1H), 4.30 (d, J = 9.6 Hz, 1H), 4.11 (d, J = 2.4 Hz, 1H), 3.75 – 3.59 (m, 3H), 2.44 (s, 3H). Example 15 5-Chloro-1-{5-{3-deoxy-3-{4-[2,3-difluoro-4-(1-methylethenyl)phenyl]-1H-1,2- pyrazol-1-yl}-β-^D-galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-2- (trifluoromethyl)benzene

To a solution of 1-{5-{3-[4-(4-bromo-2,3-difluorophenyl)-1H-1,2-pyrazol-1-yl]-3- deoxy-β-^D-galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-5-chloro-2- (trifluoromethyl)benzene (100 mg, 0.15 mmol) in 1,4-dioxane/H₂O (8 mL, 7:1) 2- isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (37.9 mg, 0.23 mmol), Pd(dppf)Cl2 (11 mg, 0.015 mmol) and K2CO3 (20.8 mg, 0.15 mmol) were added and the mixture was stirred 2 h at 70 °C. The mixture was concentrated and purified by prep HPLC [MeCN/H₂O (10 mmol/L NH₄HCO₃), X-Select 10 µm 19*250 mm, 20 mL/min, UV 254] to afford the title compound (29 mg, 31 %). ESI-MS m/z calcd for [C + 1 28H25ClF5N5O4] [M+H] : 626.2; found: 626.2. H NMR (400 MHz, DMSO-d6) δ 8.22 (s, 1H), 8.03 (d, J = 8.4 Hz, 1H), 7.98 (s, 1H), 7.94 (dd, J = 8.4, 1.2 Hz, 1H), 7.76 (s, 1H), 7.56 – 7.52 (m, 1H), 7.25 – 7.21 (m, 1H), 5.42 (d, J = 6.8 Hz, 1H), 5.35 (s, 2H), 5.09 (d, J = 5.6 Hz, 1H), 4.69 – 4.62 (m, 2H), 4.48 (dd, J = 10.4, 2.4 Hz, 1H), 4.23 (d, J = 8.8 Hz, 1H), 3.92 (dd, J = 5.6, 2.8 Hz, 1H), 3.57 (t, J = 6.4 Hz, 1H), 3.43 – 3.37 (m, 2H), 2.45 (s, 3H), 2.13 (s, 3H). Example 16 5-Chloro-1-{5-{3-deoxy-3-[4-(4,5-difluorobenzothiazol-6-yl)-1H-1,2-pyrazol-1- yl]-β-D-galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-2- (trifluoromethyl)benzene

To a solution of 5-chloro-1-{5-[3-deoxy-3-(4-iodo-1H-1,2-pyrazol-1-yl)-β-D- galactopyranosyl]-3-methyl-1H-1,2,4-triazol-1-yl}-2-(trifluoromethyl)benzene (30 mg, 0.050 mmol) and 4,5-difluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 1,3-benzothiazole (22.3 mg, 0.075 mmol) in 1,4-dioxane/H2O (3 mL, 2:1) Pd(dppf)Cl2 (7.32 mg, 0.010 mmol) and K₂CO₃ (20.7 mg, 0.15 mmol) were added. The mixture was purged three times with nitrogen, and stirred 2 h at 60 °C. The mixture was filtered, and the filtrate was acidified to pH 3-4 using TFA. The mixture was concentrated and purified by prep HPLC [MeCN/H₂O (10 mmol/L NH₄HCO₃), X-Select 10 µm 19*250 mm, 20 mL/min, UV 254] to afford the title compound (5.2 mg, 16 %). ESI-MS m/z calcd for [C H ClF N O S] [M+H]+: 643.1; fou 1 26 20 5 6 4 nd: 643.1. H NMR (400 MHz, Methanol-d₄) δ 9.26 (s, 1H), 8.33 (d, J = 2.0 Hz, 1H), 8.19 (dd, J = 6.0, 2.0 Hz, 1H), 8.05 (s, 1H), 7.96 (d, J = 8.8 Hz, 1H), 7.86 (dd, J = 8.4, 1.2 Hz, 1H), 7.78 (s, 1H), 4.80 – 4.78 (m, 1H), 4.45 (dd, J = 10.8, 2.8 Hz, 1H), 4.31 (d, J = 9.2 Hz, 1H), 4.12 (d, J = 2.4 Hz, 1H), 3.67 – 3.64 (m, 3H), 2.45 (s, 3H). Example 17 5-Chloro-3-{5-{3-deoxy-3-[4-(4,5-difluorobenzothiazol-6-yl)-1H-1,2-pyrazol-1- yl]-β-D-galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-2- (trifluoromethyl)pyridine

To a solution of 5-chloro-3-{5-[3-deoxy-3-(4-iodo-1H-1,2-pyrazol-1-yl)-β-D- galactopyranosyl]-3-methyl-1H-1,2,4-triazol-1-yl}-2-(trifluoromethyl)pyridine (30 mg, 0.050 mmol) in 1,4-dioxane/H₂O (3 mL, 2:1) 4,5-difluoro-6-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1,3-benzothiazole (44.5 mg, 0.15 mmol), Pd(dppf)Cl₂ (11.0 mg, 0.015 mmol) and K2CO3 (34.5 mg, 0.25 mmol) were added. The mixture was purged three times with nitrogen, and stirred 1 h at 60 °C. The mixture was filtered, and the filtrate was acidified to pH 3-4 using TFA. The mixture was concentrated and purified by prep HPLC [MeCN/H2O (10 mmol/L NH4HCO3), X-Select 10 µm 19*250 mm, 20 mL/min, UV 254] to afford the title compound (7.65 mg, 24 %). ESI-MS m/z calcd. For [C₂₅H₁₉ClF₅N₇O₄S] [M+H]+: 644.1; found: 644.1. 1H NMR (400 MHz, Methanol-d₄) δ 9.26 (s, 1H), 8.94 (d, J = 2.0 Hz, 1H), 8.34 – 8.31 (m, 2H), 8.19 – 8.17 (m, 1H), 8.05 (s, 1H), 4.73 (t, J = 10.4 Hz, 1H), 4.47 – 4.43 (m, 2H), 4.10 (d, J = 2.0 Hz, 1H), 3.71 (t, J = 6.0 Hz, 1H), 3.65 – 3.59 (m, 2H), 2.45 (s, 3H). Example 18 5-Bromo-3-{5-{3-deoxy-3-[4-(4,5-difluorobenzothiazol-6-yl)-1H-1,2-pyrazol-1- yl]-β-D-galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-2- (trifluoromethyl)pyridine

The compound 5-Bromo-3-{5-{3-deoxy-3-[4-(4,5-difluorobenzothiazol-6-yl)-1H-1,2- pyrazol-1-yl]-β-D-galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-2- (trifluoromethyl)pyridine may be prepared by the skilled person using the processes described above under a1) to a67). Example 19 5-Bromo-1-{5-{3-deoxy-3-[4-(4,5-difluorobenzothiazol-6-yl)-1H-1,2-pyrazol-1- yl]-β-D-galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-2- (trifluoromethyl)benzene

To a solution of 5-bromo-1-{5-[3-deoxy-3-(4-iodo-1H-1,2-pyrazol-1-yl)-β-D- galactopyranosyl]-3-methyl-1H-1,2,4-triazol-1-yl}-2-(trifluoromethyl)benzene (50 mg, 0.078 mmol) in 1,4-dioxane/H2O (4 mL, 3:1) 4,5-difluoro-6-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1,3-benzothiazole (69.2 mg, 0.23 mmol), Pd(dppf)Cl2 (11.4 mg, 0.016 mmol) and K₂CO₃ (32.2 mg, 0.23 mmol) were added. The mixture was purged three times with nitrogen, and stirred 3 h at 40 °C. The mixture was filtered, concentrated, and purified by prep HPLC [MeCN/H₂O (10 mmol/L NH₄HCO₃), X- Select 10 µm 19*250 mm, 20 mL/min, UV 254] to afford the title compound (8.0 mg, 15 %). ESI-MS m/z calcd. For [C + 1 26H20BrF5N6O4S] [M+H] : 687.0; found: 687.0. H NMR (400 MHz, DMSO-d6) δ 9.45 (s, 1H), 8.42 (dd, J = 6.4, 1.6 Hz, 1H), 8.29 (d, J = 2.4 Hz, 1H), 8.08 (d, J = 8.4 Hz, 1H), 8.03 (s, 1H), 7.95 (d, J = 8.8 Hz, 1H), 7.86 (br s, 1H), 5.42 (d, J = 6.4 Hz, 1H), 5.12 (d, J = 5.6 Hz, 1H), 4.73 – 4.63 (m, 2H), 4.50 (dd, J = 10.4, 2.4 Hz, 1H), 4.23 (dd, J = 8.8, 2.4 Hz, 1H), 3.94 (dd, J = 6.0, 2.4 Hz, 1H), 3.60 – 3.56 (m, 1H), 3.47 – 3.39 (m, 2H), 2.43 (s, 3H). Example 20 5-Bromo-1-{5-{3-[4-(4-chloro-2,3-difluorophenyl)-1H-1,2-pyrazol-1-yl]-3-deoxy- β-D-galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-2- (trifluoromethyl)benzene

To a solution of 5-bromo-1-{5-[3-deoxy-3-(4-iodo-1H-1,2-pyrazol-1-yl)-β-D- galactopyranosyl]-3-methyl-1H-1,2,4-triazol-1-yl}-2-(trifluoromethyl)benzene (40 mg, 0.062 mmol) in 1,4-dioxane/H₂O (4 mL, 3:1) (4-chloro-2,3-difluorophenyl) boronic acid (35.8 mg, 0.19 mmol), Pd(dppf)Cl₂ (9.09 mg, 0.012 mmol) and K₂CO₃ (25.7 mg, 0.19 mmol) were added. The mixture was purged three times with nitrogen, and stirred 3 h at 40 °C. The mixture was filtered, and the filtrate was acidified to pH 3-4 using TFA. The mixture was concentrated and purified by prep HPLC [MeCN/H₂O (10 mmol/L NH4HCO3), X-Select 10 µm 19*250 mm, 20 mL/min, UV 254] to afford the title compound (5.0 mg, 12 %). ESI-MS m/z calcd. For [C26H20BrClF5N5O4] [M+H]+: 664.0; found: 664.0.1H NMR (400 MHz, DMSO-d₆) δ 8.25 (s, 1H), 8.07 (d, J = 8.8 Hz, 1H), 7.99 (s, 1H), 7.94 (d, J = 8.8 Hz, 1H), 7.86 (br s, 1H), 7.66 – 7.62 (m, 1H), 7.47 – 7.43 (m, 1H), 5.41 (d, J = 6.8 Hz, 1H), 5.09 (d, J = 6.0 Hz, 1H), 4.65 – 4.62 (m, 2H), 4.48 (dd, J = 10.8, 2.8 Hz, 1H), 4.23 (d, J = 9.2 Hz, 1H), 3.93 – 3.91 (m, 1H), 3.57 (t, J = 6.4 Hz, 1H), 3.44 – 3.37 (m, 2H), 2.36 (s, 3H). Example 21 3-{5-{3-[4-(4-Chloro-2,3-difluorophenyl)-1H-1,2-pyrazol-1-yl]-3-deoxy-β-D- galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-5-chloro-2- (trifluoromethyl)pyridine

To a solution of 5-chloro-3-{5-[3-deoxy-3-(4-iodo-1H-1,2-pyrazol-1-yl)-β-D- galactopyranosyl]-3-methyl-1H-1,2,4-triazol-1-yl}-2-(trifluoromethyl)pyridine (30 mg, 0.050 mmol) in 1,4-dioxane/H2O (3 mL, 2:1) (4-chloro-2,3-difluorophenyl)boronic acid (28.8 mg, 0.15 mmol), Pd(dppf)Cl₂ (11.0 mg, 0.015 mmol) and K₂CO₃ (34.5 mg, 0.25 mmol) were added. The mixture was purged three times with nitrogen, and stirred 1 h at 60 °C. The mixture was filtered, and the filtrate was acidified to pH 3-4 using TFA. The mixture was concentrated and purified by prep HPLC [MeCN/H₂O (10 mmol/L NH₄HCO₃), X-Select 10 µm 19*250 mm, 20 mL/min, UV 254] to afford the title compound (7.32 mg, 24 %). ESI-MS m/z calcd. For [C + 24H19Cl2F5N6O4] [M+H] : 621.1; found: 621.1.1H NMR (400 MHz, Methanol-d₄) δ 8.94 (d, J = 2.0 Hz, 1H), 8.33 (d, J = 1.6 Hz, 1H), 8.24 (d, J = 1.6 Hz, 1H), 7.96 (d, J = 0.8 Hz, 1H), 7.50 – 7.46 (m, 1H), 7.31 – 7.26 (m, 1H), 4.72 – 4.67 (m, 1H), 4.45 – 4.41 (m, 2H), 4.08 (d, J = 2.4 Hz, 1H), 3.71 – 3.56 (m, 3H), 2.44 (s, 3H). Example 22 5-Bromo-3-{5-{3-[4-(4-chloro-2,3-difluorophenyl)-1H-1,2-pyrazol-1-yl]-3-deoxy- β-^D-galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-2- (trifluoromethyl)pyridine

To a solution of 3-{5-{4,6-O-benzylidene-3-[(2-tert-butoxycarbonyl)hydrazinyl]-3- deoxy-β-D-galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-5-bromo-2- (trifluoromethyl)pyridine (25 mg, 0.037 mmol) in EtOH (3 mL) 2-(4-chloro-2,3- difluorophenyl)-3-(dimethylamino)prop-2-enal (11.4 mg, 0.047 mmol) and concentrated HCl (0.2 mL) were added and the mixture was stirred 2 h at 80 °C. The mixture was cooled to 0 °C and basified using aq NaHCO3. The mixture was concentrated and purified by prep HPLC [MeCN/H2O (10 mmol/L NaHCO3), X-Select 10 µm 19*250 mm, 20 mL/min, UV 254] to afford the title compound (2.5 mg, 10 %). ESI-MS m/z calcd for [C + 1 24H19BrClF5N6O4] [M+H] : 665.0; found: 665.0. H NMR (400 MHz, DMSO-d6) δ 9.16 (d, J = 1.6 Hz, 1H), 8.51 (s, 1H), 8.23 (s, 1H), 8.00 (s, 1H), 7.65 – 7.61 (m, 1H), 7.47 – 7.43 (m, 1H), 5.41 (d, J = 6.8 Hz, 1H), 5.08 (d, J = 6.0 Hz, 1H), 4.64 – 4.56 (m, 2H), 4.46 (dd, J = 10.4, 2.4 Hz, 1H), 4.41 (d, J = 9.2 Hz, 1H), 3.91 – 3.89 (m, 1H), 3.60 (t, J = 5.6 Hz, 1H), 3.38 – 3.35 (m, 2H), 2.37 (s, 3H). Example 23 3-{5-{3-[4-(4-Chloro-2,3-difluorophenyl)-1H-1,2-pyrazol-1-yl]-3-deoxy-β-D- galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-5-chloro-2- cyclopropylpyridine

To a solution of 3-{5-{4,6-O-benzylidene-3-[(2-tert-butoxycarbonyl)hydrazinyl]-3- deoxy-β-^D-galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-5-chloro-2- cyclopropylpyridine (30 mg, 0.049 mmol) in EtOH (2 mL) 2-(4-chloro-2,3- difluorophenyl)-3-(dimethylamino)prop-2-enal (14.4 mg, 0.059 mmol) and concentrated HCl (0.2 mL) were added and the mixture was stirred 2 h at 80 °C. The mixture was concentrated and purified by prep HPLC [MeCN/H₂O (10 mmol/L NaHCO3), X-Select 10 µm 19*250 mm, 20 mL/min, UV 254] to afford the title compound (7.9 mg, 27 %). ESI-MS m/z calcd for [C + 26H24ClF2N6O4] [M+H] : 593.1; found: 593.2.1H NMR (400 MHz, DMSO-d₆) δ 8.59 (d, J = 2.4 Hz, 1H), 8.23 (s, 1H), 7.96 (s, 1H), 7.90 (s, 1H), 7.50 – 7.46 (m, 1H), 7.31 – 7.26 (m, 1H), 4.70 (br s, 1H), 4.43 (dd, J = 10.8, 2.8 Hz, 1H), 4.39 (d, J = 8.8 Hz, 1H), 4.07 (d, J = 2.4 Hz, 1H), 3.75 – 3.62 (m, 3H), 2.46 (m, 3H), 1.69 – 1.63 (m, 1H), 1.13 – 0.88 (m, 4H). Example 24 1-{5-{3-[4-(4-Chloro-2,3-difluorophenyl)-1H-1,2-pyrazol-1-yl]-3-deoxy-β-^D- galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-5-chloro-2- cyclopropylbenzene

To a solution of 3-{5-{4,6-O-benzylidene-3-[(2-tert-butoxycarbonyl)hydrazinyl]-3- deoxy-β-^D-galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-5-chloro-2- cyclopropylbenzene (40 mg, 0.067 mmol) in EtOH (3.0 mL) 2-(4-chloro-2,3- difluorophenyl)-3-(dimethylamino)prop-2-enal (18.1 mg, 0.074 mmol) and concentrated HCl (0.1 mL) were added and the mixture was stirred 1 h at 70 °C. The mixture was concentrated and purified by prep HPLC [MeCN/H₂O (10 mmol/L NaHCO3), X-Select 10 µm 19*250 mm, 20 mL/min, UV 254] to afford the title compound (11.4 mg, 29 %). ESI-MS m/z calcd for [C + 27H25ClF2N5O4] [M+H] : 592.1; found: 592.0.1H NMR (400 MHz, Methanol-d₄) δ 8.26 (s, 1H), 7.96 (s, 1H), 7.52 – 7.43 (m, 3H), 7.30 – 7.26 (m, 1H), 7.12 (d, J = 8.4 Hz, 1H), 4.84 – 4.75 (m, 1H), 4.42 (dd, J = 10.4, 2.4 Hz, 1H), 4.30 – 4.27 (m, 1H), 4.09 (d, J = 2.8 Hz, 1H), 3.73 – 3.66 (m, 3H), 2.46 (s, 3H), 1.57 (m, 1H), 0.97 – 0.71 (m, 4H). Example 25 5-Bromo-1-{5-{3-[4-(4-chloro-2,3-difluorophenyl)-1H-1,2-pyrazol-1-yl]-3-deoxy- β-D-galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-2-cyanobenzene

To a solution of 5-bromo-1-{5-{3-[4-(4-chloro-2,3-difluorophenyl)-1H-1,2-pyrazol-1- yl]-3-deoxy-β-D-galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-2-iodobenzene (40.0 mg, 0.055 mmol) in DMF (3.0 mL) Zn(CN)2 (13.0 mg, 0.11 mmol), zinc (7.24 mg, 0.11 mmol), Pd₂(dba)₃ (6.37 mg, 0.011 mmol) and 1,1’-ferrocenediyl- bis(diphenylphosphine) (6.25 mg, 0.011 mmol) were added. The mixture was purged three times with nitrogen and stirred 45 min at 100 °C using microwave irradiation. The mixture was filtered, concentrated, and purified by prep HPLC [MeCN/H₂O (10 mmol/L NH4HCO3), X-Select 10 µm 19*250 mm, 20 mL/min, UV 254] to afford the title compound (4.0 mg, 12 %). ESI-MS m/z calcd for [C + 25H20BrClF2N6O4] [M+H] : 621.0; found: 621.1. 1H NMR (400 MHz, DMSO-d6) δ 8.24 (s, 1H), 8.09 – 8.07 (m, 2H), 8.03 (dd, J = 8.4, 1.2 Hz, 1H), 8.00 (s, 1H), 7.65 – 7.62 (m, 1H), 7.48 – 7.43 (m, 1H), 5.50 (d, J = 7.2, Hz, 1H), 5.13 (d, J = 6.4 Hz, 1H), 4.70 – 4.66 (m, 2H), 4.52 (dd, J = 10.0, 2.0 Hz, 1H), 4.45 (d, J = 9.2 Hz, 1H), 3.96 – 3.93 (m, 1H), 3.72 – 3.69 (m, 1H), 3.51 – 3.41 (m, 2H), 2.40 (s, 3H). Example 26 6-{5-{3-[4-(4-Chloro-2,3-difluorophenyl)-1H-1,2-pyrazol-1-yl]-3-deoxy-β-D- galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-2-methylbenzothiazole

To a solution of 6-{5-[3-(4-bromo-1H-1,2-pyrazol-1-yl)-3-deoxy-β-^D- galactopyranosyl]-3-methyl-1H-1,2,4-triazol-1-yl}-2-methylbenzothiazole (30 mg, 0.058 mmol) in 1,4-dioxane/H2O (3 mL, 4:1) (4-chloro-2,3-difluorophenyl)boronic acid (22.1 mg, 0.12 mmol), Pd(dppf)Cl₂ (8.42 mg, 0.012 mmol) and K₂CO₃ (23.9 mg, 0.17 mmol) were added. The mixture was purged three times with nitrogen, and stirred 16 h at 80 °C. The mixture was filtered, concentrated, and purified by prep HPLC [MeCN/H2O (10 mmol/L NH4HCO3), X-Select 10 µm 19*250 mm, 20 mL/min, UV 254] to afford the title compound (4.7 mg, 14 %). ESI-MS m/z calcd for [C₂₆H₂₃ClF₂N₆O₄S] [M+H]+: 589.1; found: 589.2.1H NMR (400 MHz, Methanol-d₄) δ 8.37 (d, J = 2.0 Hz, 1H), 8.26 (d, J = 1.6 Hz, 1H), 8.06 (d, J = 8.8 Hz, 1H), 7.97 (s, 1H), 7.79 (dd, J = 8.8, 2.4 Hz, 1H), 7.51 – 7.46 (m, 1H), 7.31 – 7.26 (m, 1H), 4.95 – 4.93 (m, 1H), 4.50 (d, J = 9.6 Hz, 1H), 4.47 (dd, J = 10.8, 2.8 Hz, 1H), 4.11 (d, J = 2.8 Hz, 1H), 3.83 – 3.70 (m, 3H), 2.89 (s, 3H), 2.47 (s, 3H). Example 27 1-{5-{3-[4-(4-Chloro-2,3-difluorophenyl)-1H-1,2-pyrazol-1-yl]-3-deoxy-β-D- galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-5-chloro-2- (trifluoromethoxy)benzene

To a solution of 1-[5-(4,6-O-benzylidene-3-[(2-tert-butoxycarbonyl)hydrazinyl]-3- deoxy-β-D-galactopyranosyl)-3-methyl-1H-1,2,4-triazol-1-yl]-5-chloro-2- (trifluoromethoxy)benzene (40 mg, 0.062 mmol) in EtOH (4 mL) 2-(4-chloro-2,3- difluorophenyl)-3-(dimethylamino)prop-2-enal (19.9 mg, 0.081 mmol) and concentrated HCl (0.2 mL) were added and the mixture was stirred 2 h at 70 °C. The mixture was concentrated and purified by prep HPLC [MeCN/H2O (10 mmol/L NH₄HCO₃), X-Select 10 µm 19*250 mm, 20 mL/min, UV 254] to afford the title compound (8.41 mg, 21 %). ESI-MS m/z calcd for [C₂₅H₂₀Cl₂F₅N₅O₅] [M+H]+: 636.1; found: 636.1. 1H NMR (400 MHz, Methanol-d4) δ 8.26 (d, J = 1.6 Hz, 1H), 7.97 (s, 1H), 7.79 (d, J = 2.4 Hz, 1H), 7.73 (dd, J = 8.8, 2.4 Hz, 1H), 7.61 (dd, J = 9.2, 1.2 Hz, 1H), 7.51 – 7.46 (m,1H), 7.31 – 7.26 (m, 1H), 4.76 (t, J = 10.0 Hz, 1H), 4.45 (dd, J = 10.8, 2.8 Hz, 1H), 4.35 (d, J = 9.6 Hz, 1H), 4.12 (d, J = 2.4 Hz, 1H), 3.75 – 3.64 (m, 3H) , 2.45 (s, 3H). Example 28 3-{5-{3-[4-(4-Chloro-2,3-difluorophenyl)-1H-1,2-pyrazol-1-yl]-3-deoxy-β-D- galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-5-chloro-2- (trifluoromethoxy)pyridine

The compound 3-{5-{3-[4-(4-Chloro-2,3-difluorophenyl)-1H-1,2-pyrazol-1-yl]-3- deoxy-β-D-galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-5-chloro-2- (trifluoromethoxy)pyridine may be prepared by the skilled person using the processes described above under a1) to a67). Example 29 1-{5-{3-[4-(4-Bromo-2,3-difluorophenyl)-1H-1,2-pyrazol-1-yl]-3-deoxy-β-D- galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-5-chloro-2- (trifluoromethyl)benzene

To a solution of 1-{5-{3-[4-(4-bromo-2,3-difluorophenyl)-1H-1,2-pyrazol-1-yl]-3- deoxy-β-D-galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-5-chloro-2- (trifluoromethyl)benzene (60 mg, 0.090 mmol) in DMF (5.0 mL) Zn(CN)₂ (31.8 mg, 0.27 mmol), zinc (11.8 mg, 0.18 mmol), Pd2(dba)3 (10.4 mg, 0.018 mmol) and 1,1’- ferrocenediyl-bis(diphenylphosphine) (10.2 mg, 0.018 mmol) were added. The mixture was purged three times with nitrogen and stirred 4 h at 100 °C using microwave irradiation. The mixture was filtered, concentrated, and purified by prep HPLC [MeCN/H2O (10 mmol/L NH4HCO3), X-Select 10 µm 19*250 mm, 20 mL/min, UV 254] to afford the title compound (25 mg, 45 %). ESI-MS m/z calcd for [C26H20ClF5N6O4] [M+H]+: 611.2; found: 611.2. 1H NMR (400 MHz, DMSO-d6) δ 8.38 (s, 1H), 8.11 (s, 1H), 8.03 (d, J = 8.4 Hz, 1H), 7.94 (d, J = 8.4 Hz, 1H), 7.84 – 7.76 (m, 3H), 5.45 (d, J = 6.8 Hz, 1H), 5.11 (d, J = 6.0 Hz, 1H), 4.66 – 4.63 (m, 2H), 4.51 (dd, J = 10.8, 2.8 Hz, 1H), 4.24 (d, J = 8.8 Hz, 1H), 3.93 – 3.91 (m, 1H), 3.58 (t, J = 6.4 Hz, 1H), 3.42 – 3.40 (m, 2H), 2.36 (s, 3H). Example 30 1-{5-{3-[4-(4-Chloro-2,5-difluorophenyl)-1H-1,2-pyrazol-1-yl]-3-deoxy-β-D- galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-5-chloro-2- (trifluoromethyl)benzene

To a solution of 1-[5-(4,6-O-benzylidene-3-[(2-tert-butoxycarbonyl)hydrazinyl]-3- deoxy-β-D-galactopyranosyl)-3-methyl-1H-1,2,4-triazol-1-yl]-5-chloro-2- (trifluoromethoxy)benzene (35 mg, 0.056 mmol) in EtOH (3 mL) 2-(4-chloro-2,5- difluorophenyl)-3-(dimethylamino)prop-2-enal (15.1 mg, 0.062 mmol) and concentrated HCl (0.1 mL) were added and the mixture was stirred 1 h at 70 °C. The mixture was concentrated and purified by prep HPLC [MeCN/H2O (10 mmol/L NH₄HCO₃), X-Select 10 µm 19*250 mm, 20 mL/min, UV 254] to afford the title compound (2.1 mg, 6 %). ESI-MS m/z calcd for [C₂₅H₂₀Cl₂F₅N₅O₅] [M+H]+: 620.1; found: 620.0.1H NMR (400 MHz, Methanol-d4) δ 8.26 (s, 1H), 7.97 – 7.94 (m, 2H), 7.85 (d, J = 8.4 Hz, 1H), 7.77 (br s, 1H), 7.63 (dd, J = 10.0, 6.8 Hz, 1H), 7.38 (dd, J = 10.4, 6.4 Hz, 1H), 4.76 – 4.73 (m, 1H), 4.41 (dd, J = 10.4, 2.4 Hz, 1H), 4.29 (d, J = 9.6 Hz, 1H), 4.08 (d, J = 2.4 Hz, 1H), 3.65 – 3.62 (m, 3H), 2.44 (s, 3H). Example 31 1-{5-{3-[4-(4-Chloro-5-fluoro-2-methoxyphenyl)-1H-1,2-pyrazol-1-yl]-3-deoxy-β- D-galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-5-chloro-2- (trifluoromethyl)benzene

To a solution of 5-chloro-1-{5-[3-deoxy-3-(4-iodo-1H-1,2-pyrazol-1-yl)-β-D- galactopyranosyl]-3-methyl-1H-1,2,4-triazol-1-yl}-2-(trifluoromethyl)benzene (20 mg, 0.031 mmol) in 1,4-dioxane/H2O (4.0 mL, 3:1) (4-chloro-5-fluoro-2- methoxyphenyl)boronic acid (19.0 mg, 0.093 mmol), Pd(dppf)Cl₂ (4.54 mg, 0.0062 mmol) and K₂CO₃ (12.9 mg, 0.093 mmol) were added. The mixture was purged three times with nitrogen, and stirred 3 h at 60 °C. The mixture was filtered, and the filtrate was acidified to pH 3-4 using TFA. The mixture was concentrated and purified by prep HPLC [MeCN/H2O (10 mmol/L NH4HCO3), X-Select 10 µm 19*250 mm, 20 mL/min, UV 254] to afford the title compound (2.4 mg, 12 %). ESI-MS m/z calcd. For [C26H23Cl2F4N5O5] [M+H]+: 632.1; found: 632.0.1H NMR (400 MHz, Methanol-d4) δ 8.30 (s, 1H), 7.98 (s, 1H), 7.95 (d, J = 8.8 Hz, 1H), 7.85 (d, J = 8.8 Hz, 1H), 7.79 – 7.77 (m, 1H), 7.50 (d, J = 10.4 Hz, 1H), 7.12 (d, J = 6.4 Hz, 1H), 4.78 – 4.75 (m, 1H), 4.37 (dd, J = 10.8, 2.8 Hz, 1H), 4.28 (d, J = 9.6 Hz, 1H), 4.08 (d, J = 2.8 Hz, 1H), 3.92 (s, 3H), 3.67 – 3.63 (m, 3H), 2.44 (s, 3H). Example 32 1-{5-{3-{4-[4-Chloro-5-fluoro-2-(trifluoromethyl)phenyl]-1H-1,2-pyrazol-1-yl}-3- deoxy-β-^D-galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-5-chloro-2- (trifluoromethyl)benzene

A nitrogen purged solution of 1-{5-[3-(4-borono-1H-1,2-pyrazol-1-yl)-3-deoxy-β-D- galactopyranosyl]-3-methyl-1H-1,2,4-triazol-1-yl}-5-chloro-2- (trifluoromethyl)benzene (35 mg, 0.068 mmol), 1-chloro-2-fluoro-4-iodo-5- (trifluoromethyl)benzene (43.9 mg, 0.14 mmol), Pd(dppf)Cl2 (2.47 mg, 0.0034 mmol) and K2CO3 (28.0 mg, 0.20 mmol) in DMF (5 mL) and H2O (1 mL) was stirred 4 h at 100 °C. The mixture was filtered, concentrated, and purified by prep HPLC [MeCN/H2O (10 mmol/L NH4HCO3), X-Select 10 µm 19*250 mm, 20 mL/min, UV 254] to afford the title compound (13.9 mg, 31 %). ESI-MS m/z calcd. For [C + 1 26H20Cl2F7N5O4] [M+H] : 670.1; found: 670.0. H NMR (400 MHz, DMSO-d6) δ 8.07 – 8.02 (m, 3H), 7.94 (dd, J = 8.4, 1.2 Hz, 1H), 7.75 – 7.71 (m, 3H), 5.41 (d, J = 6.8 Hz, 1H), 5.08 (d, J = 6.0 Hz, 1H), 4.64 – 4.62 (m, 2H), 4.47 (dd, J = 10.4, 2.4 Hz, 1H), 4.24 (d, J = 9.2 Hz, 1H), 3.92 (dd, J = 5.6, 2.4 Hz, 1H), 3.58 (t, J = 6.4 Hz, 1H), 3.43 – 3.40 (m, 2H), 2.36 (s, 3H). Example 33 1-{5-{3-{4-[4-Chloro-5-fluoro-2-(trifluoromethoxy)phenyl]-1H-1,2-pyrazol-1-yl}- 3-deoxy-β-D-galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-5-chloro-2- (trifluoromethyl)benzene

A nitrogen purged solution of 1-{5-[3-(4-borono-1H-1,2-pyrazol-1-yl)-3-deoxy-β-D- galactopyranosyl]-3-methyl-1H-1,2,4-triazol-1-yl}-5-chloro-2- (trifluoromethyl)benzene (28 mg, 0.054 mmol), 1-chloro-2-fluoro-4-iodo-5- (trifluoromethoxy)benzene (36.8 mg, 0.11 mmol), Pd(dppf)Cl₂ (10.0 mg, 0.014 mmol) and K₂CO₃ (22.4 mg, 0.16 mmol) in 1,4-dioxane (4 mL) and H₂O (1 mL) was stirred 4 h at 100 °C. The mixture was filtered, concentrated, and purified by prep HPLC [MeCN/H₂O (10 mmol/L NH₄HCO₃), X-Select 10 µm 19*250 mm, 20 mL/min, UV 254] to afford the title compound (8.44 mg, 23 %). ESI-MS m/z calcd. For [C H Cl F7N5O5] [M+H]+: 686.1; f 1 26 20 2 ound: 686.1. H NMR (400 MHz, Methanol-d4) δ 8.27 (s, 1H), 7.96 – 7.94 (m, 2H), 7.85 (dd, J = 8.4, 1.2 Hz, 1H), 7.77 (br s, 1H), 7.68 (d, J = 10.0 Hz, 1H), 7.54 (dd, J = 6.4, 1.2 Hz, 1H), 4.78 – 4.72 (m, 1H), 4.42 (dd, J = 10.4, 2.8 Hz, 1H), 4.29 (d, J = 9.2 Hz, 1H), 4.09 (d, J = 2.8 Hz, 1H), 3.68 – 3.62 (m, 3H), 2.44 (s, 3H). Example 34 1-{5-{3-[4-(4-Chloro-2,3-difluorophenyl)-1H-1,2-pyrazol-1-yl]-3-deoxy-β-^D- galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-5-chloro-4-fluoro-2- (trifluoromethyl)benzene

To a solution of 1-[5-(4,6-O-benzylidene-3-[(2-tert-butoxycarbonyl)hydrazinyl]-3- deoxy-β-D-galactopyranosyl)-3-methyl-1H-1,2,4-triazol-1-yl]-5-chloro-4-fluoro-2- (trifluoromethyl)benzene (45 mg, purity 60 %, 0.042 mmol) in EtOH (5.0 mL) 2-(4- chloro-2,3-difluorophenyl)-3-(dimethylamino)prop-2-enal (20.6 mg, 0.084 mmol) and concentrated HCl (0.2 mL) were added and the mixture was stirred 2 h at 80 °C. The mixture was concentrated and purified by prep HPLC [MeCN/H2O (10 mmol/L NH4HCO3), X-Select 10 µm 19*250 mm, 20 mL/min, UV 254] to afford the title compound (2.41 mg, 9 %). ESI-MS m/z calcd for [C₂₅H₁₉Cl₂F₆N₅O₄] [M+H]+: 638.1; found: 638.3.1H NMR (400 MHz, Methanol-d4) δ 8.25 (s, 1H), 7.97 – 7.90 (m, 3H), 7.51 – 7.46 (m, 1H), 7.31 – 7.26 (m, 1H), 4.82 – 4.74 (m, 1H), 4.42 (dd, J = 11.2, 2.8 Hz, 1H), 4.32 (d, J = 9.2 Hz, 1H), 4.09 (d, J = 2.4 Hz, 1H), 3.68 – 3.62 (m, 3H), 2.43 (s, 3H). Example 35 5-Chloro-1-{5-{3-deoxy-3-[4-(4,5-difluorobenzothiazol-6-yl)-1H-1,2-pyrazol-1- yl]-β-D-galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-4-fluoro-2- (trifluoromethyl)benzene

A nitrogen purged solution of 5-chloro-1-{5-[3-deoxy-3-(4-iodo-1H-1,2-pyrazol-1-yl)- β-D-galactopyranosyl)-3-methyl-1H-1,2,4-triazol-1-yl]-4-fluoro-2- (trifluoromethyl)benzene (50 mg, 0.081 mmol), 4,5-difluoro-6-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1,3-benzothiazole (31.3 mg, 0.11 mmol), Pd(dppf)Cl₂ (11.8 mg, 0.016 mmol) and K2CO3 (33.5 mg, 0.24 mmol) in 1,4-dioxane/H2O (5 mL, 4:1) was stirred 3 h at 100 °C. The mixture was filtered, concentrated, and purified by prep HPLC [MeCN/H₂O (10 mmol/L NH₄HCO₃), X-Select 10 µm 19*250 mm, 20 mL/min, UV 254] to afford the title compound (6.59 mg, 12 %). ESI-MS m/z calcd for [C H ClF6N6O4S] [M+H + 1 26 19 ] : 661.1; found: 661.1. H NMR (400 MHz, Methanol-d4) δ 9.26 (s, 1H), 8.33 (d, J = 1.6 Hz, 1H), 8.19 (dd, J = 6.0, 1.6 Hz, 1H), 8.05 (s, 1H), 7.97 – 7.93 (m, 2H), 4.83 – 4.75 (m, 1H), 4.45 (dd, J = 10.8, 3.2 Hz, 1H), 4.34 (d, J = 8.8 Hz, 1H), 4.11 (d, J = 2.8 Hz, 1H), 3.71 – 3.63 (m, 3H), 2.44 (s, 3H). Example 36 1-{5-{3-[4-(4-Chloro-2,3-difluorophenyl)-1H-1,2-pyrazol-1-yl]-3-deoxy-β-D- galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-4,5-dichloro-2- (trifluoromethyl)benzene

To a solution of 1-[5-(4,6-O-benzylidene-3-[(2-tert-butoxycarbonyl)hydrazinyl]-3- deoxy-β-^D-galactopyranosyl)-3-methyl-1H-1,2,4-triazol-1-yl]-4,5-dichloro-2- (trifluoromethyl)benzene (43 mg, 0.065 mmol) in EtOH (3.0 mL) 2-(4-chloro-2,3- difluorophenyl)-3-(dimethylamino)prop-2-enal (19.2 mg, 0.078 mmol) followed by concentrated HCl (0.15 mL) were added and the mixture was stirred 2 h at 80 °C. The mixture was concentrated and purified by prep HPLC [MeCN/H₂O (10 mmol/L NH4HCO3), X-Select 10 µm 19*250 mm, 20 mL/min, UV 254] to afford the title compound (8.19 mg, 19 %). ESI-MS m/z calcd for [C + 25H19Cl3F5N5O4] [M+H] : 654.0; found: 654.0. 1H NMR (400 MHz, Methanol-d₄) δ 8.25 (d, J = 1.2 Hz, 1H), 8.17 (s, 1H), 7.97 (s, 1H), 7.95 (s, 1H), 7.51 – 7.46 (m, 1H), 7.31 – 7.26 (m, 1H), 4.76 – 4.72 (m, 1H), 4.43 (dd, J = 10.8, 2.8 Hz, 1H), 4.34 (d , J = 9.2 Hz, 1H), 4.09 (d , J = 2.4 Hz, 1H), 3.70 – 3.62 (m, 3H), 2.43 (s, 3H). Example 37 4,5-Dichloro-1-{5-{3-deoxy-3-[4-(4,5-difluorobenzothiazol-6-yl)-1H-1,2-pyrazol- 1-yl]-β-D-galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-2- (trifluoromethyl)benzene

A nitrogen purged solution of 4,5-dichloro-1-{5-[3-deoxy-3-(4-iodo-1H-1,2-pyrazol- 1-yl)-β-D-galactopyranosyl)-3-methyl-1H-1,2,4-triazol-1-yl]-2- (trifluoromethyl)benzene (56 mg, 0.088 mmol), 4,5-difluoro-6-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1,3-benzothiazole (34.1 mg, 0.12 mmol), Pd(dppf)Cl₂ (12.9 mg, 0.018 mmol) and K₂CO₃ (36.6 mg, 0.27 mmol) in 1,4-dioxane/H₂O (3 mL, 2:1) was stirred 1 h at 60 °C. The mixture was filtered, concentrated, and purified by prep HPLC [MeCN/H₂O (10 mmol/L NH₄HCO₃), X-Select 10 µm 19*250 mm, 20 mL/min, UV 254] to afford the title compound (12.3 mg, 21 %). ESI-MS m/z calcd for [C H Cl F N O S] [M+H]+: 677.1; fou 1 26 19 2 5 6 4 nd: 677.2. H NMR (400 MHz, Methanol-d4) δ 9.26 (s, 1H), 8.33 (d , J = 2.0 Hz, 1H), 8.19 (d , J = 2.0 Hz, 1H), 8.17 (s, 1H), 8.05 (s, 1H), 7.95 (s, 1H), 4.86 – 4.75 (m, 1H), 4.45 (dd, J = 10.8, 2.8 Hz, 1H), 4.36 (d , J = 9.6 Hz, 1H), 4.12 (d , J = 2.8 Hz, 1H), 3.71 – 3.63 (m, 3H), 2.44 (s, 3H). Example 38 6-{5-{3-Deoxy-3-[4-(4,5-difluorobenzothiazol-6-yl)-1H-1,2-pyrazol-1-yl]-β-D- galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-2-methylbenzothiazole

To a solution of 6-{5-[3-(4-bromo-1H-1,2-pyrazol-1-yl)-3-deoxy-β-D- galactopyranosyl]-3-methyl-1H-1,2,4-triazol-1-yl}-2-methylbenzothiazole (30 mg, 0.058 mmol) in 1,4-dioxane/H2O (4.0 mL, 3:1) 4,5-difluoro-6-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1,3-benzothiazole (25.6 mg, 0.086 mmol), Pd(dppf)Cl2 (8.42 mg, 0.012 mmol) and K₂CO₃ (15.9 mg, 0.12 mmol) were added. The mixture was purged three times with nitrogen, and stirred 5 h at 100 °C. The mixture was filtered, concentrated, and purified by prep HPLC [MeCN/H₂O (10 mmol/L NH₄HCO₃), X- Select 10 µm 19*250 mm, 20 mL/min, UV 254] to afford the title compound (4.5 mg, 13 %). ESI-MS m/z calcd for [C + 1 27H23F2N7O4S2] [M+H] : 612.1; found: 612.2. H NMR (400 MHz, DMSO-d6) δ 9.45 (s, 1H), 8.46 (d, J = 2.0 Hz, 1H), 8.43 (dd, J = 6.0, 1.6 Hz, 1H), 8.32 (d, J = 1.6 Hz, 1H), 8.07 (d, J = 8.4 Hz, 1H), 8.04 (d, J = 1.2 Hz, 1H), 7.76 (dd, J = 8.8, 2.4 Hz, 1H), 5.41 (d, J = 7.2 Hz, 1H), 5.21 (d, J = 6.0 Hz, 1H), 4.93 – 4.84 (m, 2H), 4.55 (dd, J = 10.8, 2.8 Hz, 1H), 4.42 (d, J = 9.2 Hz, 1H), 3.99 – 3.96 (m, 1H), 3.77 (dd, J = 7.2, 4.4 Hz, 1H), 3.63 – 3.56 (m, 1H), 3.53 – 3.48 (m, 1H), 2.86 (s, 3H), 2.40 (s, 3H). Example 39 6-{5-{3-Deoxy-3-[4-(2,3,4-trifluorophenyl)-1H-1,2-pyrazol-1-yl]-β-D- galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-2-methylbenzothiazole

To a solution of 6-{5-{4,6-O-benzylidene-3-[(2-tert-butoxycarbonyl)hydrazinyl]-3- deoxy-β-D-galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-2-methylbenzothiazole (55 mg, 0.093 mmol) in EtOH (5 mL) 3-(dimethylamino)-2-(2,3,4- trifluorophenyl)prop-2-enal (25.4 mg, 0.11 mmol) and concentrated HCl (0.3 mL) were added and the mixture was stirred 2 h at 80 °C. The mixture was cooled to 0 °C and basified using aq NaHCO3. The mixture was concentrated and purified by prep HPLC [MeCN/H₂O (10 mmol/L NH₄HCO₃), X-Select 10 µm 19*250 mm, 20 mL/min, UV 254] to afford the title compound (25 mg, 47 %). ESI-MS m/z calcd for [C H F N O S] [M+H + 1 26 23 3 6 4 ] : 573.2; found: 573.2. H NMR (400 MHz, DMSO-d6) δ 8.45 (d, J = 2.0 Hz, 1H), 8.23 (d, J = 0.8 Hz, 1H), 8.06 (d, J = 8.8 Hz, 1H), 7.96 (s, 1H), 7.75 (dd, J = 8.4, 2.0 Hz, 1H), 7.65 – 7.59 (m, 1H), 7.39 – 7.32 (m, 1H), 5.40 (d, J = 7.2, Hz, 1H), 5.17 (d, J = 6.4 Hz, 1H), 4.90 (t, J = 5.6 Hz, 1H), 4.88 – 4.82 (m, 1H), 4.52 (dd, J = 10.8, 2.8 Hz, 1H), 4.40 (d, J = 9.2 Hz, 1H), 3.97 – 3.94 (m, 1H), 3.76 (dd, J = 7.2, 4.4 Hz, 1H), 3.61 – 3.55 (m, 1H), 3.53 – 3.47 (m, 1H), 2.86 (s, 3H), 2.40 (s, 3H). Example 40 6-{5-{3-[4-(4-Chloro-2,3-difluorophenyl)-1H-1,2-pyrazol-1-yl]-3-deoxy-β-^D- galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-5-fluoro-2- methylbenzothiazole

To a solution of 6-{5-{4,6-O-benzylidene-3-[(2-tert-butoxycarbonyl)hydrazinyl]-3- deoxy-β-D-galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-5-fluoro-2- methylbenzothiazole (60 mg, 0.098 mmol) in EtOH (4 mL) 2-(4-chloro-2,3- difluorophenyl)-3-(dimethylamino)prop-2-enal (28.9 mg, 0.12 mmol) and concentrated HCl (0.2 mL) were added and the mixture was stirred 2 h at 80 °C. The mixture was concentrated and purified by prep HPLC [MeCN/H2O (10 mmol/L NH4HCO3), X- Select 10 µm 19*250 mm, 20 mL/min, UV 254] to afford the title compound (17.2 mg, 29 %). ESI-MS m/z calcd for [C₂₆H₂₂ClF₃N₆O₄S] [M+H]+: 607.1; found: 607.2. 1H NMR (400 MHz, Methanol-d4) δ 8.30 (d, J = 7.2 Hz, 1H), 8.23 (d, J = 1.6 Hz, 1H), 7.95 (s, 1H), 7.89 (d, J = 10.4 Hz, 1H), 7.50 – 7.46 (m, 1H), 7.31 – 7.26 (m, 1H), 4.78 (dd, J = 10.4, 9.6 Hz, 1H), 4.42 (dd, J = 10.8, 2.8 Hz, 1H), 4.40 (d, J = 9.6 Hz, 1H), 4.06 (d, J = 2.8 Hz, 1H), 3.72 – 3.63 (m, 3H) , 2.89 (s, 3H), 2.47 (s, 3H). Example 41 5-Bromo-6-{5-{3-[4-(4-chloro-2,3-difluorophenyl)-1H-1,2-pyrazol-1-yl]-3-deoxy- β-D-galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-2-methylbenzothiazole

To a solution of 6-{5-{4,6-O-benzylidene-3-[(2-tert-butoxycarbonyl)hydrazinyl]-3- deoxy-β-D-galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-5-bromo-2- methylbenzothiazole (115 mg, 0.17 mmol) in EtOH (4 mL) 2-(4-chloro-2,3- difluorophenyl)-3-(dimethylamino)prop-2-enal (50.3 mg, 0.21 mmol) and concentrated HCl (0.2 mL) were added and the mixture was stirred 2 h at 80 °C. The mixture was concentrated and purified by prep HPLC [MeCN/H2O (10 mmol/L NH4HCO3), X- Select 10 µm 19*250 mm, 20 mL/min, UV 254] to afford the title compound (32 mg, 28 %). ESI-MS m/z calcd for [C H BrClF N + 1 26 22 2 6O4S] [M+H] : 667.0; found: 667.0. H NMR (400 MHz, DMSO-d6) δ 8.41 – 8.24 (m, 3H), 7.98 (s, 1H), 7.65 – 7.61 (m, 1H), 7.46 – 7.43 (m, 1H), 5.38 (d, J = 6.8 Hz, 1H), 5.04 (d, J = 6.0 Hz, 1H), 4.64 – 4.58 (m, 2H), 4.44 (dd, J = 10.8, 2.8 Hz, 1H), 4.15 – 4.11 (m, 1H), 3.88 (s, 1H), 3.52 – 3.41 (m, 3H) , 2.88 (s, 3H), 2.39 (s, 3H). Example 42 6-{5-{3-[4-(4-Chloro-2,3-difluorophenyl)-1H-1,2-pyrazol-1-yl]-3-deoxy-β-D- galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-5-cyano-2- methylbenzothiazole

To a solution 5-bromo-6-{5-{3-[4-(4-chloro-2,3-difluorophenyl)-1H-1,2-pyrazol-1- yl]-3-deoxy-β-D-galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-2- methylbenzothiazole (25.0 mg, 0.037 mmol) in dry DMSO (5 mL) CuCN (33.5 mg, 0.37 mmol) was added. The mixture was purged three times with nitrogen and stirred 6 h at 120 °C. The mixture was filtered, concentrated, and purified by prep HPLC [MeCN/H2O (10 mmol/L NH4HCO3), X-Select 10 µm 19*250 mm, 20 mL/min, UV 254] to afford the title compound (1.15 mg, 5 %). ESI-MS m/z calcd for [C₂₇H₂₂ClF₂N₇O₄S] [M+H]+: 614.1; found: 614.2.1H NMR (400 MHz, Methanol-d₄) δ 8.52 (s, 1H), 8.49 (s, 1H), 8.24 (d, J = 1.6 Hz, 1H), 7.95 (s, 1H), 7.50 – 7.46 (m, 1H), 7.31 – 7.26 (m, 1H), 4.82 (dd, J = 10.8, 9.6 Hz, 1H), 4.44 (d, J = 9.2 Hz, 1H), 4.42 (dd, J = 10.8, 2.7 Hz, 1H), 4.07 (d, J = 2.8 Hz, 1H), 3.74 – 3.63 (m, 3H) , 2.93 (s, 3H), 2.49 (s, 3H). Example 43 6-{5-{3-[4-(4-Chloro-2,3-difluorophenyl)-1H-1,2-pyrazol-1-yl]-3-deoxy-β-D- galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-5-(trifluoromethyl)-2- methylbenzothiazole

To a solution of 6-{5-{4,6-O-benzylidene-3-[(2-tert-butoxycarbonyl)hydrazinyl]-3- deoxy-β-D-galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-5-(trifluoromethyl)-2- methylbenzothiazole (35 mg, 0.053 mmol) in EtOH (5 mL) 2-(4-chloro-2,3- difluorophenyl)-3-(dimethylamino)prop-2-enal (15.6 mg, 0.063 mmol) and concentrated HCl (0.2 mL) were added and the mixture was stirred 2 h at 80 °C. The mixture was cooled to rt and basified to pH=8 using aq NaHCO3. The mixture was concentrated and purified by prep HPLC [MeCN/H₂O (10 mmol/L NH₄HCO₃), X- Select 10 µm 19*250 mm, 20 mL/min, UV 254] to afford the title compound (15 mg, 43 %). ESI-MS m/z calcd for [C + 1 27H22ClF5N6O4S] [M+H] : 657.1; found: 657.2. H NMR (400 MHz, DMSO-d6) δ 8.48 (s, 1H), 8.45 – 8.36 (m, 1H), 8.25 (s, 1H), 7.98 (s, 1H), 7.64 (dd, J = 8.8, 7.6 Hz, 1H), 7.45 (dd, J = 8.4, 7.2 Hz, 1H), 5.39 (d, J = 7.6, Hz, 1H), 5.07 (d, J = 6.0, Hz, 1H), 4.81 – 4.64 (m, 2H), 4.42 (dd, J = 10.8, 2.4, Hz, 1H), 4.16 – 4.11 (m, 1H), 3.87 – 3.84 (m, 1H), 3.49 – 3.33 (m, 3H), 2.89 (s, 3H), 2.38 (s, 3H). Example 44 6-{5-{3-Deoxy-3-[4-(4,5-difluorobenzothiazol-6-yl)-1H-1,2-pyrazol-1-yl]-β-D- galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-5-fluoro-2- methylbenzothiazole

To a solution of 6-{5-[3-deoxy-3-(4-iodo-1H-1,2-pyrazol-1-yl)-β-D-galactopyranosyl]- 3-methyl-1H-1,2,4-triazol-1-yl}-5-fluoro-2-methylbenzothiazole (38 mg, 0.065 mmol) in 1,4-dioxane/H2O (4 mL, 3:1) Pd(dppf)Cl2 (9.48 mg, 0.013 mmol), 4,5-difluoro-6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-benzothiazole (28.9 mg, 0.097 mmol) and K₂CO₃ (17.9 mg, 0.13 mmol) were added. The mixture was purged three times with nitrogen, and stirred 2 h at 65 °C. The mixture was cooled to rt, filtered, concentrated, and purified by prep HPLC [MeCN/H₂O (10 mmol/L NH₄HCO₃), X- Select 10 µm 19*250 mm, 20 mL/min, UV 254] to afford the title compound (2.5 mg, 6 %). ESI-MS m/z calcd for [C H F N O S ] [ + 1 27 22 3 7 4 2 M+H] : 630.1; found: 630.2. H NMR (400 MHz, DMSO-d6) δ 9.45 (s, 1H), 8.42 – 8.39 (m, 2H), 8.29 (d, J = 1.6 Hz, 1H), 8.09 (d, J = 10.4 Hz, 1H), 8.02 (d, J = 0.8 Hz, 1H), 5.42 – 5.41 (m, 1H), 5.12 (d, J = 4.8 Hz, 1H), 4.77 – 4.72 (m, 2H), 4.48 (dd, J = 10.8, 2.8 Hz, 1H), 4.29 (d, J = 9.2 Hz, 1H), 3.92 (s, 1H), 3.60 (t, J = 6.8 Hz, 1H), 3.46 – 3.44 (m, 2H), 2.86 (s, 3H), 2.39 (s, 3H). Example 45 1-{5-{3-[4-(4-Chloro-2,3-difluorophenyl)-1H-1,2-pyrazol-1-yl]-3-deoxy-β-^D- galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-5-cyano-2- (trifluoromethyl)benzene

To a solution of 5-bromo-1-{5-{3-[4-(4-chloro-2,3-difluorophenyl)-1H-1,2-pyrazol-1- yl]-3-deoxy-β-D-galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-2- (trifluoromethyl)benzene (35 mg, 0.053 mmol) in DMF (3.0 mL) Zn(CN)2 (18.5 mg, 0.16 mmol), zinc (3.44 mg, 0.053 mmol), Pd2(dba)3 (3.85 mg, 0.0042 mmol) and 1,1’- ferrocenediyl-bis(diphenylphosphine) (2.38 mg, 0.0042 mmol) were added and the mixture was stirred 2 h at 105 °C. The mixture was filtered, and purified by prep HPLC [MeCN/H2O (10 mmol/L NH4HCO3), X-Select 10 µm 19*250 mm, 20 mL/min, UV 254] to afford the title compound (13.1 mg, 41 %). ESI-MS m/z calcd for [C₂₆H₂₀ClF₅N₆O₄] [M+H]+: 611.1; found: 611.2.1H NMR (400 MHz, Methanol-d₄) δ 8.25 (d, J = 0.8 Hz, 1H), 8.19 (d, J = 7.6 Hz, 1H), 8.17 – 8.11 (m, 2H), 7.96 (s, 1H), 7.52 – 7.45 (m, 1H), 7.33 – 7.25 (m, 1H), 4.80 – 4.71 (m, 1H), 4.42 (dd, J = 10.4, 2.8 Hz, 1H), 4.33 (d, J = 9.2 Hz, 1H), 4.08 (d, J = 2.8 Hz, 1H), 3.69 – 3.59 (m, 3H), 2.44 (s, 3H). Example 46 1-{5-{3-[4-(4-Chloro-2,3-difluorophenyl)-1H-1,2-pyrazol-1-yl]-3-deoxy-β-D- galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-5-cyclopropyl-2- (trifluoromethyl)benzene

To a solution of 5-bromo-1-{5-{3-[4-(4-chloro-2,3-difluorophenyl)-1H-1,2-pyrazol-1- yl]-3-deoxy-β-^D-galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-2- (trifluoromethyl)benzene (46 mg, 0.069 mmol) in 1,4-dioxane/ H₂O (5 mL, 4:1) potassium cyclopropyltrifluoroborate (102 mg, 0.69 mmol), K₂CO₃ (28.7 mg, 0.21 mmol) and Pd(dppf)Cl2 (10.1 mg, 0.014 mmol) were added. The mixture was purged three times with nitrogen, and stirred 4 h at 100 °C. The mixture was filtered, evaporated, and purified by prep HPLC [MeCN/H₂O (10 mmol/L NH₄HCO₃), X-Select 10 µm 19*250 mm, 20 mL/min, UV 254] to afford the title compound (25.4 mg, 59 %). ESI-MS m/z calcd for [C + 1 28H25ClF5N5O4] [M+H] : 626.2; found: 626.2. H NMR (400 MHz, Methanol-d₄) δ 8.26 (s, 1H), 7.96 (s, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.50 – 7.46 (m, 2H), 7.30 – 7.26 (m, 2H), 4.78 – 4.63 (m, 1H), 4.41 – 4.39 (m, 1H), 4.22 (d, J = 9.2 Hz, 1H), 4.09 (s, 1H), 3.68 – 3.62 (m, 3H), 2.43 (s, 3H), 2.08 – 2.05 (m, 1H), 1.13 – 1.11 (m, 2H), 0.85 (m, 2H). Example 47 1-{5-{3-[4-(4-Chloro-2,3-difluorophenyl)-1H-1,2-pyrazol-1-yl]-3-deoxy-β-^D- galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-2- (trifluoromethyl)-5-methylbenzene

To a solution of 5-bromo-1-{5-{3-[4-(4-chloro-2,3-difluorophenyl)-1H-1,2-pyrazol-1- yl]-3-deoxy-β-D-galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-2- (trifluoromethyl)benzene (35 mg, 0.053 mmol) in 1,4-dioxane/water (3.0 mL, v/v 2:1) Cs₂CO₃ (85.8 mg, 0.26 mmol), Pd(dppf)Cl₂ (7.7 mg, 0.011 mmol) and 2,4,6-trimethyl- 1,3,5,2,4,6-trioxatriborinane (50 wt% in THF, 39.7 mg, 0.16 mmol) were added. The mixture was purged three times with nitrogen and stirred 2 h at 100 °C. The mixture was filtered, concentrated, and purified by prep HPLC [MeCN/H₂O (10 mmol/L NH4HCO3), X-Select 10 µm 19*250 mm, 20 mL/min, UV 254] to afford the title compound (15.5 mg, 49 %). ESI-MS m/z calcd for [C H ClF N O ] [M+ + 26 23 5 5 4 H] : 600.1; found: 600.2. 1H NMR (400 MHz, Methanol-d₄) δ 8.26 (d, J = 1.2 Hz, 1H), 7.96 (s, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.53 – 7.44 (m, 2H), 7.34 – 7.25 (m, 1H), 4.83 – 4.76 (m, 1H), 4.40 (dd, J = 10.8, 2.8 Hz, 1H), 4.21 (d, J = 9.2 Hz, 1H), 4.08 (d, J = 2.8 Hz, 1H), 3.71 – 3.60 (m, 3H), 2.49 (s, 3H), 2.44 (s, 3H). Example 48 1-{5-{3-[4-(4-Chloro-2,3-difluorophenyl)-1H-1,2-pyrazol-1-yl]-3-deoxy-β-^D- galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-2- (trifluoromethyl)-5-(1-methylcyclopropyl)benzene

To a solution of 5-bromo-1-{5-{3-[4-(4-chloro-2,3-difluorophenyl)-1H-1,2-pyrazol-1- yl]-3-deoxy-β-D-galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-2- (trifluoromethyl)benzene (35 mg, 0.053 mmol) in 1,4-dioxane/water (3.0 mL, v/v 2:1) Cs2CO3 (85.8 mg, 0.26 mmol), Pd(dppf)Cl2 (7.7 mg, 0.011 mmol) and 4,4,5,5- tetramethyl-2-(1-methylcyclopropyl)-1,3,2-dioxaborolane (28.8 mg, 0.16 mmol) were added. The mixture was purged three times with nitrogen and stirred 2 h at 100 °C. The mixture was filtered, concentrated, and purified by prep HPLC [MeCN/H₂O (10 mmol/L NH4HCO3), X-Select 10 µm 19*250 mm, 20 mL/min, UV 254] to afford the title compound (8.27 mg, 25 %). ESI-MS m/z calcd for [C₂₉H₂₇ClF₅N₅O₄] [M+H]+: 640.2; found: 640.2. 1H NMR (400 MHz, Methanol-d4) δ 8.25 (s, 1H), 7.96 (s, 1H), 7.83 (d, J = 8.4 Hz, 1H), 7.63 (d, J = 8.8 Hz, 1H), 7.53 – 7.46 (m, 1H), 7.41 (s, 1H), 7.33 – 7.25 (m, 1H), 4.82 – 4.75 (m, 1H), 4.39 (dd, J = 10.8, 2.8 Hz, 1H), 4.23 (d, J = 9.2 Hz, 1H), 4.09 (d, J = 2.8 Hz, 1H), 3.71 – 3.60 (m, 3H), 2.44 (s, 3H), 1.47 (s, 3H), 1.07 – 0.87 (m, 4H). Example 49 1-{5-{3-[4-(4-Chloro-2,3-difluorophenyl)-1H-1,2-pyrazol-1-yl]-3-deoxy-β-D- galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-2-(trifluoromethyl)-5- (methylthio)benzene

To a solution of 1-{5-{4,6-O-benzylidene-3-[(2-tert-butoxycarbonyl)hydrazinyl]-3- deoxy-β-D-galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-2-(trifluoromethyl)-5- (methylthio)benzene (20 mg, 0.031 mmol) in EtOH (2.0 mL) 2-(4-chloro-2,3- difluorophenyl)-3-(dimethylamino)prop-2-enal (8.5 mg, 0.035 mmol) was added followed by concentrated HCl (0.1 mL) and the mixture was stirred 1 h at 80 °C. The mixture was concentrated and purified by prep HPLC [MeCN/H2O (10 mmol/L NH4HCO3), X-Select 10 µm 19*250 mm, 20 mL/min, UV 254] to afford the title compound (4.9 mg, 25 %). ESI-MS m/z calcd for [C₂₆H₂₃ClF₅N₅O₄S] [M+H]+: 632.2; found: 632.1. 1H NMR (400 MHz, Methanol-d₄) δ 8.26 (d, J = 1.6 Hz, 1H), 7.96 (s, 1H), 7.80 (d, J = 8.4 Hz, 1H), 7.61 (d, J = 8.4, 1H), 7.51 – 7.46 (m, 1H), 7.43 (s, 1H), 7.34 – 7.24 (m, 1H), 4.82 – 4.72 (m, 1H), 4.42 (dd, J = 10.4, 2.8 Hz, 1H), 4.28 (d, J = 9.2 Hz, 1H), 4.10 (d, J = 2.8 Hz, 1H), 3.70 – 3.62 (m, 3H), 2.54 (s, 3H), 2.44 (s, 3H). Example 50 5-Bromo-1-{5-{3-[4-(4-chloro-2,3-difluorophenyl)-1H-1,2-pyrazol-1-yl]-3-deoxy- β-D-galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-4-fluoro-2- (trifluoromethyl)benzene

To a solution of 1-[5-(4,6-O-benzylidene-3-[(2-tert-butoxycarbonyl)hydrazinyl]-3- deoxy-β-D-galactopyranosyl)-3-methyl-1H-1,2,4-triazol-1-yl]-5-bromo-4-fluoro-2- (trifluoromethyl)benzene (43 mg, 0.063 mmol) in EtOH (2.0 mL) 2-(4-chloro-2,3- difluorophenyl)-3-(dimethylamino)prop-2-enal (16.1 mg, 0.066 mmol) was added followed by concentrated HCl (0.2 mL) and the mixture was stirred 2 h at 80 °C. The mixture was concentrated and purified by prep HPLC [MeCN/H2O (10 mmol/L NH₄HCO₃), X-Select 10 µm 19*250 mm, 20 mL/min, UV 254] to afford the title compound (8.31 mg, 20 %). ESI-MS m/z calcd for [C₂₅H₁₉BrClF₆N₅O₄] [M+H]+: 682.0; found: 682.0.1H NMR (400 MHz, Methanol-d4) δ 8.25 – 8.24 (m, 1H), 8.05 – 8.02 (m, 1H), 7.97 (s, 1H), 7.89 (d, J = 8.4 Hz, 1H), 7.51 – 7.46 (m, 1H), 7.31 – 7.26 (m, 1H), 4.78 – 4.72 (m, 1H), 4.42 (dd, J = 10.8, 2.8 Hz, 1H), 4.32 (d, J = 9.6 Hz, 1H), 4.09 (d, J = 2.8 Hz, 1H), 3.69 – 3.62 (m, 3H), 2.43 (s, 3H). Example 51 3-{5-{3-[4-(4-Chloro-2,3-difluorophenyl)-1H-1,2-pyrazol-1-yl]-3-deoxy-β-D- galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-2-(trifluoromethyl)-5- methylpyridine

To a solution of 5-bromo-3-{5-{3-[4-(4-chloro-2,3-difluorophenyl)-1H-1,2-pyrazol-1- yl]-3-deoxy-β-D-galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-2- (trifluoromethyl)pyridine (50 mg, 0.075 mmol) in 1,4-dioxane/water (5.0 mL, v/v 4:1) K2CO3 (51.9 mg, 0.38 mmol), Pd(dppf)Cl2 (11.0 mg, 0.015 mmol) and 2,4,6-trimethyl- 1,3,5,2,4,6-trioxatriborinane (50 wt% in THF, 189 mg, 0.75 mmol) were added. The mixture was purged three times with nitrogen and stirred 2 h at 80 °C. The mixture was filtered, concentrated, and purified by prep HPLC [MeCN/H2O (10 mmol/L NH₄HCO₃), X-Select 10 µm 19*250 mm, 20 mL/min, UV 254] to afford the title compound (16.4 mg, 36 %). ESI-MS m/z calcd for [C H C + 25 22 lF5N6O4] [M+H] : 601.1; found: 601.2. 1H NMR (400 MHz, Methanol-d4) δ 8.74 (s, 1H), 8.24 (d, J = 1.6 Hz, 1H), 7.99 – 7.96 (m, 2H), 7.50 – 7.45 (m, 1H), 7.30 – 7.26 (m, 1H), 4.82 – 4.74 (m, 1H), 4.41 (dd, J = 10.8, 2.8 Hz, 1H), 4.31 (d, J = 9.6 Hz, 1H), 4.07 (d, J = 2.8 Hz, 1H), 3.66 – 3.59 (m, 3H), 2.53 (s, 3H), 2.44 (s, 3H). Example 52 5-Chloro-1-{5-{3-deoxy-3-[4-(2,3-difluoro-4-isopropylphenyl)-1H-1,2-pyrazol-1- yl]-β-^D-galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-2- (trifluoromethyl)benzene

To a solution of 5-chloro-1-{5-{3-deoxy-3-{4-[2,3-difluoro-4-(1- methylethenyl)phenyl]-1H-1,2-pyrazol-1-yl}-β-D-galactopyranosyl}-3-methyl-1H- 1,2,4-triazol-1-yl}-2-(trifluoromethyl)benzene (70 mg, 0.11 mmol) in THF (6 mL) platinum(IV) oxide (5.1 mg, 0.022 mmol) was added and the mixture was stirred 8 h at rt under H₂. The mixture was filtered, concentrated, and purified by prep HPLC [MeCN/H2O (10 mmol/L NH4HCO3), X-Select 10 µm 19*250 mm, 20 mL/min, UV 254] to afford the title compound (25 mg, 36 %). ESI-MS m/z calcd for [C₂₈H₂₇ClF₅N₅O₄] [M+H]+: 628.2; found: 628.2. 1H NMR (400 MHz, DMSO-d₆) δ 8.16 (s, 1H), 8.03 (d, J = 8.8 Hz, 1H), 7.95 – 7.92 (m, 2H), 7.76 (s, 1H), 7.51 – 7.47 (m, 1H), 7.17 – 7.13 (m, 1H), 5.41 (d, J = 6.4 Hz, 1H), 5.07 (d, J = 5.6 Hz, 1H), 4.67 – 4.61 (m, 2H), 4.46 (dd, J = 10.4, 2.4 Hz, 1H), 4.23 (d, J = 9.2 Hz, 1H), 3.92 (dd, J = 6.0, 2.8 Hz, 1H), 3.56 (t, J = 6.8 Hz, 1H), 3.44 – 3.36 (m, 2H), 3.22 – 3.15 (m, 1H), 2.36 (s, 3H), 1.24 (d, J = 7.2 Hz, 6H). Example 53 5-Chloro-1-{5-{3-deoxy-3-[4-(2,3-difluoro-4-ethenylphenyl)-1H-1,2-pyrazol-1-yl]- β-^D-galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-2- (trifluoromethyl)benzene

To a solution of 1-{5-{3-[4-(4-bromo-2,3-difluorophenyl)-1H-1,2-pyrazol-1-yl]-3- deoxy-β-D-galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-5-chloro-2- (trifluoromethyl)benzene (47 mg, 0.071 mmol) in 1,4-dioxane/water (6 mL, v/v 5:1) K₂CO₃ (29.3 mg, 0.21 mmol), Pd(PPh₃)₄ (8.17 mg, 0.007 mmol) and 2,4,6- trivinylcyclotriboroxane pyridine complex (25.5 mg, 0.11 mmol) were added and the mixture was stirred 2 h at 80 °C. The mixture was cooled to rt, filtered, concentrated, and purified by prep HPLC [MeCN/H₂O (10 mmol/L NH₄HCO₃), X-Select 10 µm 19*250 mm, 20 mL/min, UV 254] to afford the title compound (31 mg, 57 %). ESI-MS m/z calcd for [C + 1 27H23ClF5N5O4] [M+H] : 612.1; found: 612.0. H NMR (400 MHz, Methanol-d₄) δ 8.25 (d, J = 1.2 Hz, 1H), 7.96 – 7.93 (m, 2H), 7.85 (dd, J = 8.4, 1.2 Hz, 1H), 7.77 (br s, 1H), 7.46 – 7.42 (m, 1H), 7.38 – 7.34 (m, 1H), 6.85 (dd, J = 17.6, 11.2 Hz, 1H), 5.91 (dd, J = 18.0, 1.2 Hz, 1H), 5.43 (d, J = 11.2 Hz, 1H), 4.82 – 4.77 (m, 1H), 4.42 (dd, J = 10.8, 2.8 Hz, 1H), 4.29 (d, J = 9.2 Hz, 1H), 4.10 (d, J = 2.8 Hz, 1H), 3.68 – 3.64 (m, 3H), 2.44 (s, 3H). Example 54 5-Chloro-1-{5-{3-deoxy-3-[4-(2,3-difluoro-4-etylphenyl)-1H-1,2-pyrazol-1-yl]-β- D-galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-2-(trifluoromethyl)benzene

To a solution of 5-chloro-1-{5-{3-deoxy-3-[4-(2,3-difluoro-4-ethenylphenyl)-1H-1,2- pyrazol-1-yl]-β-D-galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-2- (trifluoromethyl)benzene (31 mg, 0.041 mmol) in THF (5 mL) platinum(IV) oxide (2.8 mg, 0.012 mmol) was added and the mixture was stirred 5 h at rt under H2. The mixture was filtered, concentrated, and purified by prep HPLC [MeCN/H₂O (10 mmol/L NH4HCO3), X-Select 10 µm 19*250 mm, 20 mL/min, UV 254] to afford the title compound (2.5 mg, 10 %). ESI-MS m/z calcd for [C + 27H25ClF5N5O4] [M+H] : 614.2; found: 614.1.1H NMR (400 MHz, Methanol-d₄) δ 8.21 (d, J = 1.2 Hz, 1H), 7.95 (d, J = 8.4 Hz, 1H), 7.92 (s, 1H), 7.85 (d, J = 8.8 Hz, 1H), 7.78 – 7.76 (m, 1H), 7.39 – 7.35 (m, 1H), 7.06 – 7.03 (m, 1H), 4.84 – 4.80 (m, 1H), 4.40 (dd, J = 10.4, 2.8 Hz, 1H), 4.29 (d, J = 9.2 Hz, 1H), 4.09 (d, J = 3.2 Hz, 1H), 3.66 (s, 3H), 2.70 (q, J = 7.2 Hz, 2H), 2.44 (s, 3H), 1.24 (t, J = 7.6 Hz, 3H). Example 55 5-Bromo-3-{5-{3-deoxy-3-[4-(2,3-difluoro-4-methoxyphenyl)-1H-1,2-pyrazol-1- yl]-β-D-galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-2- (trifluoromethyl)pyridine

To a solution of 3-{5-{4,6-O-benzylidene-3-[(2-tert-butoxycarbonyl)hydrazinyl]-3- deoxy-β-D-galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-5-bromo-2- (trifluoromethyl)pyridine (20 mg, 0.034 mmol) in EtOH (5.0 mL) 2-(2,3-difluoro-4- methoxyphenyl)-3-(dimethylamino)prop-2-enal (7.9 mg, 0.033 mmol) was added followed by concentrated HCl (0.2 mL) and the mixture was stirred 2 h at 80 °C. The mixture was cooled to 0 °C and basified to pH=8 using aq NaHCO₃. The mixture was concentrated and purified by prep HPLC [MeCN/H2O (10 mmol/L NaHCO3), X-Select 10 µm 19*250 mm, 20 mL/min, UV 254] to afford the title compound (3.3 mg, 15 %). ESI-MS m/z calcd for [C₂₅H₂₂BrF₅N₆O₅] [M+H]+: 661.1; found: 660.9.1H NMR (400 MHz, Methanol-d4) δ 9.04 (d, J = 2.0 Hz, 1H), 8.46 (s, 1H), 8.12 (d, J = 1.2 Hz, 1H), 7.87 (s, 1H), 7.39 – 7.34 (m, 1H), 6.97 – 6.92 (m, 1H), 4.70 – 4.65 (m, 1H), 4.44 – 4.38 (m, 2H), 4.08 (d, J = 2.4 Hz, 1H), 3.91 (s, 3H), 3.70 – 3.67 (m, 1H), 3.61 – 3.58 (m, 2H), 2.44 (s, 3H). Example 56 5-Chloro-3-{5-{3-deoxy-3-{4-[2,3-difluoro-4-(trifluoromethoxy)phenyl]-1H-1,2- pyrazol-1-yl}-β-D-galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-2- (trifluoromethyl)pyridine

To a solution of 5-chloro-3-{5-[3-deoxy-3-(4-iodo-1H-1,2-pyrazol-1-yl)-β-D- galactopyranosyl]-3-methyl-1H-1,2,4-triazol-1-yl}-2-(trifluoromethyl)pyridine (30 mg, 0.050 mmol) and 2,3-difluoro-4-(trifluoromethoxy)phenylboronic acid (30.2 mg, 0.13 mmol) in 1,4-dioxane/H₂O (4 mL, 3:1) Pd(dppf)Cl₂ (7.2 mg, 0.01 mmol) and K₂CO₃ (17.3 mg, 0.13 mmol) were added. The mixture was purged three times with nitrogen, and stirred 90 min at 50 °C. The mixture was filtered, concentrated, and purified by prep HPLC [MeCN/H2O (10 mmol/L NH4HCO3), X-Select 10 µm 19*250 mm, 20 mL/min, UV 254] to afford the title compound (5.94 mg, 18 %). ESI-MS m/z calcd. For [C H ClF N O ] [M+H]+: 6 1 25 19 8 6 5 71.1; found: 671.0. H NMR (400 MHz, Methanol-d4) δ 8.94 (d, J = 2.0 Hz, 1H), 8.33 (d, J = 1.2 Hz, 1H), 8.26 (d, J = 1.6 Hz, 1H), 7.98 (s, 1H), 7.59 – 7.54 (m, 1H), 7.27 (t, J = 10.0 Hz, 1H), 4.70 (t, J = 10.0 Hz, 1H), 4.46 – 4.42 (m, 2H), 4.08 (d, J = 2.4 Hz, 1H), 3.69 (t, J = 6.0 Hz, 1H), 3.61 – 3.59 (m, 2H), 2.45 (s, 3H). Example 57 1-{5-{3-[4-(4-Chloro-2,3-difluoro-5-methoxyphenyl)-1H-1,2-pyrazol-1-yl]-3- deoxy-β-^D-galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-5-chloro-2- (trifluoromethyl)benzene

To a solution of 5-chloro-1-{5-[3-deoxy-3-(4-iodo-1H-1,2-pyrazol-1-yl)-β-D- galactopyranosyl]-3-methyl-1H-1,2,4-triazol-1-yl}-2-(trifluoromethyl)benzene (26 mg, 0.043 mmol) and (4-chloro-2,3-difluoro-5-methoxyphenyl)boronic acid (19.3 mg, 0.087 mmol) in 1,4-dioxane/H₂O (5.0 mL, 4:1) Pd(dppf)Cl₂ (3.17 mg, 0.0043 mmol) and K₂CO₃ (30.0 mg, 0.22 mmol) were added. The mixture was purged three times with nitrogen, and stirred 3 h at 50 °C. The mixture was filtered, concentrated, and purified by prep HPLC [MeCN/H2O (10 mmol/L TFA), X-Select 10 µm 19*250 mm, 20 mL/min, UV 254] to afford the title compound (8.0 mg, 28 %). ESI-MS m/z calcd for [C H Cl F N O ] [M+H]+: 650. 1 26 22 2 5 5 5 1; found: 650.0. H NMR (400 MHz, DMSO-d6) δ 8.34 (s, 1H), 8.04 – 8.02 (m, 2H), 7.94 (dd, J = 8.8, 1.6 Hz, 1H), 7.75 (s, 1H), 7.29 (dd, J = 6.0, 1.6 Hz, 1H), 5.40 (d, J = 7.2 Hz, 1H), 5.10 (d, J = 6.0 Hz, 1H), 4.70 – 4.68 (m, 1H), 4.63 (t, J = 5.6 Hz, 1H), 4.48 (dd, J = 10.8, 2.4 Hz, 1H), 4.23 (d, J = 9.2 Hz, 1H), 3.96 (s, 3H), 3.92 (dd, J = 6.0, 2.8 Hz, 1H), 3.57 (t, J = 6.4 Hz, 1H), 3.43 – 3.38 (m, 2H), 2.36 (s, 3H). Example 58 5-Chloro-1-{5-{3-deoxy-3-[4-(6,7-difluoro-2-methylbenzothiazol-5-yl)-1H-1,2- pyrazol-1-yl]-β-D-galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-2- (trifluoromethyl)benzene

To a solution of 5-chloro-1-{5-[3-deoxy-3-(4-iodo-1H-1,2-pyrazol-1-yl)-β-^D- galactopyranosyl]-3-methyl-1H-1,2,4-triazol-1-yl}-2-(trifluoromethyl)benzene (30 mg, 0.05 mmol) in 1,4-dioxane/H2O (6 mL, 5:1) 6,7-difluoro-2-methyl-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-benzothiazole (23.3 mg, 0.075 mmol), Pd(dppf)Cl₂ (7.32 mg, 0.01 mmol) and K₂CO₃ (20.7 mg, 0.15 mmol) were added. The mixture was purged three times with nitrogen, and stirred 4 h at 60 °C. The mixture was filtered, and the filtrate was acidified to pH 3-4 using TFA. The mixture was concentrated and purified by prep HPLC [MeCN/H₂O (10 mmol/L TFA), X-Select 10 µm 19*250 mm, 20 mL/min, UV 254] to afford the title compound (14.7 mg, 45 %). ESI-MS m/z calcd for [C H ClF N O S] [M+H + 1 27 22 5 6 4 ] : 657.1; found: 657.0. H NMR (400 MHz, DMSO-d6) δ 8.30 (d, J = 2.0 Hz, 1H), 8.19 (dd, J = 5.6, 1.2 Hz, 1H), 8.09 (s, 1H), 8.03 (d, J = 8.4 Hz, 1H), 7.94 (dd, J = 8.8, 2.0 Hz, 1H), 7.77 (br s, 1H), 5.43 (d, J = 6.8 Hz, 1H), 5.10 (d, J = 5.6 Hz, 1H), 4.73 – 4.61 (m, 2H), 4.49 (dd, J = 10.8, 2.8 Hz, 1H), 4.25 (d, J = 8.8 Hz, 1H), 3.94 – 3.93 (m, 1H), 3.60 – 3.56 (m, 1H), 3.43 – 3.39 (m, 2H), 2.84 (s, 3H), 2.37 (s, 3H). Example 59 5-Chloro-1-{5-{3-deoxy-3-[4-(5,6-difluorobenzothiazol-4-yl)-1H-1,2-pyrazol-1- yl]-β-D-galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-2- (trifluoromethyl)benzene

A nitrogen purged solution of 1-{5-[3-(4-borono-1H-1,2-pyrazol-1-yl)-3-deoxy-β-^D- galactopyranosyl]-3-methyl-1H-1,2,4-triazol-1-yl}-5-chloro-2- (trifluoromethyl)benzene (35 mg, 0.068 mmol), 4-bromo-5,6-difluoro-1,3- benzothiazole (33.8 mg, 0.14 mmol), Pd(dppf)Cl2 (9.89 mg, 0.014 mmol) and K2CO3 (28.0 mg, 0.20 mmol) in 1,4-dioxane/H₂O (3.0 mL, 2:1) was stirred 2 h at 80 °C. The mixture was filtered, concentrated, and purified by prep HPLC [MeCN/H₂O (10 mmol/L NH4HCO3), X-Select 10 µm 19*250 mm, 20 mL/min, UV 254] to afford the title compound (4.2 mg, 10 %). ESI-MS m/z calcd. For [C H C + 26 20 lF5N6O4S] [M+H] : 643.1; found: 643.0. 1H NMR (400 MHz, Methanol-d₄) δ 9.29 (s, 1H), 8.82 (s, 1H), 8.42 (d, J = 2.0 Hz, 1H), 7.96 (d, J = 8.8 Hz, 1H), 7.89 – 7.85 (m, 2H), 7.78 (s, 1H), 4.80 – 4.79 (m, 1H), 4.48 (dd, J = 10.8, 2.8 Hz, 1H), 4.32 (d, J = 9.2 Hz, 1H), 4.13 (d, J = 2.8 Hz, 1H), 3.69 – 3.66 (m, 3H), 2.45 (s, 3H). Example 60 6-{5-{3-[4-(4-Chloro-2,3-difluorophenyl)-1H-1,2-pyrazol-1-yl]-3-deoxy-β-D- galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-2,5-dimethylbenzothiazole

A nitrogen purged solution of 5-bromo-6-{5-{3-[4-(4-chloro-2,3-difluorophenyl)-lJ7- l,2-pyrazol-l-yl]-3-deoxy-P-D-galactopyranosyl}-3-methyl-lJ7-l,2,4-triazol-l-yl}-2- methylbenzothiazole (50 mg, 0.075 mmol), K2CO3 (51.7 mg, 0.37 mmol), Pd(dppf)C12 (11.0 mg, 0.015 mmol) and 2,4,6-trimethyl-l,3,5,2,4,6-trioxatriborinane (50 wt% in THF, 188 mg, 0.75 mmol) in 1,4-dioxane/water (2.0 mL, 4: 1) was stirred 30 min at 100 °C using microwave irradiation. The mixture was filtered, concentrated, and purified by prep HPLC [MeCN/H₂O (10 mmol/L NH4HCO3), X-Select 10 pm 19*250 mm, 20 mL/min, UV 254] to afford the title compound (2.8 mg, 6 %). ESI-MS m/z calcd for [C27H25CIF2N6O4S] [M+H]⁺: 603.1; found: 603.0. 'HNMR (400 MHz, Methanol-d₄) 8

8.23 (d, J = 1.6 Hz, 1H), 8.07 (s, 1H), 7.95 (s, 1H), 7.93 (s, 1H), 7.50 - 7.45 (m, 1H), 7.31 - 7.26 (m, 1H), 4.81 - 4.78 (m, 1H), 4.37 (dd, J= 10.4, 2.8 Hz, 1H), 4.23 (d, J= 9.6 Hz, 1H), 4.04 (d, J = 2.8 Hz, 1H), 3.74 - 3.60 (m, 3H), 2.88 (s, 3H), 2.47 (s, 3H),

2.24 (s, 3H).

Example 61

6-{5-{3-[4-(4-Chloro-2,3-difluorophenyl)-lEZ-l,2-pyrazol-l-yl]-3-deoxy-p-D- galactopyranosyl}-3-methyl-lEZ-l,2,4-triazol-l-yl}-5-methoxy-2- methylbenzothiazole

To a solution of 6-{5-{4,6-O-benzylidene-3-[(2-tert-butoxycarbonyl)hydrazinyl]-3- deoxy-β-D-galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-5-methoxy-2- methylbenzothiazole (24 mg, 30 % purity, 0.12 mmol) in EtOH (3.0 mL) 2-(4-chloro- 2,3-difluorophenyl)-3-(dimethylamino)prop-2-enal (11.3 mg, 0.046 mmol) was added followed by concentrated HCl (0.1 mL) and the mixture was stirred 2 h at 80 °C. The mixture was concentrated and purified by prep HPLC [MeCN/H2O (10 mmol/L NH4HCO3), X-Select 10 µm 19*250 mm, 20 mL/min, UV 254]. The obtained material was purified by prep SFC to afford the title compound (2.5 mg, 35 %). ESI-MS m/z calcd for [C₂₇H₂₅ClF₂N₆O₅S] [M+H]+: 619.1; found: 619.0. 1H NMR (400 MHz, Methanol-d4) δ 8.23 (s, 1H), 8.03 (s, 1H), 7.94 (s, 1H), 7.67 (s, 1H), 7.49 – 7.45 (m, 1H), 7.30 – 7.26 (m, 1H), 4.76 – 4.69 (m, 1H), 4.38 (dd, J = 10.4, 2.4 Hz, 1H), 4.29 (d, J = 8.4 Hz, 1H), 4.05 (d, J = 2.4 Hz, 1H), 3.92 (s, 3H), 3.71 – 3.63 (m, 3H), 2.86 (s, 3H), 2.45 (s, 3H). Example 62 6-{5-{3-[4-(4-Chloro-2,3-difluorophenyl)-1H-1,2-pyrazol-1-yl]-3-deoxy-β-D- galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-2-methyl-5- (methylthio)benzothiazole

To a solution of 6-{5-{4,6-O-benzylidene-3-[(2-tert-butoxycarbonyl)hydrazinyl]-3- deoxy-β-D-galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-2-methyl-5- (methylthio)benzothiazole (10 mg, 0.016 mmol) in EtOH (3.0 mL) 2-(4-chloro-2,3- difluorophenyl)-3-(dimethylamino)prop-2-enal (5.0 mg, 0.020 mmol) was added followed by concentrated HCl (0.1 mL) and the mixture was stirred 2 h at 80 °C. The mixture was concentrated and purified by prep HPLC [MeCN/H₂O (10 mmol/L NH₄HCO₃), X-Select 10 µm 19*250 mm, 20 mL/min, UV 254] to afford the title compound (2.6 mg, 26 %). ESI-MS m/z calcd for [C + 27H25ClF2N6O4S2] [M+H] : 635.1; found: 635.0.1H NMR (400 MHz, Methanol-d₄) δ 8.23 (s, 1H), 8.08 (s, 1H), 7.95 (m, 2H), 7.50 – 7.45 (m, 1H), 7.30 – 7.26 (m, 1H), 4.83 – 4.82 (m, 1H), 4.38 (dd, J = 10.8, 2.8 Hz, 1H), 4.26 – 4.24 (m, 1H), 4.05 (d, J = 2.8 Hz, 1H), 3.70 – 3.60 (m, 3H), 2.88 (s, 3H), 2.52 (s, 3H), 2.46 (s, 3H). Example 63 6-{5-{3-[4-(4-Chloro-2,3-difluorophenyl)-1H-1,2-pyrazol-1-yl]-3-deoxy-β-^D- galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-2-methyl-5- (methylsulfonyl)benzothiazole

To a cooled (0 °C) solution of 6-{5-{2,4,6-tri-O-acetyl-3-[4-(4-chloro-2,3- difluorophenyl)-1H-1,2-pyrazol-1-yl]-3-deoxy-β-D-galactopyranosyl}-3-methyl-1H- 1,2,4-triazol-1-yl}-2-methyl-5-(methylthio)benzothiazole (12 mg, 0.016 mmol) in DCM (5 mL) 3-chloroperbenzoic acid (10.9 mg, 0.063 mmol) was added and the mixture was stirred 3 h at rt. The mixture was partitioned between water (20 mL) and EtOAc (50 mL). The aqueous phase was extracted with EtOAc (2 x 50 mL). The combined organic phases were washed with water (20 mL) and brine (20 mL), dried over Na2SO4, and evaporated. The residue was dissolved in MeOH (5 mL) and a solution of lithium hydroxide monohydrate (6.6 mg, 0.16 mmol) in water (1 mL) was added. The mixture was stirred 1 h at rt. The mixture was concentrated and purified by prep HPLC [MeCN/H2O (10 mmol/L NH4HCO3), X-Select 10 µm 19*250 mm, 20 mL/min, UV 254] to afford the title compound (7.2 mg, 69 %). ESI-MS m/z calcd for [C H ClF N O S ] [M+H]+: 667.1; found: 667. 1 27 25 2 6 6 2 1. H NMR (400 MHz, Methanol-d4) δ 8.69 (s, 1H), 8.47 – 8.35 (m, 1H), 8.27 – 8.16 (m, 1H), 7.94 (s, 1H), 7.49 – 7.45 (m, 1H), 7.30 – 7.26 (m, 1H), 4.97 – 4.92 (m, 1H), 4.39 (dd, J = 10.8, 2.8 Hz, 2H), 4.02 (d, J = 2.4 Hz, 1H), 3.69 – 3.57 (m, 3H), 3.37 (s, 3H), 2.94 (s, 3H), 2.47 (s, 3H). Example 64 6-{5-{3-[4-(4-Chloro-2,3-difluorophenyl)-1H-1,2-pyrazol-1-yl]-3-deoxy-β-D- galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-4-fluoro-2- methylbenzothiazole

To a solution of 6-{5-{4,6-O-benzylidene-3-[(2-tert-butoxycarbonyl)hydrazinyl]-3- deoxy-β-D-galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-4-fluoro-2- methylbenzothiazole (35 mg, 0.057 mmol) in EtOH (3.0 mL) 2-(4-chloro-2,3- difluorophenyl)-3-(dimethylamino)prop-2-enal (15 mg, 0.063 mmol) and concentrated HCl (0.1 mL) were added and the mixture was stirred 2 h at 80 °C. The mixture was concentrated and purified by prep HPLC (MeCN/H2O (10 mmol/L NH4HCO3), X- Select 10 μm 19*250 mm, 20 mL/min, UV 254) to afford the title compound (4.2 mg, 12 %). ESI-MS m/z calcd for [C₂₆H₂₂ClF₃N₆O₄S] [M+H]+: 607.1; found: 607.0.1H NMR (400 MHz, Methanol-d4) δ 8.26 (d, J = 1.2 Hz, 2H), 7.97 (s, 1H), 7.64 (dd, J = 10.8, 2.0 Hz, 1H), 7.51 – 7.46 (m, 1H), 7.31 – 7.26 (m, 1H), 4.93 – 4.87 (m, 1H), 4.54 (d, J = 9.6 Hz, 1H), 4.49 (dd, J = 10.8, 2.8 Hz, 1H), 4.12 (d, J = 2.4 Hz, 1H), 3.84 – 3.80 (m, 2H), 3.71 (d, J = 8.4 Hz, 1H), 2.91 (s, 3H), 2.46 (s, 3H). Example 65 4-Bromo-6-{5-{3-[4-(4-chloro-2,3-difluorophenyl)-1H-1,2-pyrazol-1-yl]-3-deoxy- β-D-galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-2-methylbenzothiazole

To a solution of 6-{5-{4,6-O-benzylidene-3-[(2-tert-butoxycarbonyl)hydrazinyl]-3- deoxy-β-D-galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-4-bromo-2- methylbenzothiazole (40 mg, 0.06 mmol) in EtOH (5 mL) 2-(4-chloro-2,3- difluorophenyl)-3-(dimethylamino)prop-2-enal (22 mg, 0.089 mmol) and concentrated HCl (0.25 mL) were added and the mixture was stirred 2 h at 80 °C. The mixture was concentrated and purified by prep HPLC (MeCN/H2O (10 mmol/L NH4HCO3), X- Select 10 μm 19*250 mm, 20 mL/min, UV 254) to afford the title compound (6.9 mg, 17 %). ESI-MS m/z calcd for [C₂₆H₂₂BrClF₂N₆O₄S] [M+H]+: 667.1; found: 667.0.1H NMR (400 MHz, DMSO-d6) δ 8.51 (d, J = 2.0 Hz, 1H), 8.27 (s, 1H), 8.00 (s, 1H), 7.98 (d, J = 2.0 Hz, 1H), 7.66 – 7.62 (m, 1H), 7.47 – 7.43 (m, 1H), 5.41 (d, J = 6.8 Hz, 1H), 5.18 (d, J = 6.0 Hz, 1H), 4.91 (t, J = 5.6 Hz, 1H), 4.84 – 4.82 (m, 1H), 4.54 (dd, J = 10.8, 2.8 Hz, 1H), 4.45 (d, J = 9.2 Hz, 1H), 3.97 (dd, J = 6.0, 2.8 Hz, 1H), 3.81 – 3.78 (m, 1H), 3.62 – 3.56 (m, 1H), 3.53 – 3.48 (m, 1H), 2.89 (s, 3H), 2.40 (s, 3H). Example 66 6-{5-{3-[4-(4-Chloro-2,3-difluorophenyl)-1H-1,2-pyrazol-1-yl]-3-deoxy-β-D- galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-4-(trifluoromethyl)-2- methylbenzothiazole

To a solution of 6-{5-{4,6-O-benzylidene-3-[(2-tert-butoxycarbonyl)hydrazinyl]-3- deoxy-β-D-galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-4-(trifluoromethyl)— 2-methylbenzothiazole (32 mg, 0.048 mmol) in EtOH (5 mL) 2-(4-chloro-2,3- difluorophenyl)-3-(dimethylamino)prop-2-enal (17 mg, 0.068 mmol) and concentrated HCl (0.25 mL) were added and the mixture was stirred 2 h at 80 °C. The mixture was concentrated and purified by prep HPLC (MeCN/H2O (10 mmol/L NH4HCO3), X- Select 10 μm 19*250 mm, 20 mL/min, UV 254) to afford the title compound (6.9 mg, 22 %). ESI-MS m/z calcd for [C₂₇H₂₂ClF₅N₆O₄S] [M+H]+: 657.1; found: 657.1.1H NMR (400 MHz, Methanol-d₄) δ 8.71 (d, J = 2.0 Hz, 1H), 8.22 (d, J = 1.6 Hz, 1H), 8.08 (d, J = 1.6 Hz, 1H), 7.96 (s, 1H), 7.50 – 7.45 (m, 1H), 7.30 – 7.26 (m, 1H), 4.85 – 4.84 (m, 1H), 4.53 (d, J = 9.6 Hz, 1H), 4.48 (dd, J = 10.8, 2.8 Hz, 1H), 4.12 (d, J = 2.4 Hz, 1H), 3.86 – 3.80 (m, 2H), 3.74 – 3.69 (m, 1H), 2.94 (s, 3H), 2.47 (s, 3H). Example 67 1-{5-{3-[4-(4-Chloro-5,6-difluorobenzothiazol-7-yl)-1H-1,2-pyrazol-1-yl]-3- deoxy-β-D-galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-5-chloro-2- (trifluoromethyl)benzene

A nitrogen purged solution of 1-{5-[3-(4-borono-1H-1,2-pyrazol-1-yl)-3-deoxy-β-D- galactopyranosyl]-3-methyl-1H-1,2,4-triazol-1-yl}-5-chloro-2- (trifluoromethyl)benzene (40 mg, 0.077 mmol), 7-bromo-4-chloro-5,6-difluoro-1,3- benzothiazole (66 mg, 0.23 mmol), Pd(dppf)Cl₂ (5.65 mg, 0.0077 mmol) and K₂CO₃ (32.0 mg, 0.23 mmol) in 1,4-dioxane/H₂O (5 mL, 4:1) was stirred 4 h at 80 °C. The mixture was filtered, concentrated, and purified by prep HPLC [MeCN/H2O (10 mmol/L NH₄HCO₃), X-Select 10 µm 19*250 mm, 20 mL/min, UV 254] to afford the title compound (3.5 mg, 7 %). ESI-MS m/z calcd. For [C₂₆H₁₉Cl₂F₅N₆O₄S] [M+H]+: 677.1; found: 676.9. 1H NMR (400 MHz, Methanol-d4) δ 9.40 (s, 1H), 8.41 (s, 1H), 8.09 (d, J = 1.2 Hz, 1H), 7.96 (d, J = 8.8 Hz, 1H), 7.86 (d, J = 8.4 Hz, 1H), 7.79 – 7.77 (m, 1H), 4.82 – 4.80 (m, 1H), 4.51 (dd, J = 10.8, 2.8 Hz, 1H), 4.32 (d, J = 9.6 Hz, 1H), 4.14 (d, J = 2.8 Hz, 1H), 3.69 – 3.65 (m, 3H), 2.44 (s, 3H). Example 68 1-{5-{3-[4-(7-Chloro-5,6-difluorobenzothiazol-4-yl)-1H-1,2-pyrazol-1-yl]-3- deoxy-β-D-galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-5-chloro-2- (trifluoromethyl)benzene

A nitrogen purged solution of 1-{5-[3-(4-borono-1H-1,2-pyrazol-1-yl)-3-deoxy-β-D- galactopyranosyl]-3-methyl-1H-1,2,4-triazol-1-yl}-5-chloro-2- (trifluoromethyl)benzene (35 mg, 0.068 mmol), 4-bromo-7-chloro-5,6-difluoro-1,3- benzothiazole (38.5 mg, 0.14 mmol), Pd(dppf)Cl₂ (9.89 mg, 0.014 mmol) and K₂CO₃ (28.0 mg, 0.20 mmol) in 1,4-dioxane/H2O (3.0 mL, 2:1) was stirred 2 h at 80 °C. The mixture was filtered, and the filtrate was acidified to pH 3-4 using TFA. The mixture was concentrated, and purified by prep HPLC [MeCN/H₂O (10 mmol/L NH₄HCO₃), X-Select 10 µm 19*250 mm, 20 mL/min, UV 254] to afford the title compound (1.1 mg, 2 %). ESI-MS m/z calcd. For [C + 26H19Cl2F5N6O4S] [M+H] : 677.1; found: 676.9. 1H NMR (400 MHz, Methanol-d4) δ 9.36 (s, 1H), 8.82 (s, 1H), 8.43 (d, J = 2.0 Hz, 1H), 7.96 (d, J = 8.4 Hz, 1H), 7.86 (d, J = 8.4 Hz, 1H), 7.78 – 7.77 (m, 1H), 4.82 – 4.81 (m, 1H), 4.48 (dd, J = 10.8, 2.8 Hz, 1H), 4.32 (d, J = 8.8 Hz, 1H), 4.13 (d, J = 2.8 Hz, 1H), 3.69 – 3.66 (m, 3H), 2.45 (s, 3H). Example 69 1-{5-{3-[4-(4-Chloro-5,6-difluorobenzothiazol-7-yl)-1H-1,2-pyrazol-1-yl]-3- deoxy-β-D-galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-5-chloro-4-fluoro- 2-(trifluoromethyl)benzene

A nitrogen purged solution of 1-{5-[3-(4-borono-1H-1,2-pyrazol-1-yl)-3-deoxy-β-D- galactopyranosyl]-3-methyl-1H-1,2,4-triazol-1-yl}-5-chloro-4-fluoro-2- (trifluoromethyl)benzene (33 mg, 0.047 mmol), 7-bromo-4-chloro-5,6-difluoro-1,3- benzothiazole (27 mg, 0.095 mmol), Pd(dppf)Cl2 (6.94 mg, 0.0095 mmol) and K2CO3 (19.6 mg, 0.14 mmol) in 1,4-dioxane/H₂O (5 mL, 4:1) was stirred 3 h at 80 °C. The mixture was filtered, concentrated, and purified by prep HPLC [MeCN/H2O (10 mmol/L NH4HCO3), X-Select 10 µm 19*250 mm, 20 mL/min, UV 254] to afford the title compound (2.55 mg, 8 %). ESI-MS m/z calcd. For [C₂₆H₁₈Cl₂F₆N₆O₄S] [M+H]+: 695.0; found: 695.0. 1H NMR (400 MHz, Methanol-d4) δ 9.40 (s, 1H), 8.40 (s, 1H), 8.09 (s, 1H), 7.96 – 7.94 (m, 2H), 4.82 – 4.77 (m, 1H), 4.52 (dd, J = 10.4, 2.8 Hz, 1H), 4.35 (d, J = 9.2 Hz, 1H), 4.14 (d, J = 2.8 Hz, 1H), 3.72 – 3.65 (m, 3H), 2.44 (s, 3H). Example 70 3-{5-{3-[4-(3,4-Dichloro-2-fluorophenyl)-1H-1,2-pyrazol-1-yl]-3-deoxy-β-D- galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-5-chloro-2- (trifluoromethyl)pyridine

To a solution of 5-chloro-3-{5-[3-deoxy-3-(4-iodo-1H-1,2-pyrazol-1-yl)-β-^D- galactopyranosyl]-3-methyl-1H-1,2,4-triazol-1-yl}-2-(trifluoromethyl)pyridine (40 mg, 0.067 mmol) in 1,4-dioxane/H2O (4.0 mL, 3:1) 3,4-dichloro-2- fluorophenylboronic acid (16.7 mg, 0.080 mmol), Pd(dppf)Cl₂ (4.9 mg, 0.0067 mmol) and K₂CO₃ (27.6 mg, 0.20 mmol) were added. The mixture was purged three times with nitrogen, and stirred 2 h at 65 °C. The mixture was filtered, and the filtrate was acidified to pH 3-4 using TFA. The mixture was concentrated and purified by prep HPLC [MeCN/H2O (10 mmol/L NH4HCO3), X-Select 10 µm 19*250 mm, 20 mL/min, UV 254] to afford the title compound (21 mg, 49 %). ESI-MS m/z calcd. For [C H Cl F N O ] [M+ + 1 24 19 3 4 6 4 H] : 637.1; found: 637.3. H NMR (400 MHz, DMSO-d6) δ 9.09 (d, J = 2.0 Hz, 1H), 8.42 (d, J = 1.2 Hz, 1H), 8.24 (d, J = 1.6 Hz, 1H), 8.00 (d, J = 1.2 Hz, 1H), 7.79 (t, J = 8.4 Hz, 1H), 7.54 (dd, J = 8.8, 1.6 Hz, 1H), 5.42 (d, J = 6.8 Hz, 1H), 5.08 (d, J = 6.0 Hz, 1H), 4.66 – 4.58 (m, 2H), 4.46 (dd, J = 10.8, 2.8 Hz, 1H), 4.42 (d, J = 9.2 Hz, 1H), 3.90 (dd, J = 5.6, 2.4 Hz, 1H), 3.61 (t, J = 6.0 Hz, 1H), 3.46 – 3.39 (m, 2H), 2.37 (s, 3H). Example 71 3-{5-{3-[4-(4-Chloro-2,3-difluorophenyl)-1H-1,2-pyrazol-1-yl]-3-deoxy-β-^D- galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-2-(trifluoromethyl)-5- (methylthio)pyridine

To a solution of 3-[5-(4,6-O-benzylidene-3-[(2-tert-butoxycarbonyl)hydrazinyl]-3- deoxy-β-D-galactopyranosyl)-3-methyl-1H-1,2,4-triazol-1-yl]-2-(trifluoromethyl)-5- (methylthio)pyridine (22 mg, 0.034 mmol) in EtOH (5 mL) 2-(4-chloro-2,3- difluorophenyl)-3-(dimethylamino)prop-2-enal (8.9 mg, 0.036 mmol) and concentrated HCl (0.25 mL) were added and the mixture was stirred 2 h at 80 °C. The mixture was concentrated and purified by prep HPLC (MeCN/H2O (10 mmol/L NH4HCO3), X- Select 10 μm 19*250 mm, 20 mL/min, UV 254) to afford the title compound (1.2 mg, 5 %). ESI-MS m/z calcd for [C₂₅H₂₂ClF₅N₆O₄S] [M+H]+: 633.1; found: 633.0.1H NMR (400 MHz, Methanol-d₄) δ 8.72 (d, J = 2.0 Hz, 1H), 8.24 (d, J = 1.2 Hz, 1H), 7.96 (s, 1H), 7.90 (s, 1H), 7.50 – 7.46 (m, 1H), 7.31 – 7.26 (m, 1H), 4.75 – 4.69 (m, 1H), 4.43 (dd, J = 10.8, 2.8 Hz, 1H), 4.39 (d, J = 9.2 Hz, 1H), 4.09 (d, J = 2.4 Hz, 1H), 3.69 (t, J = 6.4 Hz, 1H), 3.63 – 3.59 (m, 2H), 2.62 (s, 3H), 2.44 (s, 3H). Example 72 3-{5-{3-[4-(4-Chloro-2,3-difluorophenyl)-1H-1,2-pyrazol-1-yl]-3-deoxy-β-D- galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-2-(trifluoromethyl)-5- ethylpyridine

To a solution of 5-bromo-3-{5-{3-[4-(4-chloro-2,3-difluorophenyl)-1H-1,2-pyrazol-1- yl]-3-deoxy-β-D-galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-2- (trifluoromethyl)pyridine (30 mg, 0.045 mmol) and potassium ethyltrifluoroborate (12.3 mg, 0.090 mmol) in 1,4-dioxane/H₂O (3.0 mL, 6:1) Pd(dppf)Cl₂ (6.59 mg, 0.0090 mmol) and Cs₂CO₃ (44.0 mg, 0.14 mmol) were added. The mixture was purged three times with nitrogen, and stirred overnight at 70 °C. The mixture was filtered, concentrated, and purified by prep HPLC [MeCN/H₂O (10 mmol/L TFA), X-Select 10 µm 19*250 mm, 20 mL/min, UV 254] to afford the title compound (7.1 mg, 26 %). ESI-MS m/z calcd for [C H ClF N O ] [M+H]+: 615 1 26 24 5 6 4 .1; found: 615.0. H NMR (400 MHz, Methanol-d4) δ 8.77 (d, J = 1.2 Hz, 1H), 8.24 (d, J = 1.6 Hz, 1H), 8.00 (s, 1H), 7.96 (s, 1H), 7.50 – 7.46 (m, 1H), 7.31 – 7.26 (m, 1H), 4.78 – 4.67 (m, 1H), 4.41 (dd, J = 10.4, 2.8 Hz, 1H), 4.32 (d, J = 9.6 Hz, 1H), 4.08 (d, J = 2.8 Hz, 1H), 3.69 – 3.57 (m, 3H), 2.88 (q, J = 7.6 Hz, 2H), 2.44 (s, 3H), 1.34 (t, J = 7.6 Hz, 3H). Example 73 5-Bromo-3-{5-{3-[4-(4-chloro-2,3-difluorophenyl)-1H-1,2-pyrazol-1-yl]-3-deoxy- β-D-galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-2-(trifluoromethyl)-6- methylpyridine

To a solution of 3-{5-{4,6-O-benzylidene-3-[(2-tert-butoxycarbonyl)hydrazinyl]-3- deoxy-β-D-galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-5-bromo-2- (trifluoromethyl)-6-methylpyridine (55 mg, 0.080 mmol) in EtOH (6 mL) 2-(4-chloro- 2,3-difluorophenyl)-3-(dimethylamino)prop-2-enal (29.6 mg, 0.12 mmol) and concentrated HCl (0.3 mL) were added and the mixture was stirred 2 h at 80 °C. The mixture was cooled to rt, basified to pH=8 by addition of aq NaHCO3. The mixture was concentrated and purified by prep HPLC (MeCN/H2O (10 mmol/L NH4HCO3), X- Select 10 μm 19*250 mm, 20 mL/min, UV 254) to afford the title compound (21 mg, 39 %). ESI-MS m/z calcd for [C₂₅H₂₁BrClF₅N₆O₄S] [M+H]+: 679.0; found: 679.1.1H NMR (400 MHz, DMSO-d6) δ 8.41 (s, 1H), 8.23 (d, J = 1.2 Hz, 1H), 7.99 (s, 1H), 7.65 – 7.61 (m, 1H), 7.47 – 7.43 (m, 1H), 5.39 (d, J = 6.8, Hz, 1H), 5.07 (d, J = 6.0, Hz, 1H), 4.64 – 4.57 (m, 2H), 4.46 (dd, J = 10.8, 2.8 Hz, 1H), 4.37 (d, J = 9.2 Hz, 1H), 3.91 (dd, J = 6.0, 2.8 Hz, 1H), 3.61 – 3.58 (m, 1H), 3.41 – 3.36 (m, 2H), 2.76 (s, 3H), 2.36 (s, 3H). Example 74 1-{5-{3-[4-(4-Chloro-2,3-difluorophenyl)-1H-1,2-pyrazol-1-yl]-3-deoxy-β-D- galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-5-chloro-3-fluoro-2- (trifluoromethyl)benzene

To a solution of 1-[5-(4,6-O-benzylidene-3-[(2-tert-butoxycarbonyl)hydrazinyl]-3- deoxy-β-D-galactopyranosyl)-3-methyl-1H-1,2,4-triazol-1-yl]-5-chloro-3-fluoro-2- (trifluoromethyl)benzene (40 mg, 0.062 mmol) in EtOH (5.0 mL) 2-(4-chloro-2,3- difluorophenyl)-3-(dimethylamino)prop-2-enal (18.3 mg, 0.075 mmol) was added followed by concentrated HCl (0.2 mL) and the mixture was stirred 2 h at 80 °C. The mixture was concentrated and purified by prep HPLC [MeCN/H2O (10 mmol/L NH4HCO3), X-Select 10 µm 19*250 mm, 20 mL/min, UV 254] to afford the title compound (10.2 mg, 26 %). ESI-MS m/z calcd for [C₂₅H₁₉Cl₂F₆N₅O₄] [M+H]+: 638.1; found: 638.2. 1H NMR (400 MHz, Methanol-d₄) δ 8.24 (d, J = 1.6 Hz, 1H), 7.97 (s, 1H), 7.82 (d, J = 10.8 Hz, 1H), 7.74 – 7.56 (m, 1H), 7.51 – 7.46 (m, 1H), 7.31 – 7.26 (m, 1H), 4.81 – 4.77 (m, 1H), 4.45 – 4.39 (m, 2H), 4.10 (s, 1H), 3.70 – 3.60 (m, 3H), 2.43 (m, 3H). Example 75 1-{5-{3-[4-(4-Chloro-2,3-difluorophenyl)-1H-1,2-pyrazol-1-yl]-3-deoxy-β-D- galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-3,5-dichloro-2- (trifluoromethyl)benzene

To a solution of 1-[5-(4,6-O-benzylidene-3-[(2-tert-butoxycarbonyl)hydrazinyl]-3- deoxy-β-D-galactopyranosyl)-3-methyl-1H-1,2,4-triazol-1-yl]-3,5-dichloro-2- (trifluoromethyl)benzene (65 mg, 0.098 mmol) in EtOH (5.0 mL) 2-(4-chloro-2,3- difluorophenyl)-3-(dimethylamino)prop-2-enal (26.6 mg, 0.11 mmol) was added followed by concentrated HCl (0.25 mL) and the mixture was stirred 1 h at 80 °C. The mixture was concentrated and purified by prep HPLC [MeCN/H2O (10 mmol/L NH₄HCO₃), X-Select 10 µm 19*250 mm, 20 mL/min, UV 254] to afford the title compound (15.2 mg, 24 %). ESI-MS m/z calcd for [C₂₅H₁₉Cl₃F₅N₅O₄] [M+H]+: 654.0; found: 654.0.1H NMR (400 MHz, Methanol-d4) δ 8.23 (s, 1H), 8.05 – 8.03 (m, 1H), 7.96 (s, 1H), 7.81 – 7.66 (m, 1H), 7.50 – 7.46 (m, 1H), 7.30 – 7.26 (m, 1H), 4.73 – 4.62 (m, 1H), 4.47 – 4.41 (m, 2H), 4.12 – 4.07 (m, 1H), 3.71 – 3.52 (m, 3H), 2.43 (s, 3H). Example 76 1-{5-{3-[4-(4-Chloro-2,3-difluorophenyl)-1H-1,2-pyrazol-1-yl]-3-deoxy-β-D- galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-5-chloro-2-(trifluoromethyl)- 3-methylbenzene

To a solution of 1-[5-(4,6-O-benzylidene-3-[(2-tert-butoxycarbonyl)hydrazinyl]-3- deoxy-β-D-galactopyranosyl)-3-methyl-1H-1,2,4-triazol-1-yl]-5-chloro-2- (trifluoromethyl)-3-methylbenzene (40 mg, 0.056 mmol) in EtOH (5.0 mL) 2-(4- chloro-2,3-difluorophenyl)-3-(dimethylamino)prop-2-enal (20.7 mg, 0.84 mmol) was added followed by concentrated HCl (0.30 mL) and the mixture was stirred 2 h at 80 °C. The mixture was cooled to rt and basified to pH=8 by addition of saturated aq NaHCO₃. The mixture was concentrated and purified by prep HPLC [MeCN/H₂O (10 mmol/L NH₄HCO₃), X-Select 10 µm 19*250 mm, 20 mL/min, UV 254] to afford the title compound (15 mg, 42 %). ESI-MS m/z calcd for [C + 26H22Cl2F5N5O4] [M+H] : 634.1; found: 634.1.1H NMR (400 MHz, DMSO-d6) δ 8.20 (s, 1H), 7.93 (s, 1H), 7.80 (s, 1H), 7.59 – 7.37 (m, 3H), 5.19 – 5.12 (s, 1H), 4.84 – 4.81 (s, 1H), 4.68 – 4.59 (m, 1H), 4.45 – 4.41 (m, 1H), 4.41 – 4.28 (m, 1H), 4.25 (d, J = 9.2 Hz, 1H), 3.96 (s, 1H), 3.54 – 3.53 (m, 1H), 3.46 – 3.26 (m, 2H), 2.57 – 2.52 (m, 3H), 2.32 (s, 3H). Example 77 3-{5-{3-[4-(4-Chloro-2,3-difluorophenyl)-1H-1,2-pyrazol-1-yl]-3-deoxy-β-^D- galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-5-chloro-2-(N- methylcarbamoyl)pyridine

To a solution of 3-{5-{3-[4-(4-chloro-2,3-difluorophenyl)-1H-1,2-pyrazol-1-yl]-3- deoxy-β-D-galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-5-chloro-2- (methoxycarbonyl)pyridine (31 mg, 0.051 mmol) in MeOH (2 mL) methylamine (1.00 mL, 2 M in THF, 2.00 mmol) was added and the mixture was stirred 4 h at 50 °C. The mixture was concentrated and purified by prep HPLC (MeCN/H₂O (10 mmol/L NH4HCO3), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254) to afford the title compound (14.5 mg, 47 %). ESI-MS m/z calcd for [C₂₅H₂₃Cl₂F₂N₇O₅] [M+H]+: 610.1; found: 610.2.1H NMR (400 MHz, Methanol-d₄) δ 8.81 (d, J = 2.4 Hz, 1H), 8.22 (d, J = 2.0 Hz, 1H), 8.14 (d, J = 1.6 Hz, 1H), 7.94 (s, 1H), 7.48 – 7.44 (m, 1H), 7.30 – 7.25 (m, 1H), 4.60 – 4.48 (m, 2H), 4.41 (dd, J = 10.4, 2.4 Hz, 1H), 4.05 (d, J = 2.4 Hz, 1H), 3.72 – 3.57 (m, 3H), 2.83 (s, 3H), 2.42 (s, 3H). Example 78 3-{5-{3-[4-(4-Chloro-2,3-difluorophenyl)-1H-1,2-pyrazol-1-yl]-3-deoxy-β-D- galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-5-chloro-2-(N,N- dimethylcarbamoyl)pyridine

To a solution of 3-{5-{3-[4-(4-chloro-2,3-difluorophenyl)-1H-1,2-pyrazol-1-yl]-3- deoxy-β-D-galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-5-chloro-2- (methoxycarbonyl)pyridine (31 mg, 0.051 mmol) in MeOH (2 mL) dimethylamine (3.00 mL, 2 M in THF, 6.00 mmol) was added and the mixture was stirred 24 h at 50 °C. The mixture was concentrated and purified by prep HPLC (MeCN/H₂O (10 mmol/L NH₄HCO₃), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254) to afford the title compound (4.0 mg, 13 %). ESI-MS m/z calcd for [C₂₆H₂₅Cl₂F₂N₇O₅] [M+H]+: 624.1; found: 624.2.1H NMR (400 MHz, Methanol-d4) δ 8.78 (d, J = 2.0 Hz, 1H), 8.45 (d, J = 2.4 Hz, 1H), 8.14 (d, J = 1.6 Hz, 1H), 7.95 (s, 1H), 7.48 – 7.44 (m, 1H), 7.30 – 7.25 (m, 1H), 4.64 – 4.56 (m, 2H), 4.47 (dd, J = 10.0, 2.4 Hz, 1H), 4.11 (d, J = 2.4 Hz, 1H), 3.85 – 3.77 (m, 2H), 3.71 – 3.67 (m, 1H), 2.99 (s, 3H), 2.98 (s, 3H), 2.40 (s, 3H). Example 79 1-{5-{3-[4-(4-Chloro-2,3-difluorophenyl)-1H-1,2-pyrazol-1-yl]-3-deoxy-β-D- galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-5-chloro-3-cyano-2- (trifluoromethyl)benzene

To a solution of 3-bromo-1-{5-{3-[4-(4-chloro-2,3-difluorophenyl)-1H-1,2-pyrazol-1- yl]-3-deoxy-β-D-galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-5-chloro-2- (trifluoromethyl)benzene (30 mg, 0.043 mmol) in DMSO (5 mL) CuCN (76.9 mg, 0.86 mmol) was added. The mixture was purged three times with nitrogen and stirred 4 h at 120 °C. The mixture was filtered, concentrated, and purified by prep HPLC [MeCN/H2O (10 mmol/L NH4HCO3), X-Select 10 µm 19*250 mm, 20 mL/min, UV 254] to afford the title compound (1.6 mg, 6 %). ESI-MS m/z calcd for [C₂₆H₁₉Cl₂F₅N₆O₄] [M+H]+: 645.1; found: 645.2.1H NMR (400 MHz, Methanol-d₄) δ 8.39 (s, 1H), 8.23 (s, 1H), 8.18 – 8.04 (m, 1H), 7.97 (s, 1H), 7.50 – 7.46 (m, 1H), 7.31 – 7.26 (m, 1H), 4.60 – 4.59 (m, 1H), 4.45 – 4.42 (m, 2H), 4.08 (d, J = 2.0 Hz, 1H), 3.69 (t, J = 6.0 Hz, 1H), 3.63 – 3.58 (m, 2H), 2.43 (s, 3H). Example 80 1-{5-{3-[4-(2,4-Dichloro-3-fluorophenyl)-1H-1,2-pyrazol-1-yl]-3-deoxy-β-D- galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-5-chloro-2- (trifluoromethyl)benzene

To a solution of 5-chloro-1-{5-[3-deoxy-3-(4-iodo-1H-1,2-pyrazol-1-yl)-β-D- galactopyranosyl]-3-methyl-1H-1,2,4-triazol-1-yl}-2-(trifluoromethyl)benzene (30 mg, 0.05 mmol) and 2,4-dichloro-3-fluorophenylboronic acid (20.9 mg, 0.1 mmol) in 1,4-dioxane/H₂O (3.0 mL, 2:1) Pd(dppf)Cl₂ (7.3 mg, 0.01 mmol) and K₂CO₃ (20.7 mg, 0.15 mmol) were added. The mixture was purged three times with nitrogen, and stirred 3 h at 50 °C. The mixture was filtered, and the filtrate was acidified to pH 3-4 using TFA. The mixture was concentrated and purified by prep HPLC [MeCN/H2O (10 mmol/L NH₄HCO₃), X-Select 10 µm 19*250 mm, 20 mL/min, UV 254] to afford the title compound (6.2 mg, 20 %). ESI-MS m/z calcd. For [C + 25H20Cl3F4N5O4] [M+H] : 636.1; found: 636.1. 1H NMR (400 MHz, DMSO-d6) δ 8.29 (s, 1H), 7.96 – 7.94 (m, 2H), 7.85 (dd, J = 8.4, 1.2 Hz, 1H), 7.78 (s, 1H), 7.46 – 7.40 (m, 2H), 4.84 – 4.72 (m, 1H), 4.42 (dd, J = 10.4, 2.8 Hz, 1H), 4.29 (d, J = 9.6 Hz, 1H), 4.10 (d, J = 2.4 Hz, 1H), 3.68 – 3.62 (m, 3H), 2.44 (s, 3H). Example 81 3-{5-{3-[4-(2,4-Dichloro-3-fluorophenyl)-1H-1,2-pyrazol-1-yl]-3-deoxy-β-D- galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-5-chloro-2- (trifluoromethyl)pyridine

To a solution of 5-chloro-3-{5-[3-deoxy-3-(4-iodo-1H-1,2-pyrazol-1-yl)-β-D- galactopyranosyl]-3-methyl-1H-1,2,4-triazol-1-yl}-2-(trifluoromethyl)pyridine (30 mg, 0.05 mmol) in 1,4-dioxane/H₂O (3.0 mL, 2:1) 2,4-dichloro-3-fluorophenylboronic acid (31.3 mg, 0.15 mmol), Pd(dppf)Cl₂ (11.0 mg, 0.015 mmol) and K₂CO₃ (34.5 mg, 0.25 mmol) were added. The mixture was purged three times with nitrogen, and stirred 1 h at 60 °C. The mixture was filtered, and the filtrate was acidified to pH 3-4 using TFA. The mixture was concentrated and purified by prep HPLC [MeCN/H2O (10 mmol/L NH₄HCO₃), X-Select 10 µm 19*250 mm, 20 mL/min, UV 254] to afford the title compound (5.5 mg, 17 %). ESI-MS m/z calcd. For [C + 24H19Cl3F4N6O4] [M+H] : 637.1; found: 637.0.1H NMR (400 MHz, Methanol-d4) δ 8.94 (d, J = 2.0 Hz, 1H), 8.33 (d, J = 2.0 Hz, 1H), 8.27 (s, 1H), 7.94 (d, J = 0.4 Hz, 1H), 7.46 – 7.40 (m, 2H), 4.71 – 4.66 (m, 1H), 4.45 – 4.41 (m, 2H), 4.09 (d, J = 2.4 Hz, 1H), 3.71 – 3.56 (m, 3H), 2.44 (s, 3H). Example 82 6-{5-{3-[4-(4-Chloro-2,3-difluorophenyl)-1H-1,2-pyrazol-1-yl]-3-deoxy-β-D- galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-4-chloro-7-(trifluoromethyl) benzothiazole

To a solution of 6-{5-{4,6-O-benzylidene-3-[(2-tert-butoxycarbonyl)hydrazinyl]-3- deoxy-β-^D-galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-4-chloro-7- (trifluoromethyl)benzothiazole (48 mg, 0.070 mmol) in EtOH (5 mL) 2-(4-chloro-2,3- difluorophenyl)-3-(dimethylamino)prop-2-enal (19 mg, 0.077 mmol) was added followed by concentrated HCl (0.25 mL) and the mixture was stirred 1 h at 80 °C. The mixture was cooled to rt, neutralized by addition of saturated aq NaHCO₃. The mixture was concentrated and purified by prep HPLC (MeCN/H2O (10 mmol/L NH4HCO3), X- Select 10 μm 19*250 mm, 20 mL/min, UV 254) to afford the title compound (12 mg, 25 %). ESI-MS m/z calcd for [C H Cl F N O S] [M+H]+: 6 1 26 19 2 5 6 4 77.0; found: 677.1. H NMR (400 MHz, Methanol-d₄) δ 9.62 (s, 1H), 8.24 (s, 1H), 8.04 – 7.85 (m, 2H), 7.50 – 7.46 (m, 1H), 7.30 – 7.26 (m, 1H), 4.85 – 4.83 (m, 1H), 4.40 (dd, J = 10.8, 2.8 Hz, 2H), 4.06 (d, J = 2.8 Hz, 1H), 3.69 – 3.55 (m, 3H), 2.46 (s, 3H). Example 83 1-{5-{3-[4-(4-Chloro-2,3-difluorophenyl)-1H-1,2-pyrazol-1-yl]-3-deoxy-β-D- galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-5-chloro-2-methylbenzene

To a solution of 1-[5-(4,6-O-benzylidene-3-[(2-tert-butoxycarbonyl)hydrazinyl]-3- deoxy-β-D-galactopyranosyl)-3-methyl-1H-1,2,4-triazol-1-yl]-5-chloro-2- methylbenzene (30 mg, 0.052 mmol) in EtOH (4 mL) 2-(4-chloro-2,3-difluorophenyl)- 3-(dimethylamino)prop-2-enal (14.2 mg, 0.058 mmol) was added followed by concentrated HCl (0.2 mL) and the mixture was stirred 1 h at 80 °C. The mixture was concentrated and purified by prep HPLC [MeCN/H2O (10 mmol/L NH4HCO3), X- Select 10 µm 19*250 mm, 20 mL/min, UV 254] to afford the title compound (4.6 mg, 16 %). ESI-MS m/z calcd for [C₂₅H₂₃Cl₂F₂N₅O₄] [M+H]+: 566.1; found: 566.4. 1H NMR (400 MHz, Methanol-d₄) δ 8.25 (d, J = 1.6 Hz, 1H), 7.96 (d, J = 0.8 Hz, 1H), 7.53 – 7.43 (m, 4H), 7.31 – 7.26 (m, 1H), 4.78 (t, J = 10.0 Hz, 1H), 4.41 (dd, J = 10.8, 2.8 Hz, 1H), 4.24 (d, J = 9.2 Hz, 1H), 4.08 (d, J = 2.8 Hz, 1H), 3.73 – 3.66 (m, 3H), 2.45 (s, 3H), 2.11 (s, 3H). Example 84 1-{5-{3-[4-(4-Chloro-2,3-difluoro-6-methoxyphenyl)-1H-1,2-pyrazol-1-yl]-3- deoxy-β-D-galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-5-chloro-2- (trifluoromethyl)benzene

To a solution of 5-chloro-1-{5-[3-deoxy-3-(4-iodo-1H-1,2-pyrazol-1-yl)-β-D- galactopyranosyl]-3-methyl-1H-1,2,4-triazol-1-yl}-2-(trifluoromethyl)benzene (20 mg, 0.033 mmol) in 1,4-dioxane/H2O (1.3 mL, 3:1) 2-(4-chloro-2,3-difluoro-6- methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (51 mg, 0.17 mmol), Pd(dppf)Cl₂ (7.3 mg, 0.010 mmol) and K₂CO₃ (18 mg, 0.17 mmol) were added. The mixture was purged three times with nitrogen, and stirred 2 h at 60 °C. The mixture was purified by prep TLC (PE/EtOAc=5/1). The obtained material was further purified by prep HPLC [MeCN/H₂O (10 mmol/L NH₄HCO₃), X-Select 10 µm 19*250 mm, 20 mL/min, UV 254] to afford the title compound (2.8 mg, 13 %). ESI-MS m/z calcd for [C + 1 26H22Cl2F5N5O5] [M+H] : 650.1; found: 649.8. H NMR (400 MHz, Methanol-d4) δ 8.33 (d, J = 0.8 Hz, 1H), 8.01 (d, J = 2.4 Hz, 1H), 7.95 (d, J = 8.8 Hz, 1H), 7.85 (dd, J = 8.4, 1.2 Hz, 1H), 7.77 (br s, 1H), 6.99 (dd, J = 6.0, 2.4 Hz, 1H), 4.76 – 4.74 (m, 1H), 4.41 (dd, J = 10.8, 2.8 Hz, 1H), 4.29 (d, J = 9.6 Hz, 1H), 4.09 (d, J = 2.8 Hz, 1H), 3.92 (s, 3H), 3.66 (s, 3H), 2.44 (s, 3H). Example 85 1-{5-{3-Deoxy-3-[4-(2,3-difluoro-5-methoxyphenyl)-1H-1,2-pyrazol-1-yl]-β-^D- galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-5-chloro-2- (trifluoromethyl)benzene

A nitrogen purged solution of 5-chloro-1-{5-[3-deoxy-3-(4-iodo-1H-1,2-pyrazol-1-yl)- β-D-galactopyranosyl]-3-methyl-1H-1,2,4-triazol-1-yl}-2-(trifluoromethyl)benzene (33 mg, 0.055 mmol), (2,3-difluoro-5-methoxyphenyl)boronic acid (20.7 mg, 0.11 mmol), Pd(PPh₃)Cl₂ (12.0 mg, 0.017 mmol) and K₂CO₃ (30.4 mg, 0.22 mmol) in 1,4- dioxane/H2O (5 mL, 4:1) was stirred 4 h at 80 °C. The mixture was filtered, concentrated, and purified by prep HPLC [MeCN/H2O (10 mmol/L NH4HCO3), X- Select 10 µm 19*250 mm, 20 mL/min, UV 254] to afford the title compound (13.1 mg, 39 %). ESI-MS m/z calcd for [C + 1 26H23ClF5N5O5] [M+H] : 616.1; found: 616.4. H NMR (400 MHz, Methanol-d4) δ 8.34 (s, 1H), 8.02 (d, J = 2.4 Hz, 1H), 7.96 – 7.93 (m, 1H), 7.87 – 7.84 (m, 1H), 7.78 – 7.75 (m, 1H), 7.08 (q, J = 9.2 Hz, 1H), 6.85 – 6.81 (m, 1H), 4.85 – 4.76 (m, 1H), 4.41 (dd, J = 10.8, 2.8 Hz, 1H), 4.29 (d, J = 9.6 Hz, 1H), 4.09 (d, J = 2.8 Hz, 1H), 3.91 (s, 3H), 3.68 – 3.64 (m, 3H), 2.44 (s, 3H). Example 86 3-{5-{3-[4-(4-Chloro-2,3-difluoro-6-methoxyphenyl)-1H-1,2-pyrazol-1-yl]-3- deoxy-β-^D-galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-5-chloro-2- (trifluoromethyl)pyridine

To a solution of 5-chloro-3-{5-[3-deoxy-3-(4-iodo-1H-1,2-pyrazol-1-yl)-β-D- galactopyranosyl]-3-methyl-1H-1,2,4-triazol-1-yl}-2-(trifluoromethyl)pyridine (30 mg, 0.050 mmol) in 1,4-dioxane/H₂O (3.0 mL, 4:1) 2-(4-chloro-2,3-difluoro-6- methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (76 mg, 0.25 mmol), Pd(dppf)Cl2 (18 mg, 0.025 mmol) and K2CO3 (35 mg, 0.25 mmol) were added. The mixture was purged three times with nitrogen, and stirred 2 h at 60 °C. The mixture was filtered and purified by prep TLC (PE/EtOAc=5/1). The obtained material was further purified by prep HPLC [MeCN/H2O (10 mmol/L NH4HCO3), X-Select 10 µm 19*250 mm, 20 mL/min, UV 254] to afford the title compound (2.5 mg, 8 %). ESI-MS m/z calcd for [C₂₅H₂₁Cl₂F₅N₆O₅] [M+H]+: 651.1; found: 650.8. 1H NMR (400 MHz, Methanol-d4) δ 8.93 (d, J = 2.0 Hz, 1H), 8.33 (s, 1H), 8.30 (s, 1H), 8.00 (d, J = 2.4 Hz, 1H), 6.98 (dd, J= 6.0, 2.4 Hz, 1H), 4.69 - 4.61 (m, 1H), 4.44 - 4.40 (m, 2H), 4.06 (d, J= 2.0 Hz, 1H), 3.92 (s, 3H), 3.68 - 3.66 (m, 1H), 3.61 - 3.58 (m, 2H), 2.43 (s, 3H).

Example 87

3-{5-{3-[4-(4-Chloro-5-cyano-2,3-difluorophenyl)-lZ/-l ,2-pyrazol-l-yl]-3-deoxy-

P-I)-galactopyranosyl]-3-methyl-l//-l ,2,4-triazol-l-yl}-5-chloro-2-

(trifluoromethyl)pyridine

To a solution of 5-chloro-3-{5-[3-deoxy-3-(4-iodo-U/-l,2-pyrazol-l-yl)-P-D- galactopyranosyl]-3-methyl-U/-l,2,4-triazol-l-yl}-2-(trifluoromethyl)pyridine (40 mg, 0.067 mmol) in l,4-dioxane/H2O (3.2 ml, 4: 1) (4-chloro-5-cyano-2,3- difluorophenyl)boronic acid (72 mg, 0.33 mmol), Pd(dppf)C12 (15 mg, 0.020 mmol) and K2CO3 (46 mg, 0.33 mmol) were added. The mixture was purged three times with nitrogen, and stirred 2.5 h at 60 °C. The mixture was filtered and purified by prep TLC (PE/EtOAc=5/l). The obtained material was further purified by prep HPLC [MeCN/H₂O (10 mmol/L NH4HCO3), X-Select 10 pm 19*250 mm, 20 mL/min, UV 254] to afford the title compound (4.8 mg, 11 %). ESI-MS m/z calcd for [C2₅Hi₈C12F₅N7O₄] [M+H]⁺: 646.1; found: 645.8. ¹H NMR (400 MHz, Methanol-d₄) 8 8.93 (d, J = 2.0 Hz, 1H), 8.32 - 8.31 (m, 2H), 8.08 (dd, J= 6.8, 2.4 Hz, 1H), 8.05 (s, 1H), 4.70 (t, J= 10.0 Hz, 1H), 4.47 - 4.42 (m, 2H), 4.07 (d, J= 2.4 Hz, 1H), 3.69 (t, J = 6.4 Hz, 1H), 3.61 - 3.57 (m, 2H), 2.44 (s, 3H).

Example 88

3- {5- {3- [4-(4-Chloro-2,3-difluoro-5-methylphenyl)- TH- 1 ,2-pyrazol- l-yl]-3-deoxy- P-D-galactopyranosyl}-3-methyl-lZ/-l ,2,4-triazol-l-yl}-5-chloro-2- (trifluoromethyl)pyridine

To a nitrogen purged solution of 3-{5-[3-(4-borono-1H-1,2-pyrazol-1-yl)-3-deoxy-β- D-galactopyranosyl]-3-methyl-1H-1,2,4-triazol-1-yl}-5-chloro-2- (trifluoromethyl)benzene (25 mg, 0.048 mmol) and 2-chloro-3,4-difluoro-5-iodo-1- methylbenzene (43.9 mg, 0.14 mmol) in 1,4-dioxane/water (3.0 mL, 2:1) Pd(dppf)Cl2 (3.53 mg, 0.0048 mmol) and K₂CO₃ (20 mg, 0.15 mmol) were added and the mixture was stirred 2 h at 60 °C. The mixture was filtered, concentrated, and purified by prep HPLC [MeCN/H₂O (10 mmol/L NH₄HCO₃), X-Select 10 µm 19*250 mm, 20 mL/min, UV 254] to afford the title compound (3.47 mg, 11 %). ESI-MS m/z calcd. For [C H Cl F N O ] [M+H]+: 635.1; found 1 25 21 2 5 6 4 : 634.8. H NMR (400 MHz, Methanol-d4) δ 8.93 (d, J = 2.0 Hz, 1H), 8.33 (s, 1H), 8.22 (d, J = 1.2 Hz, 1H), 7.96 (s, 1H), 7.44 (d, J = 7.2 Hz, 1H), 4.67 (t, J = 10.0 Hz, 1H), 4.43 – 4.40 (m, 2H), 4.07 (d, J = 2.4 Hz, 1H), 3.70 – 3.67 (m, 1H), 3.63 – 3.58 (m, 2H), 2.43 (s, 3H), 2.39 (s, 3H). Example 89 3-{5-{3-[4-(4-Chloro-2,3-difluorophenyl)-1H-1,2-pyrazol-1-yl]-3-deoxy-β-D- galactopyranosyl}-1H-1,2,4-triazol-1-yl}-5-chloro-2-(trifluoromethyl)pyridine

To a solution of 3-{5-{4,6-O-benzylidene-3-[(2-tert-butoxycarbonyl)hydrazinyl]-3- deoxy-β-D-galactopyranosyl}-1H-1,2,4-triazol-1-yl}-5-chloro-2- (trifluoromethyl)pyridine (42 mg, 0.069 mmol) in EtOH (5.0 mL) 2-(4-chloro-2,3- difluorophenyl)-3-(dimethylamino)prop-2-enal (25.2 mg, 0.10 mmol) was added followed by concentrated HCl (0.2 mL) and the mixture was stirred 2 h at 80 °C. The mixture was cooled to rt, neutralized with Et₃N, concentrated, and purified by prep HPLC [MeCN/H₂O (10 mmol/L NH₄HCO₃), X-Select 10 µm 19*250 mm, 20 mL/min, UV 254] to afford the title compound (12.4 mg, 30 %). ESI-MS m/z calcd. For [C23H17Cl2F5N6O4] [M+H]+: 607.1; found: 606.8.1H NMR (400 MHz, Methanol-d4) δ 8.95 (d, J = 2.0 Hz, 1H), 8.36 (d, J = 2.0 Hz, 1H), 8.24 (d, J = 1.6 Hz, 1H), 8.22 (s, 1H), 7.96 (s, 1H), 7.50 – 7.45 (m, 1H), 7.30 – 7.26 (m, 1H), 4.73 (t, J = 9.6 Hz, 1H), 4.50 (d, J = 9.2 Hz, 1H), 4.44 (dd, J = 10.8, 2.8 Hz, 1H), 4.08 (d, J = 2.4 Hz, 1H), 3.70 (t, J = 6.4 Hz, 1H), 3.63 – 3.55 (m, 2H). Example 90 3-{5-{3-Deoxy-3-[4-(2,3-difluoro-4-methylphenyl)-1H-1,2-pyrazol-1-yl]-β-D- galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-2-(trifluoromethyl)-5- methylpyridine

To a solution of 3-{5-{4,6-O-benzylidene-3-[(2-tert-butoxycarbonyl)hydrazinyl]-3- deoxy-β-D-galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-2-(trifluoromethyl)-5- methylpyridine (40 mg, 0.065 mmol) in EtOH (5.0 mL) 3-(dimethylamino)-2-(2,3- difluoro-4-methylphenyl)prop-2-enal (25.0 mg, 0.11 mmol) and concentrated HCl (0.25 mL) were added and the mixture was stirred 2 h at 80 °C. The mixture was cooled to rt, concentrated, and purified by prep HPLC [MeCN/H2O (10 mmol/L NH4HCO3), X-Select 10 µm 19*250 mm, 20 mL/min, UV 254] to afford the title compound (7.7 mg, 20 %). ESI-MS m/z calcd for [C₂₆H₂₅F₅N₆O₄] [M+H]+: 581.2; found: 581.2.1H NMR (400 MHz, Methanol-d₄) δ 8.74 (s, 1H), 8.19 (d, J = 1.2 Hz, 1H), 7.99 (s, 1H), 7.92 (s, 1H), 7.35 – 7.31 (m, 1H), 7.02 (t, J = 8.0 Hz, 1H), 4.76 (t, J = 10.0 Hz, 1H), 3.39 (dd, J = 10.8, 2.8 Hz, 1H), 4.30 (d, J = 9.2 Hz, 1H), 4.07 (d, J = 2.8 Hz, 1H), 3.67 – 3.59 (m, 3H), 2.53 (s, 3H), 2.44 (s, 3H), 2.30 (d, J = 1.6 Hz, 3H). Example 91 6-{5-{3-Deoxy-3-[4-(2,3,4-trifluorophenyl)-1H-1,2-pyrazol-1-yl]-β-D- galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-5-fluoro-2- methylbenzothiazole

To a solution of 6-{5-{4,6-O-benzylidene-3-[(2-tert-butoxycarbonyl)hydrazinyl]-3- deoxy-β-D-galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-5-fluoro-2- methylbenzothiazole (40 mg, 0.065 mmol) and 2-(2,3,4-trifluorophenyl)-3- (dimethylamino)prop-2-enal (30.3 mg, 0.12 mmol) in EtOH (3.0 mL) concentrated HCl (0.15 mL) was added and the mixture was stirred 2 h at 80 °C. The mixture was concentrated and purified by prep HPLC [MeCN/H2O (10 mmol/L NH4HCO3), X- Select 10 µm 19*250 mm, 20 mL/min, UV 254] to afford the title compound (13.9 mg, 36 %). ESI-MS m/z calcd for [C₂₆H₂₂F₄N₆O₄S] [M+H]+: 591.1; found: 590.9.1H NMR (400 MHz, Methanol-d₄) δ 8.30 (d, J = 6.8 Hz, 1H), 8.19 (d, J = 1.2 Hz, 1H), 7.91 (s, 1H), 7.89 (d, J = 10.4 Hz, 1H), 7.49 – 7.43 (m, 1H), 7.16 – 7.10 (m, 1H), 4.78 (t, J = 10.4 Hz, 1H), 4.42 – 4.38 (m, 2H), 4.07 (d, J = 2.8 Hz, 1H), 3.74 – 3.63 (m, 3H), 2.89 (s, 3H), 2.47 (s, 3H). Example 92 3-{5-{3-[4-(4-Chloro-2,3-difluorophenyl)-1H-1,2-pyrazol-1-yl]-3-deoxy-β-D- galactopyranosyl}-3-cyano-1H-1,2,4-triazol-1-yl}-5-chloro-2- (trifluoromethyl)pyridine

To a cooled (0 °C) solution of 3-{3-aminocarbonyl-5-{3-[4-(4-chloro-2,3- difluorophenyl)-1H-1,2-pyrazol-1-yl]-3-deoxy-2-O-methoxymethyl-β-D- galactopyranosyl)-1H-1,2,4-triazol-1-yl]-5-chloro-2-(trifluoromethyl)pyridine (31 mg, 0.048 mmol) in THF (3.0 mL) pyridine (75.4 mg, 0.95 mmol) and trifluoroacetic anhydride (300 mg, 1.43 mmol) were added and the mixture was stirred 2 h at rt. Water (20 mL) was added and the mixture was stirred 10 min. The mixture was extracted with EtOAc (3 x 20 mL). The combined organic phases were dried, concentrated, and purified by preparative HPLC [MeCN/H₂O (10 mmol/L NH₄HCO₃), X-Select 10 µm 19*250 mm, 20 mL/min, UV 254] to afford the title compound (8.8 mg, 29 %). ESI- MS m/z calcd for [C + 1 24H16Cl2F5N7O4] [M+H] : 632.1; found: 632.1. H NMR (400 MHz, Methanol-d₄) δ 9.00 (d, J = 2.0 Hz, 1H), 8.47 (d, J = 1.6 Hz, 1H), 8.23 (d, J = 1.2 Hz, 1H), 7.97 (s, 1H), 7.50 – 7.46 (m, 1H), 7.30 – 7.26 (m, 1H), 4.75 (t, J = 9.6 Hz, 1H), 4.57 (d, J = 9.2 Hz, 1H), 4.44 (dd, J = 10.4, 2.4 Hz, 1H), 4.07 (d, J = 2.4 Hz, 1H), 3.70 (t, J = 6.0 Hz, 1H), 3.61 – 3.52 (m, 2H). Example 93 3-{3-Bromo-5-{3-[4-(4-chloro-2,3-difluorophenyl)-1H-1,2-pyrazol-1-yl]-3-deoxy- β-D-galactopyranosyl}-1H-1,2,4-triazol-1-yl}-5-chloro-2- (trifluoromethyl)pyridine

To a solution of 3-[5-(4,6-O-benzylidene-3-[(2-tert-butoxycarbonyl)hydrazinyl]-3- deoxy-2-O-methoxymethyl-β-D-galactopyranosyl)-3-bromo-1H-1,2,4-triazol-1-yl]-5- chloro-2-(trifluoromethyl)pyridine (30 mg, 0.041 mmol) in EtOH (5.0 mL) 2-(4-chloro- 2,3-difluorophenyl)-3-(dimethylamino)prop-2-enal (15.0 mg, 0.061 mmol) was added followed by concentrated HCl (0.3 mL) and the mixture was stirred 2 h at 80 °C. The mixture was cooled to rt, neutralized with Et₃N, concentrated, and purified by prep HPLC [MeCN/H2O (10 mmol/L NH4HCO3), X-Select 10 µm 19*250 mm, 20 mL/min, UV 254] to afford the title compound (9.3 mg, 33 %). ESI-MS m/z calcd. for [C₂₃H₁₆BrCl₂F₅N₆O₄] [M+H]+: 685.0; found: 685.0.1H NMR (400 MHz, Methanol-d₄) δ 8.97 (d, J = 2.0 Hz, 1H), 8.40 (s, 1H), 8.23 (d, J = 1.6 Hz, 1H), 7.96 (s, 1H), 7.50 – 7.46 (m, 1H), 7.31 – 7.26 (m, 1H), 4.72 (t, J = 9.6 Hz, 1H), 4.48 (d, J = 9.6 Hz, 1H), 4.43 (dd, J = 10.4, 2.8 Hz, 1H), 4.07 (d, J = 2.0 Hz, 1H), 3.70 (t, J = 6.4 Hz, 1H), 3.64 – 3.54 (m, 2H). Example 94 3-{5-{3-[4-(4-Chloro-2,3-difluorophenyl)-1H-1,2-pyrazol-1-yl]-3-deoxy-β-D- galactopyranosyl}-3-chloro-1H-1,2,4-triazol-1-yl}-5-chloro-2- (trifluoromethyl)pyridine

To a solution of 3-[5-(4,6-O-benzylidene-3-[(2-tert-butoxycarbonyl)hydrazinyl]-3- deoxy-2-O-methoxymethyl-β-D-galactopyranosyl)-3-chloro-1H-1,2,4-triazol-1-yl]-5- chloro-2-(trifluoromethyl)pyridine (20 mg, 0.029 mmol) in EtOH (1.5 mL) 2-(4-chloro- 2,3-difluorophenyl)-3-(dimethylamino)prop-2-enal (10.7 mg, 0.043 mmol) was added followed by concentrated HCl (0.15 mL) and the mixture was stirred 1 h at 80 °C. The mixture was cooled to rt, neutralized with saturated aq NaHCO3, concentrated, and purified by prep HPLC [MeCN/H2O (10 mmol/L NH4HCO3), X-Select 10 µm 19*250 mm, 20 mL/min, UV 254] to afford the title compound (2.9 mg, 16 %). ESI-MS m/z calcd. for [C H Cl F N O ] [M+H]+: 641.0; found: 641. 1 23 16 3 5 6 4 1. H NMR (400 MHz, Methanol-d4) δ 8.97 (d, J = 2.0 Hz, 1H), 8.42 (s, 1H), 8.23 (s, 1H), 7.97 (s, 1H), 7.51 – 7.46 (m, 1H), 7.31 – 7.26 (m, 1H), 4.72 (t, J = 10.0 Hz, 1H), 4.47 (d, J = 9.2 Hz, 1H), 4.43 (dd, J = 10.8, 2.8 Hz, 1H), 4.07 (d, J = 2.4 Hz, 1H), 3.70 (t, J = 6.0 Hz, 1H), 3.64 – 3.54 (m, 2H). Example 95 3-{5-{3-[4-(4-Chloro-2,3-difluorophenyl)-1H-1,2-pyrazol-1-yl]-3-deoxy-β-D- galactopyranosyl}-3-ethyl-1H-1,2,4-triazol-1-yl}-5-chloro-2- (trifluoromethyl)pyridine

To a solution of 3-[5-(4,6-O-benzylidene-3-[(2-tert-butoxycarbonyl)hydrazinyl]-3- deoxy-2-O-methoxymethyl-β-D-galactopyranosyl)-3-ethyl-1H-1,2,4-triazol-1-yl]-5- chloro-2-(trifluoromethyl)pyridine (22 mg, 0.032 mmol) in EtOH (5.0 mL) 2-(4-chloro- 2,3-difluorophenyl)-3-(dimethylamino)prop-2-enal (12.0 mg, 0.049 mmol) was added followed by concentrated HCl (0.3 mL) and the mixture was stirred 2 h at 80 °C. The mixture was cooled to rt, neutralized with saturated aq NaHCO3, concentrated, and purified by prep HPLC [MeCN/H2O (10 mmol/L NH4HCO3), X-Select 10 µm 19*250 mm, 20 mL/min, UV 254] to afford the title compound (3.6 mg, 18 %). ESI-MS m/z calcd. for [C H Cl F N O ] [M+ + 1 25 21 2 5 6 4 H] : 635.1; found: 634.8. H NMR (400 MHz, Methanol-d4) δ 8.94 (d, J = 2.0 Hz, 1H), 8.34 (d, J = 2.0 Hz, 1H), 8.25 (d, J = 1.6 Hz, 1H), 7.96 (s, 1H), 7.51 – 7.46 (m, 1H), 7.31 – 7.26 (m, 1H), 4.71 (t, J = 10.0 Hz, 1H), 4.45 – 4.42 (m, 2H), 4.08 (d, J = 2.4 Hz, 1H), 3.70 (t, J = 6.0 Hz, 1H), 3.66 – 3.57 (m, 2H), 2.81 (q, J = 7.6 Hz, 2H), 1.35 (t, J = 7.6 Hz, 3H) Example 96 5-Chloro-3-{5-{3-deoxy-3-[4-(2,3-difluoro-4-methylphenyl)-1H-1,2-pyrazol-1-yl]- β-^D-galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-2- (trifluoromethyl)pyridine

To a solution of 5-chloro-3-{5-[3-deoxy-3-(4-iodo-1H-1,2-pyrazol-1-yl)-β-D- galactopyranosyl]-3-methyl-1H-1,2,4-triazol-1-yl}-2-(trifluoromethyl)pyridine (35 mg, 0.058 mmol) and (2,3-difluoro-3-methylphenyl)boronic acid (21.8 mg, 0.127 mmol) in 1,4-dioxane/H2O (4 mL, 3:1) Pd(dppf)Cl2 (12.7 mg, 0.017 mmol) and K2CO3 (24.2 mg, 0.18 mmol) were added. The mixture was purged three times with nitrogen, and stirred 3 h at 65 °C. The mixture was filtered, and the filtrate was acidified to pH 5-6 using TFA. The mixture was concentrated and purified by prep HPLC [MeCN/H2O (10 mmol/L NH₄HCO₃), X-Select 10 µm 19*250 mm, 20 mL/min, UV 254] to afford the title compound (9.5 mg, 27 %). ESI-MS m/z calcd. for [C₂₅H₂₂ClF₅N₆O₄] [M+H]+: 601.1; found: 601.2.1H NMR (400 MHz, Methanol-d4) δ 8.94 (d, J = 2.0 Hz, 1H), 8.33 (d, J = 1.6 Hz, 1H), 8.18 (d, J = 0.8 Hz, 1H), 7.92 (s, 1H), 7.35 – 7.31 (m, 1H), 7.02 (t, J = 7.2 Hz, 1H), 4.72 – 4.67 (m, 1H), 4.44 – 4.39 (m, 2H), 4.07 (d, J = 2.4 Hz, 1H), 3.69 (t, J = 6.4 Hz, 1H), 3.64 – 3.57 (m, 2H), 2.44 (s, 3H), 2.30 (d, J = 1.6 Hz, 3H). Example 97 3-{3-Bromo-5-{3-deoxy-3-[4-(2,3,4-trifluorophenyl)-1H-1,2-pyrazol-1-yl]-β-D- galactopyranosyl}-1H-1,2,4-triazol-1-yl}-5-chloro-2-(trifluoromethyl)pyridine

To a solution of 3-[5-(4,6-O-benzylidene-3-[(2-tert-butoxycarbonyl)hydrazinyl]-3- deoxy-2-O-methoxymethyl-β-D-galactopyranosyl)-3-bromo-1H-1,2,4-triazol-1-yl]-5- chloro-2-(trifluoromethyl)pyridine (36 mg, 0.049 mmol) in EtOH (6.0 mL) 2-(2,3,4- trifluorophenyl)-3-(dimethylamino)prop-2-enal (16.8 mg, 0.073 mmol) was added followed by concentrated HCl (0.3 mL) and the mixture was stirred 2 h at 80 °C. The mixture was cooled to rt, neutralized with saturated aq NaHCO3, concentrated, and purified by prep HPLC [MeCN/H₂O (10 mmol/L NH₄HCO₃), X-Select 10 µm 19*250 mm, 20 mL/min, UV 254] to afford the title compound (6.6 mg, 20 %). ESI-MS m/z calcd. for [C H BrClF N O ] [M + 1 23 16 6 6 4 +H] : 669.0; found: 669.1. H NMR (400 MHz, Methanol-d₄) δ 8.97 (d, J = 2.0 Hz, 1H), 8.40 (s, 1H), 8.19 (d, J = 1.6 Hz, 1H), 7.93 (s, 1H), 7.49 – 7.43 (m, 1H), 7.17 – 7.10 (m, 1H), 4.72 (t, J = 9.6 Hz, 1H), 4.48 (d, J = 9.2 Hz, 1H), 4.42 (dd, J = 10.4, 2.8 Hz, 1H), 4.07 (d, J = 2.4 Hz, 1H), 3.69 (t, J = 6.0 Hz, 1H), 3.64 – 3.54 (m, 2H). Example 98 5-Chloro-3-{5-{3-deoxy-3-[4-(2,3,4-trifluorophenyl)-1H-1,2-pyrazol-1-yl]-β-D- galactopyranosyl}-3-ethyl-1H-1,2,4-triazol-1-yl}-2-(trifluoromethyl)pyridine

To a solution of 3-[5-(4,6-O-benzylidene-3-[(2-tert-butoxycarbonyl)hydrazinyl]-3- deoxy-2-O-methoxymethyl-β-D-galactopyranosyl)-3-ethyl-1H-1,2,4-triazol-1-yl]-5- chloro-2-(trifluoromethyl)pyridine (27 mg, 0.039 mmol) in EtOH (5.0 mL) 2-(2,3,4- trifluorophenyl)-3-(dimethylamino)prop-2-enal (13.5 mg, 0.059 mmol) was added followed by concentrated HCl (0.3 mL) and the mixture was stirred 2 h at 80 °C. The mixture was cooled to rt, neutralized with saturated aq NaHCO3, concentrated, and purified by prep HPLC [MeCN/H₂O (10 mmol/L NH₄HCO₃), X-Select 10 µm 19*250 mm, 20 mL/min, UV 254] to afford the title compound (11.1 mg, 46 %). ESI-MS m/z calcd. for [C H ClF N O ] + 1 25 21 6 6 4 [M+H] : 619.1; found: 618.9. H NMR (400 MHz, Methanol-d4) δ 8.94 (d, J = 2.0 Hz, 1H), 8.34 (d, J = 1.6 Hz, 1H), 8.20 (d, J = 1.6 Hz, 1H), 7.93 (s, 1H), 7.49 – 7.43 (m, 1H), 7.17 – 7.10 (m, 1H), 4.70 (t, J = 10.0 Hz, 1H), 4.45 – 4.41 (m, 2H), 4.07 (d, J = 2.4 Hz, 1H), 3.70 (t, J = 6.0 Hz, 1H), 3.66 – 3.57 (m, 2H), 2.81 (q, J = 7.6 Hz, 2H), 1.35 (t, J = 7.6 Hz, 3H). Intermediate 1 (2-Methyl-1,3-benzothiazol-6-yl)hydrazine

To a solution of 2-methyl-1,3-benzothiazol-6-amine (3.0 g, 18.3 mmol) in water (50 mL) hydrochloric acid (50 mL, 33 % w/w) and acetic acid (15 mL) were added. A solution of NaNO₂ (1.51 g, 21.9 mmol) in water (50 mL) was added dropwise at -10 °C and the resulting mixture was stirred 2 h at -10 °C. Tin(II) chloride dihydrate (8.24 g, 36.5 mmol) was added in small portions at -10 °C. The resulting mixture was stirred 2 h at -10 °C. NaHCO3 (300 mL, 5 % w/w) was added at 0 °C. Water (200 mL) and DCM (100 mL) were added, and the phases were separated. The aqueous phase was extracted with DCM (2 x 100 mL). The combined organic phases were washed with water (50 mL) and brine (50 mL), dried over Na2SO4, and evaporated to afford the product (2.30 g, 70 %). ESI-MS m/z calcd for [C₈H₉N₃S] [M+H]+: 180.1; found: 180.1.1H NMR (400 MHz, DMSO-d₆) δ 7.66 (d, J = 8.8 Hz, 1H), 7.35 (d, J = 2.0 Hz, 1H), 7.03 (s, 1H), 6.93 (dd, J = 8.8, 2.0 Hz, 1H), 4.22 (s, 2H), 2.75 (s, 3H). 3-(Dimethylamino)-2-(2,3-difluoro-4-methylphenyl)prop-2-enal

To a cooled (0 °C) solution of DMF (1.45 g, 19.9 mmol) and phosphoryl trichloride (2.74 g, 17.9 mmol) 2-(2,3-difluoro-4-methylphenyl)acetic acid (370 mg, 1.99 mmol) was added and the mixture was stirred overnight at 60-70 °C. After cooling to rt, the mixture was slowly added to a mixture of ice and water with external cooling to keep the temperature below 10 °C. K2CO3 was added slowly until pH reached 11. To the alkaline mixture toluene (30 mL) was added, and the mixture was refluxed for 1.5 h and then cooled to rt. The aqueous phase was extracted with toluene (40 mL). The combined organic phases were washed with water, dried over Na₂SO₄, and evaporated. The obtained solid was recrystallized from hexane to give the product (335 mg, 75 %). ESI-MS m/z calcd for [C₁₂H₁₃F₂NO] [M+H]+: 226.1; found: 226.1.1H NMR (400 MHz, Chloroform-d) δ 9.09 (s, 1H), 6.94 – 6.86 (m, 3H), 2.89 (br s, 6H), 2.30 (s, 3H). 2,4,6-Tri-O-acetyl-3-azido-3-deoxy-β-^D-galactopyranosyl cyanide

To a solution of 1,2,4,6-tetra-O-acetyl-3-azido-3-deoxy-β-D-galactopyranoside (10.0 g, 26.8 mmol) and trimethylsilyl cyanide (6.70 mL, 53.6 mmol) in nitromethane (100 mL) under argon at 0 °C boron trifluoride diethyl etherate (3.31 mL, 26.8 mmol) was added and the mixture was stirred 5 h at rt. The mixture was concentrated and purified by column chromatography (PE/EtOAc=5/1~2/1, Silica-CS 80 g, 30 mL/min, silica gel, UV 254) to give the product (7.40 g, 81 %). ESI-MS m/z calcd for [C13H16N4O7] [M+NH4]+: 358.1; found: 358.1. 1H NMR (400 MHz, CDCl3) δ 5.52 – 5.41 (m, 2H), 4.25 (d, J = 10.0 Hz, 1H), 4.16 – 4.08 (m, 1H), 4.07 – 4.00 (m, 1H), 3.92 – 3.83 (m, 1H), 3.59 (dd, J = 10.0, 3.2 Hz, 1H), 2.19 (s, 6H), 2.06 (s, 3H). Methyl 2,6-anhydro-4-azido-5,7-O-benzylidene-4-deoxy-D-glycero-L-manno- heptonate

To a solution of 2,4,6-tri-O-acetyl-3-azido-3-deoxy-β-D-galactopyranosyl cyanide (13.8 g, 40.6 mmol) in MeOH (200 mL) at 0 °C acetyl chloride (15.9 g, 203 mmol) was added and the mixture was stirred 24 h at 65 °C. The mixture was concentrated, and the residue was washed by DCM (100 mL). The obtained material was dissolved in DMF (30 mL). Benzaldehyde dimethylacetal (18.5 g, 121 mmol) followed by D(+)-10- camphorsulfonic acid (1.88 g, 8.09 mmol) were added and the mixture was stirred 2 h at 50 °C under reduced pressure. The mixture was partitioned between EtOAc and brine. The organic phase was concentrated and purified by column chromatography (PE/EtOAc=5/1~1/1, Silica-CS 80 g, 50 mL/min, silica gel, UV 254) to give the product (7.1 g, 52 %). ESI-MS m/z calcd for [C₁₅H₁₇N₃O₆] [M+NH₄]+: 353.1; found: 353.1.1H NMR (400 MHz, CDCl3) δ 7.55 – 7.45 (m, 2H), 7.42 – 7.30 (m, 3H), 5.58 (s, 1H), 4.45 – 4.34 (m, 2H), 4.26 (d, J = 2.8 Hz, 1H), 4.06 (dd, J = 12.8, 2.0 Hz, 1H), 3.89 (d, J = 9.6 Hz, 1H), 3.84 (s, 3H), 3.52 (d, J = 1.2 Hz, 1H), 3.50 – 3.46 (m, 1H), 3.41 (dd, J = 10.4, 3.6 Hz, 1H). 2,6-Anhydro-4-azido-5,7-O-benzylidene-4-deoxy-D-glycero-L-manno- heptonamide

To a solution of methyl 2,6-anhydro-4-azido-5,7-O-benzylidene-4-deoxy-D-glycero-L- manno-heptonate (4.8 g, 14.3 mmol) in MeOH (50 mL) NH3 (30 mL, 7 M in MeOH) was added and the mixture was stirred 3 h at 50 °C. The mixture was evaporated to afford the product (4.0 g, 87 %). ESI-MS m/z calcd for [C₁₄H₁₆N₄O₅] [M+NH₄]+: 338.1; found: 338.2.1H NMR (400 MHz, Methanol-d₄) δ 7.53 – 7.50 (m, 2H), 7.40 – 7.34 (m, 3H), 5.68 (s, 1H), 4.38 (d, J = 2.4 Hz, 1H), 4.28 – 4.25 (m, 2H), 4.08 – 4.03 (m, 1H), 3.79 (d, J = 7.2 Hz, 1H), 3.65 (d, J = 1.2 Hz, 1H), 3.45 (dd, J = 10.4, 3.6 Hz, 1H), 1.93 (s, 2H). 6-[5-(3-Azido-4,6-O-benzylidene-3-deoxy-β-^D-galactopyranosyl)-3-methyl-1H- 1,2,4-triazol-1-yl]-2-methylbenzothiazole

To a solution of 2,6-anhydro-4-azido-5,7-O-benzylidene-4-deoxy-D-glycero-L-manno- heptonamide (3.20 g, 9.99 mmol) in 1,4-dioxane (50 mL) N,N-dimethylacetamide dimethyl acetal (1.40 g, 10.5 mmol) was added and the mixture was stirred 3 h at 50 °C. The mixture was evaporated and dissolved in MeCN (15 mL) and acetic acid (15 mL). (2-Methyl-1,3-benzothiazol-6-yl)hydrazine (1.79 g, 9.99 mmol) was added and the mixture was stirred 3 h at 80 °C. The mixture was evaporated and partitioned between water (100 mL) and DCM (100 mL). The aqueous phase was extracted with DCM (2 x 50 mL). The combined organic phases were washed with water (50 mL) and brine (3 x 50 mL), dried over Na2SO4, evaporated, and purified by column chromatography (PE/EtOAc=10/1~0/1, Silica-CS 40 g, 40 mL/min, silica gel, UV 254) to afford the product (1.50 g, 30 %). ESI-MS m/z calcd for [C + 24H23N7O4S] [M+H] : 506.2; found: 506.3.1H NMR (400 MHz, Methanol-d4) δ 8.04 (d, J = 2.0 Hz, 1H), 7.98 (d, J = 8.8 Hz, 1H), 7.61 (dd, J = 5.2, 2.0 Hz, 1H), 7.50 – 7.48 (m, 2H), 7.37 – 7.33 (m, 3H), 5.57 (s, 1H), 4.84 (t, J = 9.6 Hz, 1H), 4.40 (d, J = 9.2 Hz, 1H), 4.29 (d, J = 2.8 Hz, 1H) , 4.05 – 3.97 (m, 2H), 3.45 – 3.42 (m, 2H), 2.87 (s, 3H), 2.46 (s, 3H). 6-[5-(3-Amino-4,6-O-benzylidene-3-deoxy-β-D-galactopyranosyl)-3-methyl-1H- 1,2,4-triazol-1-yl]-2-methylbenzothiazole

To a solution of 6-[5-(3-azido-4,6-O-benzylidene-3-deoxy-β-D-galactopyranosyl)-3- methyl-1H-1,2,4-triazol-1-yl]-2-methylbenzothiazole (1.00 g, 1.98 mmol) in MeOH (20 mL) palladium on carbon (50 % Pd, 105 mg, 0.99 mmol) was added and the mixture was stirred overnight at rt under a hydrogen atmosphere. The mixture was concentrated and purified by column chromatography (PE/EtOAc = 4/1~0/1, Silica-CS 20 g, 20 mL/min, silica gel, UV 254) to give the product (900 mg, 95 %). ESI-MS m/z calcd for [C H N O + 1 24 25 5 4S] [M+H] : 480.2; found: 480.1. H NMR (400 MHz, DMSO-d6) δ 8.27 (d, J = 2.0 Hz, 1H), 7.97 (d, J = 8.8 Hz, 1H), 7.68 (dd, J = 8.8, 2.0 Hz, 1H), 7.47 – 7.44 (m, 2H), 7.43 – 7.38 (m, 3H), 5.61 (s, 1H), 5.18 (d, J = 5.6 Hz, 1H), 4.29 (d, J = 9.6 Hz, 1H), 4.12 – 4.04 (m, 3H), 3.90 – 3.84 (m, 1H), 3.64 (s, 1H), 2.83 (s, 3H), 2.68 (dd, J = 9.6, 3.2 Hz, 1H), 2.35 (s, 3H), 1.77 (br s, 2H). 6-{5-{4,6-O-Benzylidene-3-[(2-tert-butoxycarbonyl)hydrazinyl]-3-deoxy-β-D- galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-2-methylbenzothiazole

To a solution of 6-[5-(3-amino-4,6-O-benzylidene-3-deoxy-β-D-galactopyranosyl)-3- methyl-1H-1,2,4-triazol-1-yl]-2-methylbenzothiazole (900 mg, 1.88 mmol) in DCM (20 mL) N-tert-butyloxycarbonyl-3-(4-cyanophenyl)oxaziridine (462 mg, 1.88 mmol) was added and the mixture was stirred overnight at rt. The mixture was concentrated and purified by column chromatography (PE/EtOAc=4/1~0/1, Silica-CS 20 g, 20 mL/min, silica gel, UV 254) to afford the product (650 mg, 58 %). ESI-MS m/z calcd for [C29H34N6O6S] [M+H]+: 595.2; found: 595.2. 1H NMR (400 MHz, DMSO-d6) δ 8.35 (br s, 1H), 8.26 (d, J = 2.4 Hz, 1H), 7.96 (d, J = 8.8 Hz, 1H), 7.67 (dd, J = 8.8, 2.4 Hz, 1H), 7.52 – 7.37 (m, 2H), 7.40 – 7.37 (m, 3H), 5.57 (s, 1H), 5.21 (d, J = 5.2 Hz, 1H), 4.57 (br s, 1H), 4.39 (d, J = 9.6 Hz, 1H), 4.21 (d, J = 2.8 Hz, 1H), 4.12 – 4.00 (m, 3H), 3.65 (s, 1H) , 2.90 (d, J = 10.0 Hz, 1H), 2.83 (s, 3H), 2.35 (s, 3H), 1.37 (s, 9H). Intermediate 2 1-[5-(3-Azido-4,6-O-benzylidene-3-deoxy-β-^D-galactopyranosyl)-3-methyl-1H- 1,2,4-triazol-1-yl]-5-chloro-2-(trifluoromethyl)benzene

To a solution of 2,6-anhydro-4-azido-5,7-O-benzylidene-4-deoxy-D-glycero-L-manno- heptonamide (400 mg, 1.25 mmol) in 1,4-dioxane (10 mL) N,N-dimethylacetamide dimethyl acetal (175 mg, 1.31 mmol) was added and the mixture was stirred 3 h at 50 °C. The mixture was evaporated, and the residue was dissolved in MeCN (10 mL) and acetic acid (4.0 mL). To the solution [5-chloro-2-(trifluoromethyl)phenyl]hydrazine (333 mg, 1.58 mmol) was added and the mixture was stirred 2 h at 100 °C. The mixture was concentrated and partitioned between water (20 mL) and DCM (20 mL). The aqueous phase was extracted with DCM (2 x 20 mL). The combined organic phases were washed with water (20 mL) and brine (20 mL), dried over Na₂SO₄, evaporated, and purified by column chromatography (PE/EtOAc=3/1~1/2, Silica-CS 12 g, 20 mL/min, silica gel, UV 254) to afford the product (400 mg, 30 %, purity 50 %). ESI- MS m/z calcd for [C H ClF N O ] [M+H + 23 20 3 6 4 ] : 537.1; found: 536.8. 1-[5-(3-Amino-4,6-O-benzylidene-3-deoxy-β-D-galactopyranosyl)-3-methyl-1H- 1,2,4-triazol-1-yl]-5-chloro-2-(trifluoromethyl)benzene

To a solution of 1-[5-(3-azido-4,6-O-benzylidene-3-deoxy-β-D-galactopyranosyl)-3- methyl-1H-1,2,4-triazol-1-yl]-5-chloro-2-(trifluoromethyl)benzene (1.50 g, 2.79 mmol) in THF (50 mL) and water (10 mL) triphenylphosphine (3.66 g, 14.0 mmol) was added and the mixture was stirred 6 h at 50 °C. The mixture was concentrated and purified by column chromatography (MeOH/DCM=0/1~1/10, Silica-CS 12 g, 40 mL/min, silica gel, UV 254) to afford the product (1.40 g, 98 %). ESI-MS m/z calcd for [C₂₃H₂₂ClF₃N₄O₄] [M+H]+: 511.1; found: 510.9.1H NMR (400 MHz, Chloroform-d) δ 7.63 (d, J = 8.4 Hz, 1H), 7.53 (s, 1H), 7.51 (d, J = 8.4 Hz, 1H), 7.40 – 7.32 (m, 2H), 7.32 – 7.24 (m, 3H), 5.38 (s, 1H), 4.15 (d, J = 9.2 Hz, 1H), 4.08 – 4.00 (m, 1H), 3.95 (t, J = 9.2 Hz, 1H), 3.82 (dd, J = 12.4, 1.6 Hz, 1H), 3.58 (d, J = 12.0 Hz, 1H), 3.20 (d, J = 0.8 Hz, 1H), 2.76 (dd, J = 9.6, 3.2 Hz, 1H), 2.36 (s, 3H). 1-[5-(3-Amino-3-deoxy-β-D-galactopyranosyl)-3-methyl-1H-1,2,4-triazol-1-yl]-5- chloro-2-(trifluoromethyl)benzene

To a solution of 1-[5-(3-amino-4,6-O-benzylidene-3-deoxy-β-^D-galactopyranosyl)-3- methyl-1H-1,2,4-triazol-1-yl]-5-chloro-2-(trifluoromethyl)benzene (200 mg, 0.39 mmol) in DCM (10 mL) TFA (1.0 mL) was added and the mixture was stirred overnight at rt. The mixture was concentrated and purified by reversed-phase chromatography (MeCN/H₂O (10 mmol/L NH₄HCO₃) = 1/20~1/2, C-18 column, 20 mL/min, UV 214) to afford the product (140 mg, 85 %). ESI-MS m/z calcd for [C₁₆H₁₈ClF₃N₄O₄] [M+H]+: 423.1; found: 423.0.1H NMR (400 MHz, Methanol-d4) δ 7.92 (d, J = 8.8 Hz, 1H), 7.83 (dd, J = 8.8, 1.2 Hz, 1H), 7.75 (s, 1H), 4.03 (d, J = 9.6 Hz, 1H), 3.89 (br s, 1H), 3.81 (d, J = 2.4 Hz, 1H), 3.62 – 3.60 (m, 2H), 3.45 (t, J = 6.4 Hz, 1H), 2.60 (dd, J = 9.6, 1.6 Hz, 1H), 2.42 (s, 3H). 1-{5-{3-[(2-tert-Butoxycarbonyl)hydrazinyl]-3-deoxy-β-D-galactopyranosyl}-3- methyl-1H-1,2,4-triazol-1-yl}-5-chloro-2-(trifluoromethyl)benzene

To a solution of 1-[5-(3-amino-3-deoxy-β-D-galactopyranosyl)-3-methyl-1H-1,2,4- triazol-1-yl]-5-chloro-2-(trifluoromethyl)benzene (130 mg, 0.31 mmol) in DCM (10 mL) N-tert-butyloxycarbonyl-3-(4-cyanophenyl)oxaziridine (114 mg, 0.46 mmol) was added and the mixture was stirred overnight at rt. The mixture was concentrated and purified by reversed-phase chromatography (MeCN/H₂O (10 mmol/L NH₄HCO₃) =1/20~1/2, C-18 column, 20 mL/min, UV 214) to afford the product (30 mg, 18 %). ESI-MS m/z calcd for [C H Cl + 1 21 27 F3N5O6] [M+H] : 538.2; found: 538.0. H NMR (400 MHz, DMSO-d₆) δ 8.12 (s, 1H), 7.99 (d, J = 8.4 Hz, 1H), 7.90 (dd, J = 8.4, 1.2 Hz, 1H), 7.73 (s, 1H), 5.15 (d, J = 5.2 Hz, 1H), 4.64 – 4.50 (m, 2H), 4.10 – 3.98 (m, 2H), 3.87 (br s, 1H), 3.65 (s, 1H), 3.51 – 3.40 (m, 1H), 3.40 – 3.35 (m, 1H), 3.32 – 3.25 (m, 1H), 2.65 (d, J = 9.6 Hz, 1H), 2.32 (s, 3H), 1.38 (s, 9H). Intermediate 3 7-Fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-benzothiazole

To a solution of 5-bromo-7-fluoro-1,3-benzothiazole (100 mg, 0.43 mmol) and bis(pinacolato)diboron (164 mg, 0.65 mmol) in 1,4-dioxane (8.0 mL) Pd(dppf)Cl2 (63.1 mg, 0.086 mmol) and potassium acetate (127 mg, 1.29 mmol) were added. The mixture was purged three times with nitrogen, and stirred overnight at 100 °C. The mixture was concentrated and purified by column chromatography (EtOAc/PE = 0/1~1/5, Silica-CS 20 g, 30 mL/min, silica gel, UV 254) to afford the product (75 mg, 62 %). ESI-MS m/z calcd for [C H BFNO S] [M+H]+ 1 13 15 2 : 280.1; found: 280.0. H NMR (400 MHz, Chloroform-d) δ 8.94 (s, 1H), 8.32 (s, 1H), 7.49 (d, J = 9.6 Hz, 1H), 1.31 (s, 12H). 1-{5-{4,6-O-Benzylidene-3-[(2-tert-butoxycarbonyl)hydrazinyl]-3-deoxy-β-D- galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-5-chloro-2- (trifluoromethyl)benzene

To a solution of 1-[5-(3-amino-4,6-O-benzylidene-3-deoxy-β-D-galactopyranosyl)-3- methyl-1H-1,2,4-triazol-1-yl]-5-chloro-2-(trifluoromethyl)benzene (1.40 g, 2.74 mmol) in DCM (30 mL) N-tert-butyloxycarbonyl-3-(4-cyanophenyl)oxaziridine (742 mg, 3.01 mmol) was added and the mixture was stirred overnight at rt. The mixture was concentrated and purified by column chromatography (PE/EtOAc=4/1~0/1, Silica-CS 20 g, 30 mL/min, silica gel, UV 254) to afford the product (1.20 g, 70 %). ESI-MS m/z calcd for [C₂₈H₃₁ClF₃N₅O₆] [M+H]+: 626.2; found: 625.8. 1H NMR (400 MHz, Chloroform-d) δ 7.61 (d, J = 8.4 Hz, 1H), 7.51 (s, 1H), 7.47 (d, J = 8.4 Hz, 1H), 7.39 – 7.31 (m, 2H), 7.32 – 7.24 (m, 3H), 6.44 (br s, 1H), 5.37 (s, 1H), 4.58 – 4.36 (m, 2H), 4.30 – 4.17 (m, 3H), 3.82 (dd, J = 12.4, 1.6 Hz, 1H), 3.63 (dd, J = 12.4, 1.2 Hz, 1H), 3.19 (d, J = 0.8 Hz, 1H), 3.03 – 2.94 (m, 1H), 2.36 (s, 3H), 1.38 (s, 9H). 5-Chloro-1-{5-[3-deoxy-3-(1H-1,2-pyrazol-1-yl)-β-D-galactopyranosyl]-3-methyl- 1H-1,2,4-triazol-1-yl}-2-(trifluoromethyl)benzene

To a solution of 1-{5-{4,6-O-benzylidene-3-[(2-tert-butoxycarbonyl)hydrazinyl]-3- deoxy-β-D-galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-5-chloro-2- (trifluoromethyl)benzene (250 mg, 0.40 mmol) in DCM (10 mL) TFA (0.5 mL) was added at 0 °C and the mixture was stirred overnight at rt. The mixture was concentrated, and the residue was dissolved in ethanol (10 mL). To this solution 1,1,3,3- tetraethoxypropane (440 mg, 2.00 mmol) was added followed by concentrated HCl (0.25 mL). The mixture was stirred 3 h at rt before the pH was adjusted to 4-5 using saturated aq NaHCO₃. The mixture was concentrated and purified by reversed-phase chromatography (MeCN/H₂O=1/20~1/2, C-18 column, 20 mL/min, UV 214) to give the product (75 mg, 40 %). ESI-MS m/z calcd for [C + 19H19ClF3N5O4] [M+H] : 474.1; found: 474.0.1H NMR (400 MHz, Methanol-d₄) δ 7.85 (d, J = 8.8 Hz, 1H), 7.75 (d, J = 8.8 Hz, 1H), 7.69 (d, J = 2.4 Hz, 1H), 7.67 (s, 1H), 7.43 (d, J = 2.0 Hz, 1H), 6.24 (t, J = 2.0 Hz, 1H), 4.68 – 4.52 (m, 1H), 4.26 (dd, J = 10.8, 2.8 Hz, 1H), 4.16 (d, J = 9.6 Hz, 1H), 3.95 (d, J = 2.8 Hz, 1H), 3.59 – 3.48 (m, 3H), 2.33 (s, 3H). 5-Chloro-1-{5-[3-deoxy-3-(4-iodo-1H-1,2-pyrazol-1-yl)-β-D-galactopyranosyl]-3- methyl-1H-1,2,4-triazol-1-yl}-2-(trifluoromethyl)benzene

To a solution of 1-{5-[3-deoxy-3-(1H-1,2-pyrazol-1-yl)-β-D-galactopyranosyl]-3- methyl-1H-1,2,4-triazol-1-yl}-5-chloro-2-(trifluoromethyl)benzene (50 mg, 0.11 mmol) in THF (5.0 mL) N-iodosuccinimide (119 mg, 0.53 mmol) was added and the mixture was stirred overnight at rt. The mixture was concentrated and purified by reversed-phase chromatography (MeCN/H₂O=1/20~1/2, C-18 column, 20 mL/min, UV 214) to give the product (50 mg, 87 %). ESI-MS m/z calcd for [C19H18ClF3IN5O4] [M+H]+: 600.0; found: 599.7.1H NMR (400 MHz, Methanol-d₄) δ 7.85 (d, J = 8.8 Hz, 1H), 7.79 – 7.72 (m, 2H), 7.66 (s, 1H), 7.44 (s, 1H), 4.69 – 4.47 (m, 1H), 4.28 (dd, J = 10.8, 2.8 Hz, 1H), 4.16 (d, J = 9.2 Hz, 1H), 3.93 (d, J = 2.8 Hz, 1H), 3.62 – 3.44 (m, 3H), 2.33 (s, 3H). Intermediate 4 2,5-Dibromo-1-fluoro-3-nitrobenzene

To a solution of 4-bromo-2-fluoro-6-nitroaniline (1.50 g, 6.38 mmol) in MeCN (30 mL) isopentyl nitrite (1495 mg, 12.8 mmol) and copper(II) dibromide (2851 mg, 12.8 mmol) were added and the mixture was stirred overnight at rt. The mixture was poured into saturated aq NaHCO₃ (100 mL) with vigorous stirring and was then extracted with DCM (3 x 50 mL). The combined organic phases were washed with brine (50 mL), dried over Na2SO4, evaporated, and purified by column chromatography (EtOAc/PE = 0/1~1/4, Silica-CS 40 g, 30 mL/min, silica gel, UV 254) to afford the product (1.42 g, 74 %).1H NMR (400 MHz, Chloroform-d) δ 7.74 (t, J = 2.0 Hz, 1H), 7.46 (dd, J = 7.6, 2.4 Hz, 1H). 2,5-Dibromo-3-fluoroaniline

To a solution of 2,5-dibromo-1-fluoro-3-nitrobenzene (1.40 g, 4.68 mmol) in EtOH (20 mL) and H₂O (1 mL) iron (1308 mg, 23.4 mmol) and NH₄Cl (1253 mg, 23.4 mmol) were added and the mixture was stirred overnight at 80 °C. The mixture was filtered, poured into ice-water and extracted with DCM (3 x 50 mL). The combined organic phases were washed with brine (50 mL), dried over Na2SO4, evaporated, and purified by column chromatography (EtOAc/PE = 0/1~1/4, Silica-CS 40 g, 30 mL/min, silica gel, UV 254) to afford the product (860 mg, 68 %).1H NMR (400 MHz, DMSO-d6) δ 6.79 (t, J = 2.0 Hz, 1H), 7.52 (dd, J = 8.4, 2.0 Hz, 1H), 5.97 (br s, 2H). N-(2,5-Dibromo-3-fluorophenyl)acetamide

To a solution of 2,5-dibromo-3-fluoroaniline (850 mg, 3.16 mmol) in DCM (20 mL) N,N-diisopropylethylamine (2.16 mL, 12.6 mmol) and acetyl chloride (496 mg, 6.32 mmol) were added and the mixture was stirred overnight at rt. The mixture was poured into ice-water and extracted with DCM (3 x 50 mL). The combined organic phases were washed with brine (50 mL), dried over Na2SO4, evaporated, and purified by column chromatography (EtOAc/PE = 0/1~1/4, Silica-CS 20 g, 30 mL/min, silica gel, UV 254) to afford the product (380 mg, 39 %). ESI-MS m/z calcd for [C₈H₆Br₂FNO] [M+H]+: 311.9; found: 312.0.1H NMR (400 MHz, DMSO-d6) δ 9.68 (s, 1H), 7.78 (t, J = 2.0 Hz, 1H), 7.55 (dd, J = 8.4, 2.4 Hz, 1H), 2.12 (s, 3H). N-(2,5-Dibromo-3-fluorophenyl)thioacetamide

To a solution of N-(2,5-dibromo-3-fluorophenyl)acetamide (350 mg, 1.13 mmol) in toluene (10 mL) Lawesson’s reagent (364 mg, 0.90 mmol) was added and the mixture was stirred overnight at 100 °C. The mixture was concentrated and purified by column chromatography (EtOAc/PE = 0/1~1/3, Silica-CS 20 g, 30 mL/min, silica gel, UV 254) to afford the product (200 mg, 54 %). ESI-MS m/z calcd for [C₈H₆Br₂FNS] [M+H]+: 327.9; found: 328.0.1H NMR (400 MHz, DMSO-d₆) δ 11.63 (s, 1H), 7.75 (dd, J = 8.0, 2.0 Hz, 1H), 7.54 (t, J = 1.6 Hz, 1H), 2.62 (s, 3H). 5-Bromo-7-fluoro-2-methyl-1,3-benzothiazole

To a solution of N-(2,5-dibromo-3-fluorophenyl)thioacetamide (185 mg, 0.57 mmol) in 1,2-dimethoxyethane (10 mL) CuI (5.4 mg, 0.028 mmol) and 1,10-phenanthroline (5.1 mg, 0.028 mmol) were added and the mixture was stirred overnight at 80 °C. The mixture was concentrated and purified by column chromatography (EtOAc/PE = 0/1~1/4, Silica-CS 20 g, 30 mL/min, silica gel, UV 254) to afford the product (85 mg, 61 %).1H NMR (400 MHz, DMSO-d₆) δ 8.06 (d, J = 1.6 Hz, 1H), 7.66 (dd, J = 9.2, 1.6 Hz, 1H), 2.86 (s, 3H). 7-Fluoro-2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3- benzothiazole

To a solution of 5-bromo-7-fluoro-2-methyl-1,3-benzothiazole (85 mg, 0.35 mmol) and bis(pinacolato)diboron (132 mg, 0.52 mmol) in 1,4-dioxane (6.0 mL) Pd(dppf)Cl₂ (50.5 mg, 0.069 mmol) and potassium acetate (102 mg, 1.04 mmol) were added. The mixture was purged three times with nitrogen, and stirred overnight at 100 °C. The mixture was concentrated and purified by column chromatography (EtOAc/PE = 0/1~1/3, Silica-CS 20 g, 30 mL/min, silica gel, UV 254) to afford the product (35 mg, 35 %). ESI-MS m/z calcd for [C₁₄H₁₇BFNO₂S] [M+H]+: 294.1; found: 294.2. 1H NMR (400 MHz, Chloroform-d) δ 8.18 (s, 1H), 7.44 (d, J = 9.2 Hz, 1H), 2.87 (s, 3H), 1.30 (s, 12H). Intermediate 5 6-Bromo-4-fluoro-1,3-benzothiazol-2-amine

To a solution of 4-bromo-2-fluoroaniline (1.50 g, 7.89 mmol) and ammonium thiocyanate (901 mg, 11.8 mmol) in MeCN (20.0 mL) benzyltrimethylammonium tribromide (3.078 g, 7.89 mmol) was added and the mixture was stirred overnight at rt. The mixture was poured into saturated aq NaHCO₃ (100 mL) with vigorous stirring. The mixture was extracted with DCM (3 x 50 mL). The combined organic phases were washed with brine (50 mL), dried over Na2SO4, evaporated, and purified by column chromatography (EtOAc/PE = 0/1~1/4, Silica-CS 20 g, 30 mL/min, silica gel, UV 254) to afford the product (365 mg, 19 %). ESI-MS m/z calcd for [C₇H₄BrFN₂S] [M+H]+: 246.9; found: 247.1.1H NMR (400 MHz, DMSO-d6) δ 7.85 (br s, 2H), 7.77 (d, J = 1.2 Hz, 1H), 7.35 (dd, J = 10.4, 2.0 Hz, 1H). 6-Bromo-4-fluoro-1,3-benzothiazole

To a solution of 6-bromo-4-fluoro-l,3-benzothiazol-2-amine (360 mg, 1.5 mmol) in THF (20 mL) isoamyl nitrite (427 mg, 3.6 mmol) was added and the mixture was stirred overnight at rt. The mixture was concentrated and purified by column chromatography (EtOAc/PE = 0-1/4, Silica-CS 20 g, 30 mL/min, silica gel, UV 254) to afford the product (182 mg, 54 %). 'H NMR (400 MHz, Chloroform-d) 5 8.91 (s, 1H), 7.84 (s, 1H), 7.33 (dd, J= 9.6, 1.6 Hz, 1H).

4-Fluoro-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3-benzothiazole

To a solution of 6-bromo-4-fluoro-l,3-benzothiazole (300 mg, 1.29 mmol) and bis(pinacolato)diboron (492 mg, 1.94 mmol) in 1,4-dioxane (10.0 mL) Pd(dppf)C12 (189 mg, 0.26 mmol) and potassium acetate (381 mg, 3.88 mmol) were added. The mixture was purged three times with nitrogen, and stirred overnight at 100 °C. The mixture was concentrated and purified by column chromatography (EtOAc/PE = 0/1— 1/4, Silica-CS 20 g, 30 mL/min, silica gel, UV 254) to afford the product (75 mg, 21 %). ESI-MS m/z calcd for [C13H15BFNO2S] [M+H]⁺: 280.1; found: 280.3. *H NMR (400 MHz, Chloroform-d) 5 8.98 (s, 1H), 8.14 (s, 1H), 7.54 (d, J= 10.4 Hz, 1H), 1.31 (s, 12H).

Intermediate 6

7-Bromo-5-fluoro-l,3-benzothiazol-2-amine

A suspension of 2-bromo-4-fluoro-6-nitroaniline (1.00 g, 4.26 mmol) in sulfuric acid (10.0 mL) and water (10.0 mL) was stirred 1 h at 60 °C. The suspension was cooled to -5 °C, and a solution of NaNCL (352 mg, 5.11 mmol) in water (1.0 mL) was added dropwise. The mixture was stirred 1 h at -5 °C and the reaction mixture was added to a mixture of copper(I) thiocyanate (1.29 g, 10.6 mmol) and potassium thiocyanate (103 mg, 1.06 mmol) in water (5 mL). The resulting mixture was stirred 30 min at rt and was then extracted with EtOAc (50 mL). The organic phase was washed with brine, dried over Na2SO4, and concentrated. The obtained solid was dissolved in EtOH (10.0 mL) and water (10.0 mL). To this solution iron (1.90 g, 34.0 mmol) and NH4CI (1.14 g, 21.3 mmol) were added, and the mixture was stirred 1 h at 90 °C. The mixture was filtered, concentrated, and purified by column chromatography (EtOAc/PE = 0/1— 1/2, Silica- CS 40 g, 40 mL/min, silica gel, UV 254) to afford the product (350 mg, 30 %). ESIMS m/z calcd for [C₇H₄BrFN2S] [M+H]⁺: 246.9; found: 246.9. 'H NMR (400 MHz, DMSO-d₆) 8 7.91 (s, 2H), 7.25 - 7.11 (m, 2H).

7-Bromo-5-fluoro-l,3-benzothiazole

To a solution of 7-bromo-5-fluoro-l,3-benzothiazol-2-amine (350 mg, 1.4 mmol) in THF (10 mL) isoamyl nitrite (415 mg, 3.5 mmol) was added and the mixture was stirred overnight at rt. The mixture was concentrated and purified by column chromatography (EtOAc/PE = 0-1/10, Silica-CS 20 g, 30 mL/min, silica gel, UV 254) to afford the product (195 mg, 59 %). 'HNMR (400 MHz, Chloroform-d) 5 9.03 (s, 1H), 7.71 (dd, J= 9.2, 2.4 Hz, 1H), 7.35 (dd, J= 8.4, 2.0 Hz, 1H).

5-Fluoro-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3-benzothiazole

To a solution of 7-bromo-5-fluoro-l,3-benzothiazole (100 mg, 0.43 mmol) and bis(pinacolato)diboron (164 mg, 0.65 mmol) in 1,4-dioxane (8.0 mL) Pd(dppf)C12 (63.1 mg, 0.086 mmol) and potassium acetate (127 mg, 1.29 mmol) were added. The mixture was purged three times with nitrogen, and stirred overnight at 100 °C. The mixture was concentrated and purified by column chromatography (EtOAc/PE = 0/1— 1/4, Silica-CS 20 g, 30 mL/min, silica gel, UV 254) to afford the product (103 mg, 86 %). ESI-MS m/z calcd for [Ci3Hi₅BFNO₂S] [M+H]⁺: 280.1; found: 280.1. 'H NMR (400 MHz, Chloroform-d) 5 9.09 (s, 1H), 7.89 (dd, J= 9.2, 2.4 Hz, 1H), 7.67 (dd, J= 8.8, 2.4 Hz, 1H), 1.40 (s, 12H).

Intermediate 7 l-Bromo-2,3,4-trifluoro-5-nitrobenzene

To a solution of l,2,3-trifluoro-4-nitrobenzene (1.60 g, 9.04 mmol) in concentrated H2SO4 (12.0 mL) V-bromosuccinimide (2.09 g, 11.7 mmol) was added and the mixture was stirred 5 h at 70 °C. After cooling to rt, the mixture was poured into ice-water and extracted with EtOAc. The organic phase was washed with water and brine, dried over Na₂SO4, and concentrated to afford the product (1.8 g, 78 %). 'H NMR (400 MHz, DMSO-d₆) 8 8.55 - 8.50 (m, 1H).

5-Bromo-2,3,4-trifluoroaniline

To a solution of l-bromo-2,3,4-trifluoro-5-nitrobenzene (1.80 g, 7.03 mmol) in EtOH/H2O (40 mL, 3: 1) iron (1.18 g, 21.1 mmol) and NH4CI (3.76 g, 70.3 mmol) were added and the mixture was stirred 2 h at 80 °C. The mixture was filtered, evaporated, and purified by column chromatography (EtOAc/PE = 0-1/1, Silica-CS 40 g, 40 mL/min, silica gel, UV 254) to afford the product (1.3 g, 82 %). 'H NMR (400 MHz, Chloroform-d) 5 6.67 - 6.64 (m, 1H), 3.49 (br s, 2H).

(5-Bromo-2,3,4-trifluorophenyl)thiourea

A solution of benzylchloride (0.79 mL, 6.81 mmol) and KSCN (710 mg, 7.30 mmol) in dry acetone (10 mL) was refluxed 1 h. To the mixture 5-bromo-2,3,4-trifluoroaniline (1.10 g, 4.87 mmol) was added and the resulting mixture was refluxed 1 h. After cooling to rt, the mixture was evaporated. The obtained material was washed with water (30 mL) and an aqueous solution of NaOH (12 mL, 10 %) was added. The mixture was stirred 2 h at 80 °C. After cooling to rt, an aqueous solution of HC1 (IM) was added to adjust the pH to 3. An aqueous solution of NH3 (25%) was added to adjust the pH to 9. The mixture was extracted by EtOAc (3 x 30 mL). The combined organic phases were washed with water and brine, dried over Na₂SO4, concentrated, and purified by column chromatography (EtOAc/PE = 0/1— 1/2, Silica-CS 20 g, 25 mL/min, silica gel, UV 254) to afford the product (528 mg, 38 %). ESLMS m/z calcd for [Cv^BrE^S] [M+H]⁺: 286.9; found: 287.0. 'H NMR (400 MHz, DMSO-d₆) 8 9.56 (s, 1H), 8.19 (br s, 1H), 7.91 - 7.83 (m, 1H), 7.47 (br s, 1H).

5-Bromo-6,7-difluoro-l,3-benzothiazol-2-amine

To a solution of (5-bromo-2,3,4-trifluorophenyl)thiourea (508 mg, 1.78 mmol) in 1- methyl-2-pyrrolidinone (6 mL) NaH (60 %, 205 mg, 5.35 mmol) was added and the mixture was stirred 2 h at 130 °C. After cooling to rt, the mixture was poured into water (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic phases were washed with water (50 mL) and brine (50 mL), dried over Na₂SO4, concentrated, and purified by column chromatography (EtOAc/PE = 0/1— 1/1 , Silica-CS 20 g, 20 mL/min, silica gel, UV 254) to afford the product (238 mg, 50 %). ESLMS m/z calcd for [C₇H₃BrF2N2S] [M+H]⁺: 266.9; found: 267.0. ¹ H NMR (400 MHz, DMSO-d₆) 6 7.97 (s, 2H), 7.47 (dd, J= 5.2, 1.6 Hz, 1H).

5-Bromo-6,7-difluoro-l,3-benzothiazole

To a solution of 5-bromo-6,7-difluoro-l,3-benzothiazol-2-amine (228 mg, 0.86 mmol) in THF (10 mL) isoamyl nitrite (252 mg 2 2 mmol) was added and the mixture was stirred overnight at rt. The mixture was concentrated and purified by column chromatography (EtOAc/PE = 0-1/10, Silica-CS 20 g, 30 mL/min, silica gel, UV 254) to afford the product (108 mg, 50 %). ^JH NMR (400 MHz, Chloroform-d) 5 9.00 (d, J = 1.6 Hz, 1H), 8.15 (dd, J= 4.8, 1.6 Hz, 1H).

6,7-Difluoro-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3-benzothiazole

To a solution of 5-bromo-6,7-difluoro-l,3-benzothiazole (108 mg, 0.43 mmol) and bis(pinacolato)diboron (165 mg, 0.65 mmol) in 1,4-dioxane (8.0 mL) Pd(dppf)C12 (63.2 mg, 0.086 mmol) and potassium acetate (127 mg, 1.30 mmol) were added. The mixture was purged three times with nitrogen, and stirred overnight at 100 °C. The mixture was concentrated and purified by column chromatography (EtOAc/PE = 0/1-1/3, Silica-CS 20 g, 30 mL/min, silica gel, UV 254) to afford the product (95 mg, 74 %). ESLMS m/z calcd for [C13H14BF2NO2S] [M+H]⁺: 298.1; found: 298.2. 'H NMR (400 MHz, Chloroform-d) 5 8.95 (s, 1H), 8.29 - 8.27 (m, 1H), 1.40 (s, 12H).

Intermediate 9

3-(Dimethylamino)-2-(2,3,4-trifluorophenyl)prop-2-enal

To a cooled (0 °C) solution of

-di methyl form am ide (1453 mg, 19.9 mmol) and phosphoryl trichloride (2743 mg, 17.9 mmol) 2-(2,3,4-trifluorophenyl)acetic acid (378 mg, 1.99 mmol) was added and the mixture was stirred overnight at 60-70 °C. After cooling to rt, the mixture was slowly added to a mixture of ice and water with external cooling and ice intermittently to keep the temperature below 10 °C. K2CO3 was added slowly until pH reached 11. Small quantities of ethanol were added to control frothing. To the alkaline mixture toluene (30 mL) was added, and the mixture was refluxed for 1.5 h and then cooled to rt. The aqueous phase was extracted with additional toluene (40 mL). The combined organic phases were washed with water, dried over Na2SO4, and evaporated. The obtained solid was recrystallized from hexane to afford the product (245 mg, 54 %). ESLMS m/z calcd for [C11H10F3NO] [M+H]⁺: 230.1; found: 230.1. 'H NMR (400 MHz, Chloroform-d) 5 9.08 (s, 1H), 7.07 - 6.93 (m, 3H), 2.88 (br s, 6H).

Intermediate 10

3-(Dimethylamino)-2-(2-Chloro-3-fluorophenyl)prop-2-enal

To a cooled (0 °C) solution of A'A -di methyl form am ide (1357 mg, 18.6 mmol) and phosphoryl trichloride (2561 mg, 16.7 mmol) 2-(2-chl oro-3 -fluorophenyl)acetic acid (350 mg, 1.86 mmol) was added and the mixture was stirred overnight at 60-70 °C. After cooling to rt, the mixture was slowly added to a mixture of ice and water with external cooling and ice intermittently to keep the temperature below 10 °C. K2CO3 was added slowly until pH reached 11. Small quantities of ethanol were added to control frothing. To the alkaline mixture toluene (30 mL) was added, and the mixture was refluxed for 1.5 h and then cooled to rt. The aqueous phase was extracted with additional toluene (40 mL). The combined organic phases were washed with water, dried over ISfeSCU, and evaporated. The obtained solid was recrystallized from hexane to afford the product (150 mg, 36 %). ESLMS m/z calcd for [CnHnClFNO] [M+H]⁺: 228.1; found: 228.3. *H NMR (400 MHz, Chloroform-d) 5 9.02 (s, 1H), 7.18 - 7.13 (m, 1H), 7.04 - 6.97 (m, 2H), 6.87 (br s, 1H), 3.05 - 2.45 (m, 6H).

Intermediate 11

3-(Dimethylamino)-2-(4-bromo-2,3-difluorophenyl)prop-2-enal

To a cooled (0 °C) solution of N,N-dimethylformamide (236 mg, 3.23 mmol) and phosphoryl trichloride (445 mg, 2.90 mmol) 2-(4-bromo-2,3-difluorophenyl)acetic acid (81 mg, 0.32 mmol) was added and the mixture was stirred overnight at 60-70 °C. After cooling to rt, the mixture was slowly added to a mixture of ice and water with external cooling and ice intermittently to keep the temperature below 10 °C. K₂CO₃ was added slowly until pH reached 11. Small quantities of ethanol were added to control frothing. To the alkaline mixture toluene (30 mL) was added, and the mixture was refluxed for 1.5 h and then cooled to rt. The aqueous phase was extracted with additional toluene (40 mL). The combined organic phases were washed with water, dried over Na₂SO₄, and evaporated. The obtained solid was recrystallized from hexane to give the product (40 mg, 43 %). ESI-MS m/z calcd for [C₁₁H₁₀BrF₂NO] [M+H]+: 290.0; found: 290.0. 1H NMR (400 MHz, Chloroform-d) δ 9.01 (s, 1H), 7.25 – 7.21 (m, 1H), 6.92 (br s, 1H), 6.87 – 6.84 (m, 1H), 3.08 – 2.63 (m, 6H). Intermediate 12 3-(Dimethylamino)-2-(2,3-difluorophenyl)prop-2-enal

To a cooled (0 °C) solution of N,N-dimethylformamide (2 mL) and phosphoryl trichloride (2 mL) 2-(2,3-difluorophenyl)acetic acid (344 mg, 2.00 mmol) was added and the mixture was stirred overnight at 60-70 °C. After cooling to rt, the mixture was slowly added to a mixture of ice and water with external cooling and ice intermittently to keep the temperature below 10 °C. K2CO3 was added slowly until pH reached 11. Small quantities of ethanol were added to control frothing. To the alkaline mixture toluene (20 mL) was added, and the mixture was refluxed for 1.5 h and then cooled to rt. The aqueous phase was extracted with additional toluene (40 mL). The combined organic phases were washed with water, dried Na2SO4, evaporated, and purified by column chromatography (PE/EtOAc=1/1~0/1, Silica-CS 12 g, 20 mL/min, silica gel, UV 254) to afford the product (252 mg, 60 %). ESI-MS m/z calcd for [C11H11F2NO] [M+H]+: 212.1; found: 212.1.1H NMR (400 MHz, Chloroform-d) δ 9.08 (s, 1H), 7.15 – 6.98 (m, 4H), 2.88 (br s, 6H). Intermediate 13

2,3-Difluoro-l-iodo-4-methoxybenzene

To a solution of l,2-difluoro-3 -methoxybenzene (500 mg, 3.47 mmol) in THF (20 mL) at -78 °C w-butyllithium (1.53 mL, 2.5 M in hexanes, 3.82 mmol) was added dropwise and the mixture was stirred 1 h at -78 °C. A solution of iodine (969 mg, 3.82 mmol) in THF (5.0 mL) was added dropwise and the mixture was stirred 1 h at -78 °C. The mixture was allowed to reach rt and saturated aq NaHSCL was added. The aqueous phase was separated and extracted with EtOAc (30 mL). The combined organic phases were washed with brine, dried, concentrated and purified by column chromatography (EtOAc/PE = 0/1-1/10, Silica-CS 20 g, 20 mL/min, silica gel, UV 254) to afford the product (770 mg, 82 %). ESLMS m/z calcd for [C7H₅F₂IO] [M]: 269.9; found: 270.0. 'H NMR (400 MHz, Chloroform-d) 5 7.37 - 7.30 (m, 1H), 6.56 - 6.47 (m, 1H), 3.83 (s, 3H).

2-(2,3-Difluoro-4-methoxyphenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane

To a solution of 2,3-difhioro-l-iodo-4-methoxybenzene (300 mg, 1.11 mmol) and bis(pinacolato)diboron (423 mg, 1.67 mmol) in DMSO (8.0 mL) Pd(dppf)C12 (163 mg, 0.22 mmol) and potassium acetate (327 mg, 3.33 mmol) were added. The mixture was purged three times with nitrogen, and stirred overnight at 100 °C. The mixture was concentrated and purified by column chromatography (EtOAc/PE = 0/1— 1/5, Silica-CS 20 g, 30 mL/min, silica gel, UV 254) to afford the product (180 mg, 30 % purity), which was used without further purification in subsequent steps. ESLMS m/z calcd for [C13H17BF2O3] [M+H]⁺: 271.1; found: 271.2. 'H NMR (400 MHz, Chloroform-d) 5 7.38 - 7.31 (m, 1H), 6.70 - 6.62 (m, 1H), 3.85 (s, 3H), 1.28 (s, 12H). Intermediate 14

2-[2,3-Difluoro-4-(trifluoromethyl)phenyl]-4,4,5,5-tetramethyl-l,3,2- dioxaborolane

To a cooled (-78 °C) lithium diisopropylamide solution (6.04 mL, 0.5 M in THF, 3.02 mmol) a solution of l,2-difluoro-3-(trifluoromethyl)benzene (500 mg, 2.75 mmol) in THF (2.0 mL) was added dropwise and the mixture was stirred 1 h at -78 °C. 2- Isopropoxy-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (562 mg, 3.02 mmol) in THF (2.0 mL) was added and the mixture was slowly warmed to rt overnight. The mixture was added to diethyl ether and extracted with water and aq NaOH (0.1 M). The combined aqueous extracts were acidified with concentrated HC1 and extracted with DCM (30 mL). The organic phase was dried and concentrated to give the product (430 mg, 51 %). 'H NMR (400 MHz, Chloroform-d) 5 7.54 - 7.44 (m, 1H), 7.32 - 7.23 (m, 1H), 1.30 (s, 12H).

Intermediate 16

4-Bromo-2,3-difluoroaniline

To a cooled (0 °C) solution of 2, 3 -difluoroaniline (4.50 g, 34.9 mmol) in anhydrous DMF (30 mL) 7V-bromosuccinimide (6.51 g, 36.6 mmol) was added and the mixture was stirred 1 h. Water was added, and the mixture was extracted with EtOAc (3 x50 mL). The combined organic phases were washed with brine, dried over ISfeSCU, and evaporated to give the product (4.61 g, 64 %). 'H NMR (400 MHz, DMSO-de) 8 7.14 - 7.09 (m, 1H), 6.58 - 6.53 (m, 1H), 5.72 (s, 2H).

6-Bromo-4,5-difluoro-l,3-benzothiazol-2-amine

To a solution of 4-bromo-2, 3 -difluoroaniline (4.11 g, 19.8 mmol) in acetic acid (40 mL) KSCN (7.68 g, 79.0 mol) was added followed by dropwise addition of a solution of bromine (2.02 mL, 39.5 mmol) in acetic acid (10 mL). The mixture was stirred 16 h at rt before being concentrated to dryness. A solution of saturated aq NaHCCL (100 mL) was added, and the mixture was extracted with EtOAc (3 x 50 mL). The combined organic phases were washed with brine (50 mL), dried over ISfeSCL, evaporated, and purified by column chromatography (EtOAc/PE=0/l~l/4, Silica-CS 40 g, 40 mL/min, silica gel, UV 254) to give the product (2.20 g, 42 %). ¹ H NMR (400 MHz, DMSO-d₆) 5 8.03 (s, 2H), 7.88 (dd, J= 6.0, 2.0 Hz, 1H).

6-Bromo-4,5-difluorobenzothiazole

To a solution of 6-bromo-4,5-difluoro-l,3-benzothiazol-2-amine (2.40 g, 9.05 mmol) in DMF (20 mL) isoamyl nitrite (2.12 g, 18.1 mmol) was added and the mixture was stirred 1 h at 80 °C. The mixture was concentrated and partitioned between EtOAc (20 mL) and water. The organic phase was washed with brine, dried over Na2SO4, evaporated, and purified by column chromatography (PEZEtOAc= I/O- 10/1, Silica-CS 20 g, 20 mL/min, silica gel, UV 254) to afford the product (1.6 g, 71 %). ¹ H NMR (400 MHz, DMSO-d₆) 8 9.54 (s, 1H), 8.48 (dd, J= 6.0, 2.0 Hz, 1H).

4,5-Difluoro-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzothiazole

To a solution of 6-bromo-4,5-difluorobenzothiazole (200 mg, 0.80 mmol) and bis(pinacolato)diboron (305 mg, 1.20 mmol) in 1,4-dioxane (5 mL) Pd(dppf)C12 (117 mg, 0.16 mmol) and potassium acetate (235 mg, 2.40 mmol) were added. The mixture was purged three times with nitrogen, and stirred overnight at 100 °C. The mixture was concentrated and purified by column chromatography (EtOAc/PE = 0/1-1/10, Silica- CS 12 g, 20 mL/min, silica gel, UV 254) to afford the product (85 mg, 36 %). ^JH NMR (400 MHz, Chloroform-d) 5 9.02 (s, 1H), 8.01 (dd, J= 4.0, 1.6 Hz, 1H), 1.35 (s, 12H).

Intermediate 17

5-Chloro-2-(trifluoromethyl)-3-nitropyridine

A mixture of 2-bromo-5-chloro-3-nitropyridine (9.80 g, 41.3 mmol), methyl 2,2- difluoro-2 -fluorosulfonylacetate (11.9 g, 61.9 mmol) and Cui (9.43 g, 49.5 mmol) in DMF (100 mL) was stirred 2 h at 100 °C. After cooling to rt, the mixture was poured into water (300 mL) and then extracted with EtOAc (3 x 100 mL). The combined organic phases were washed with water (100 mL) and brine (100 mL), dried over Na2SO4, concentrated, and purified by column chromatography (EtOAc/PE = 0/1— 1/4, Silica-CS 80 g, 40 mL/min, silica gel, UV 254) to give the product (8.8 g, 94 %). ESIMS m/z calcd for [C6H2CIF3N2O2] [M]: 226.0; found: 226.0. 'H NMR (400 MHz, Chloroform-d) 5 8.79 (d, J= 2.0 Hz, 1H), 8.16 (d, J= 1.6 Hz, 1H).

3-Amino-5-chloro-2-(trifluoromethyl)pyridine

A solution of 5-chloro-2-(trifluoromethyl)-3-nitropyridine (8.8 g, 38.8 mmol), ammonium hydrochloride (12.5 g, 233 mmol) and Fe (10.8 g, 194 mmol) in EtOH (100 mL) and H2O (10 mL) was stirred 6 h at 85 °C. The mixture was filtered, concentrated, and purified by column chromatography (EtOAc/PE = 0/1— 1/4, Silica-CS 80 g, 40 mL/min, silica gel, UV 254) to give the product (7.1 g, 93 %). ESLMS m/z calcd for [C6H4CIF3N2] [M+H]⁺: 197.0; found: 197.2. ^XH NMR (400 MHz, Chloroform-d) 57.92 (d, J= 1.6 Hz, 1H), 7.04 (d, J= 2.0 Hz, 1H), 4.25 (br s, 2H).

[5-Chloro-2-(trifluoromethyl)-3-pyridyl]hydrazine

To a cooled (-5 °C) solution of 3-amino-5-chloro-2-(trifluoromethyl)pyridine (2.50 g, 12.7 mmol) in acetic acid (8.0 mL) concentrated HC1 (16.0 mL) was added. A solution of NaNCh (1.14 g, 16.5 mmol) in water (4.0 mL) was added dropwise over 5 min. The mixture was stirred 45 min at -5 °C. Then a cooled (0 °C) solution of tin(II) chloride dihydrate (2.87 g, 12.7 mmol) in concentrated HC1 (8.0 mL) was added dropwise over 10 min. The mixture was stirred 2 h at -5 °C. Then aqueous NaOH (5 M) was added dropwise at -5 °C to adjust pH to 8. The mixture was extracted with EtOAc (2 x 100 mL). The combined organic phases were washed with water (100 mL) and brine (100 mL), dried over ISfeSCU, evaporated, and purified by column chromatography (PE/EtOAc = 1/0-4/1, silica-CS 20 g 20 mL/min, silica gel, UV 254 nm) to afford the product (1.8 g, 67 %). ESLMS m/z calcd for [C6H5CIF3N3] [M+H]⁺: 212.0; found: 212.2. 'HNMR (400 MHz, Chloroform-d) 5 7.88 (d, J= 2.0 Hz, 1H), 7.81 (d, J= 2.0 Hz, 1H), 5.94 (s, 1H), 3.65 (s, 2H).

3-|5-(3-Azido-4.6-6M)enzylidene-3-deoxy-|Ll)-«alactopyranosyl)-3-methyl-l//- l,2,4-triazol-l-yl]-5-chloro-2-(trifluoromethyl)pyridine

To a solution of 2,6-anhydro-4-azido-5,7-O-benzylidene-4-deoxy-D-glycero-L-manno- heptonamide (1.0 g, 3.12 mmol) in 1,4-dioxane (15.0 mL) A A-di methyl acetamide dimethyl acetal (457 mg, 3.43 mmol) was added and the mixture was stirred 3 h at 50 °C. The mixture was evaporated, and the residue was dissolved in acetic acid (10 mL). [5-Chloro-2-(trifluoromethyl)-3-pyridyl]hydrazine (793 mg, 3.75 mmol) was added and the mixture was stirred 2 h at 70 °C. The mixture was concentrated and partitioned between water (20 mL) and DCM (20 mL). The aqueous phase was extracted with DCM (2 x 20 mL). The combined organic phases were washed with water (20 mL) and brine (20 mL), dried over ISfeSCU, evaporated, and purified by column chromatography (EtOAc/PE = 1/5— 2/1, Silica-CS 20 g, 30 mL/min, silica gel, UV 254). The obtained material was further purified by reversed-phase chromatography (MeCN/EEO = 1/20-1/1, C-18 column, 20 mL/min, UV 254) to afford the product (600 mg, 36 %). ESLMS m/z calcd for [C22H19CIF3N7O4] [M+H]⁺: 538.1; found: 537.8. 'H NMR (400 MHz, Chloroform-d) 5 8.55 (s, 1H), 7.81 (d, J= 1.6 Hz, 1H), 7.38 - 7.26 (m, 5H), 5.39 (s, 1H), 4.49 (d, .7= 8.8 Hz, 1H), 4.25 (t, J= 9.6 Hz, 1H), 4.14 (d, J = 3.2 Hz, 1H), 3.81 (dd, J= 12.8, 1.6 Hz, 1H), 3.51 (d, J = 12.8 Hz, 1H), 3.36 (dd, J = 10.4, 3.2 Hz, 1H), 3.29 (s, 1H), 2.39 (s, 3H).

3-[5-(3-Amino-4,6-(?-benzylidene-3-deoxy-p-D-galactopyranosyl)-3-methyLlH- l,2,4-triazol-l-yl]-5-chloro-2-(trifluoromethyl)pyridine

To a solution of 3-[5-(3-azido-4,6-O-benzylidene-3-deoxy-P-D-galactopyranosyl)-3- methyl-U/-l,2,4-triazol-l-yl]-5-chloro-2-(trifluoromethyl)pyridine (600 mg, 1.12 mmol) in THF (30 mL) and water (3.0 mL) triphenylphosphine (1.46 g, 5.58 mmol) was added and the mixture was stirred 6 h at 50 °C. The mixture was concentrated and purified by column chromatography (DCM/MeOH=l/0~10/l, Silica-CS 12 g, 40 mL/min, silica gel, UV 254). The obtained material was further purified by reversed- phase chromatography (MeCN/H2O = 1/20-1/1, C-18 column, 20 mL/min, UV 254) to afford the product (500 mg, purity 70 %, 61 %). ESLMS m/z calcd for [C22H21CIF3N5O4] [M+H]⁺: 512.1; found: 511.9. ^XH NMR (400 MHz, Chloroform-d) 5 8.63 (d, J = 2.0 Hz, 1H), 7.85 (d, J = 2.0 Hz, 1H), 7.35 - 7.25 (m, 5H), 5.36 (s, 1H), 4.29 (d, J= 9.2 Hz, 1H), 4.04 (d, J= 2.4 Hz, 1H), 3.86 - 3.75 (m, 3H), 3.44 (dd, J = 12.8, 1.2 Hz, 1H), 3.26 (s, 1H), 2.78 (dd, J= 9.6, 2.8 Hz, 1H), 2.37 (s, 3H).

3-{5-{4,6-O-Benzylidene-3-[(2-terLbutoxycarbonyl)hydrazinyl]-3-deoxy-p-D- galactopyranosyl}-3-methyl-lEZ-l,2,4-triazol-l-yl}-5-chloro-2-

(trifluoromethyl)pyridine

To a solution of 3-[5-(3-amino-4,6-O-benzylidene-3-deoxy-β-D-galactopyranosyl)-3- methyl-1H-1,2,4-triazol-1-yl]-5-chloro-2-(trifluoromethyl)pyridine (500 mg, purity 70 %, 0.68 mmol) in DCM (10.0 mL) N-tert-butyloxycarbonyl-3-(4- cyanophenyl)oxaziridine (185 mg, 0.68 mmol) was added and the mixture was stirred overnight at rt. The mixture was concentrated and purified by column chromatography (PE/EtOAc=4/1~0/1, Silica-CS 20 g, 30 mL/min, silica gel, UV 254) to afford the product (210 mg, 49 %). ESI-MS m/z calcd for [C + 27H30ClF3N6O6] [M+H] : 627.2; found: 627.0.1H NMR (400 MHz, Chloroform-d) δ 8.61 (d, J = 1.2 Hz, 1H), 7.89 (d, J = 2.0 Hz, 1H), 7.41 – 7.30 (m, 5H), 6.44 (br s, 1H), 5.41 (s, 1H), 4.70 (br s, 1H), 4.51 (s, 1H), 4.43 (d, J = 9.2 Hz, 1H), 4.28 (d, J = 2.4 Hz, 1H), 4.14 – 4.08 (m, 1H), 3.87 (dd, J = 12.4, 1.6 Hz, 1H), 3.59 (d, J = 12.4 Hz, 1H), 3.31 (s, 1H), 3.05 (d, J = 10.0 Hz, 1H), 2.42 (s, 3H), 1.44 (s, 9H). 5-Chloro-3-{5-[3-deoxy-3-(1H-1,2-pyrazol-1-yl)-β-D-galactopyranosyl]-3-methyl- 1H-1,2,4-triazol-1-yl}-2-(trifluoromethyl)pyridine

To a cooled (0 °C) solution of 3-{5-{4,6-O-benzylidene-3-[(2-tert- butoxycarbonyl)hydrazinyl]-3-deoxy-β-^D-galactopyranosyl}-3-methyl-1H-1,2,4- triazol-1-yl}-5-chloro-2-(trifluoromethyl)pyridine (210 mg, 0.34 mmol) in DCM (10.0 mL) TFA (1.0 mL) was added and the mixture was stirred overnight at rt. The mixture was concentrated, and the residue was dissolved in EtOH (10.0 mL). 1,1,3,3- Tetraethoxypropane (369 mg, 1.67 mmol) was added, followed by concentrated HCl (0.25 mL). The mixture was stirred 1.5 h at rt, before the pH was adjusted to 7-8 using saturated aq NaHCO3. The mixture was concentrated and purified by reversed-phase chromatography (MeCN/JbO = 1/20-1/2, C-18 column, 20 mL/min, UV 214) to give the product (90 mg, 57 %). ESI-MS m/z calcd for [CisHisCIFsNeCU] [M+H]⁺: 475.1; found: 474.9. 'HNMR (400 MHz, Methanol-d₄) 8 8.92 (d, J= 2.0 Hz, 1H), 8.31 (d, J = 1.2 Hz, 1H), 7.76 (d, J = 2.4 Hz, 1H), 7.51 (d, J= 1.6 Hz, 1H), 6.32 (t, J = 2.4 Hz, 1H), 4.62 (t, J= 10.0 Hz, 1H), 4.39 (d, J= 9.6 Hz, 1H), 4.35 (dd, J= 10.4, 2.4 Hz, 1H), 4.02 (d, J= 2.4 Hz, 1H), 3.66 (t, J= 6.0 Hz, 1H), 3.62 - 3.53 (m, 2H), 2.42 (s, 3H).

5-Chloro-3- {5- [3-deoxy-3-(4-iodo- 1H- 1 ,2-pyrazol- l-yl)-P-D-galactopyranosyl]-3- methyl-lH-l,2,4-triazol-l-yl}-2-(trifluoromethyl)pyridine

To a solution of 5-chloro-3-{5-[3-deoxy-3-(U7-l,2-pyrazol-l-yl)-P-D- galactopyranosyl]-3-methyl-lJ7-l,2,4-triazol-l-yl}-2-(trifluoromethyl)pyridine (45 mg, 0.095 mmol) in THF (5.0 mL) V-iodosuccinimde (107 mg, 0.47 mmol) was added and the mixture was stirred overnight at rt. The mixture was concentrated and purified by reversed-phase chromatography (MeCN/H2O = 1/20-1/2, C-18 column, 20 mL/min, UV 214) to give the product (45 mg, 79 %). ESI-MS m/z calcd for [C18H17CIF3IN6O4] [M+H]⁺: 601.0; found: 600.7. 'HNMR (400 MHz, Methanol-d₄) 6 8.92 (d, J= 1.6 Hz, 1H), 8.31 (s, 1H), 7.84 (s, 1H), 7.53 (s, 1H), 4.60 (t, J = 9.6 Hz,lH), 4.44 - 4.32 (m, 2H), 3.99 (d, J = 2.0 Hz, 1H), 3.64 (t, J = 6.0 Hz, 1H), 3.60 - 3.50 (m, 2H), 2.42 (s, 3H).

Intermediate 19

5-Bromo-2-(trifluoromethyl)aniline

To a soultion of 4-bromo-2-nitro-l-(trifluoromethyl)benzene (2.0 g, 7.41 mmol) in EtOH/H2O (30 mL, 3: 1) iron (2.07 g, 37.0 mmol) and NH₄Cl (1.98 g, 37.0 mmol) were added and the mixture was stirred 2 h at 85 °C. The mixture was concentrated and purified by column chromatography (PE/EtOAc=1/0~10/1, Silica-CS 20 g, 30 mL/min, silica gel, UV 254) to give the product (1.4 g, 79 %). ESI-MS m/z calcd for [C7H5BrF3N] [M+H]+: 240.0; found: 239.8.1H NMR (400 MHz, Chloroform-d) δ 7.19 (d, J = 8.4 Hz, 1H), 6.86 – 6.79 (m, 2H), 3.51 (br s, 2H). [5-Bromo-2(trifluoromethyl)phenyl]hydrazine

To a cooled (-10 °C) solution of 5-bromo-2-(trifluoromethyl)aniline (400 mg, 1.67 mmol) in concentrated HCl (10 mL) a solution of NaNO₂ (138 mg, 2.00 mmol) in water (1 mL) was added dropwise and the mixture was stirred 30 min at -10 °C. Tin(II) chloride dihydrate (1.13 g, 5.00 mmol) dissolved in concentrated HCl (3.0 mL) was added dropwise at -10 °C. The resulting mixture was slowly warmed to rt and then stirred 2 h. The mixture was poured into saturated aq NaHCO3 and extracted with EtOAc (3 x 20 mL). The combined organic phases were washed with brine, dried over Na₂SO₄, and evaporated to afford the product (300 mg, 71 %). ESI-MS m/z calcd for [C₇H₆BrF₃N₂] [M+H]+: 255.0; found: 254.9.1H NMR (400 MHz, Chloroform-d) δ 7.47 (d, J = 0.8 Hz, 1H), 7.20 (d, J = 8.4 Hz, 1H), 6.84 (dd, J = 8.0, 0.8 Hz, 1H), 5.80 (s, 1H), 3.56 (br s, 2H). 1-[5-(3-Azido-4,6-O-benzylidene-3-deoxy-β-D-galactopyranosyl)-3-methyl-1H- 1,2,4-triazol-1-yl]-5-bromo-2-(trifluoromethyl)benzene

To a solution of 2,6-anhydro-4-azido-5,7-O-benzylidene-4-deoxy-D-glycero-L-manno- heptonamide (247 mg, 0.77 mmol) in 1,4-dioxane (9.0 mL) N,N-dimethylacetamide dimethyl acetal (113 mg, 0.85 mmol) was added and the mixture was stirred 3 h at 50 °C. The mixture was evaporated, and the residue was dissolved in 1,4-dioxane (9.0 mL) and acetic acid (3 mL). To this solution [5-bromo-2(trifluoromethyl)phenyl]hydrazine (236 mg, 0.93 mmol) was added and the mixture was stirred 2 h at 60 °C. The mixture was evaporated and partitioned between water (20 mL) and DCM (20 mL). The aqueous phase was extracted with DCM (2 x 20 mL). The combined organic phases were washed with water (20 mL) and brine (20 mL), dried over Na₂SO₄, evaporated, and purified by column chromatography (PE/EtOAc=5/1~1/2, Silica-CS 20 g, 30 mL/min, silica gel, UV 254) to afford the product (300 mg, 67 %). ESI-MS m/z calcd for [C₂₃H₂₀BrF₃N₆O₄] [M+H]+: 581.1; found: 580.8.1H NMR (400 MHz, Chloroform- d) δ 7.71 – 7.62 (m, 2H), 7.53 (d, J = 8.4 Hz, 1H), 7.41 – 7.36 (m, 2H), 7.35 – 7.25 (m, 3H), 5.41 (s, 1H), 4.45 (t, J = 9.6 Hz, 1H), 4.34 – 4.24 (m, 1H), 4.13 (d, J = 3.2 Hz, 1H), 3.81 (dd, J = 12.4, 1.2 Hz, 1H), 3.64 – 3.54 (m, 1H), 3.36 (dd, J = 10.0, 3.2 Hz, 1H), 3.21 (s, 1H), 2.38 (s, 3H). 1-[5-(3-Amino-4,6-O-benzylidene-3-deoxy-β-^D-galactopyranosyl)-3-methyl-1H- 1,2,4-triazol-1-yl]-5-bromo-2-(trifluoromethyl)benzene

To a solution of 1-[5-(3-azido-4,6-O-benzylidene-3-deoxy-β-D-galactopyranosyl)-3- methyl-1H-1,2,4-triazol-1-yl]-5-bromo-2-(trifluoromethyl)benzene (300 mg, 0.52 mmol) in THF/water (12 mL, 5:1) triphenylphosphine (474 mg, 1.81 mmol) was added and the mixture was stirred 6 h at 50 °C. The mixture was concentrated and purified by column chromatography (DCM/MeOH = 1/0~10/1, Silica-CS 20 g, 30 mL/min, silica gel, UV 254) to give the product (200 mg, 70 %). ESI-MS m/z calcd for [C₂₃H₂₂BrF₃N₄O₄] [M+H]+: 555.1; found: 554.9.1H NMR (400 MHz, DMSO-d₆) δ 7.97 (d, J = 8.4 Hz, 1H), 7.89 (d, J = 8.4 Hz, 1H), 7.84 (s, 1H), 7.46 – 7.36 (m, 5H), 5.54 (s, 1H), 5.22 (d, J = 3.6 Hz, 1H), 4.11 – 3.97 (m, 3H), 3.88 (d, J = 11.6 Hz, 1H), 3.78 – 3.67 (m, 1H), 3.48 (s, 1H), 2.64 (dd, J = 9.2, 3.2 Hz, 1H), 2.32 (s, 3H), 1.81 (br s, 2H). 1-{5-{4,6-O-Benzylidene-3-[(2-tert-butoxycarbonyl)hydrazinyl]-3-deoxy-β-D- galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-5-bromo-2- (trifluoromethyl)benzene

To a solution of 1-[5-(3-amino-4,6-O-benzylidene-3-deoxy-β-D-galactopyranosyl)-3- methyl-1H-1,2,4-triazol-1-yl]-5-bromo-2-(trifluoromethyl)benzene (200 mg, 0.36 mmol) in DCM (10 mL) N-tert-butyloxycarbonyl-3-(4-cyanophenyl)oxaziridine (97.6 mg, 0.40 mmol) was added and the mixture was stirred overnight at rt. The mixture was concentrated and purified by column chromatography (PE/EtOAc=4/1~0/1, Silica-CS 20 g, 30 mL/min, silica gel, UV 254) to afford the product (150 mg, 62 %). ESI-MS m/z calcd for [C H BrF N O ] [M+H]+: 1 28 31 3 5 6 670.1; found: 669.9. H NMR (400 MHz, DMSO-d₆) δ 8.34 (br s, 1H), 7.98 (d, J = 8.0 Hz, 1H), 7.89 (d, J = 8.8 Hz, 1H), 7.82 (s, 1H), 7.49 – 7.34 (m, 5H), 5.50 (s, 1H), 5.22 (d, J = 4.0 Hz, 1H), 4.56 (br s, 1H), 4.19 – 4.12 (m, 2H), 4.04 – 3.92 (m, 2H), 3.88 (d, J = 12.0 Hz, 1H), 3.48 (s, 1H), 2.94 – 2.83 (m, 1H), 2.32 (s, 3H), 1.38 (s, 9H). 5-Bromo-1-{5-[3-deoxy-3-(1H-1,2-pyrazol-1-yl)-β-D-galactopyranosyl]-3-methyl- 1H-1,2,4-triazol-1-yl}-2-(trifluoromethyl)benzene

To a solution of 1-{5-{4,6-O-benzylidene-3-[(2-tert-butoxycarbonyl)hydrazinyl]-3- deoxy-β-D-galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-5-bromo-2- (trifluoromethyl)benzene (300 mg, 0.45 mmol) in EtOH (10 mL) 1,1,3,3- tetraethoxypropane (197 mg, 0.90 mmol) and concentrated HCl (0.5 mL) were added and the mixture was stirred 1 h at 80 °C. The mixture was concentrated and purified by prep HPLC (MeCN/H2O (10 mmol/L NH4HCO3), X-Select10 μm 19*250 mm, 20 mL/min, UV254) to afford the product (108 mg, 47 %). ESI-MS m/z calcd for [C₁₉H₁₉BrF₃N₅O₄] [M+H]+: 518.1; found: 518.0.1H NMR (400 MHz, Methanol-d₄) δ 8.00 (dd, J = 8.8, 1.2 Hz, 1H), 7.90 (br s, 1H), 7.86 (d, J = 8.8 Hz, 1H), 7.78 (d, J = 2.0 Hz, 1H), 7.51 (d, J = 1.6 Hz, 1H), 6.33 (t, J = 2.0 Hz, 1H), 4.70 – 4.66 (m, 1H), 4.35 (dd, J = 10.8, 2.8 Hz, 1H), 4.25 (d, J = 9.2 Hz, 1H), 4.05 (d, J = 2.8 Hz, 1H), 3.66 – 3.62 (m, 3H), 2.43 (s, 3H). 5-Bromo-1-{5-[3-deoxy-3-(4-iodo-1H-1,2-pyrazol-1-yl)-β-D-galactopyranosyl]-3- methyl-1H-1,2,4-triazol-1-yl}-2-(trifluoromethyl)benzene

To a solution 5-bromo-1-{5-[3-deoxy-3-(1H-1,2-pyrazol-1-yl)-β-^D-galactopyranosyl]- 3-methyl-1H-1,2,4-triazol-1-yl}-2-(trifluoromethyl)benzene (108 mg, 0.21 mmol) in MeCN (10 mL) ammonium cerium(IV) nitrate (114 mg, 0.21 mmol) and iodine (264 mg, 1.04 mmol) were added and the mixture was stirred 1 h at 40 °C. The mixture was concentrated and purified by prep HPLC (MeCN/H₂O (10 mmol/L NH₄HCO₃), X- Select10 μm 19*250mm, 20 mL/min, UV254) to afford the product (102 mg, 76 %). ESI-MS m/z calcd for [C H BrF IN O ] + 1 19 18 3 5 4 [M+H] : 644.0; found: 644.0. H NMR (400 MHz, Methanol-d4) δ 8.00 (dd, J = 8.4, 1.2 Hz, 1H), 7.89 – 7.85 (m, 3H), 7.54 (s, 1H), 4.69 – 4.63 (m, 1H), 4.38 (dd, J = 10.4, 2.4 Hz, 1H), 4.26 (d, J = 9.2 Hz, 1H), 4.02 (d, J = 2.8 Hz, 1H), 3.65 – 3.61 (m, 3H), 2.43 (s, 3H). Intermediate 22 Ethyl 2-(2,3-difluoro-4-nitrophenyl)acetate

To an ice-cold solution of tert-butyl ethylmalonate (5846 mg, 31.1 mmol) in 1-methyl- 2-pyrrolidinone (30 mL) sodium hydride (60 % in mineral oil, 2259 mg, 56.5 mmol) was added and the mixture was stirred 20 min at 0 °C. To the mixture a solution of 1,2,3-trifluoro-4-nitrobenzene (5.00 g, 28.2 mmol) in 1-methyl-2-pyrrolidinone (5 mL) was added dropwise, while maintaining the temperature below 20 °C. The mixture was stirred 2 h at rt. The mixture was added to an aq solution of NH₄Cl (1.5 L) and extracted with EtOAc (3 x 200 mL). The combined organic phases were washed with water (5 x 400 mL), dried over MgSO4 and evaporated. The obtained material was dissolved in DCM (48 mL) and TFA (12 mL) was added. The mixture was stirred 16 h at 40 °C. The mixture was cooled to rt and evaporated. The residue was dissolved in EtOAc (120 mL) and washed with saturated aq NaHCO3, water, and brine. The organic phase was dried over MgSO₄, evaporated, and purified by column chromatography (EtOAc/PE = 0/1~1/10, Silica-CS 40 g, 40 mL/min, silica gel, UV 254) to afford the product (3.95 g, 57 %).1H NMR (400 MHz, Chloroform-d) δ 7.80 – 7.76 (m, 1H), 7.17 – 7.13 (m, 1H), 4.14 (q, J = 7.2 Hz, 2H), 3.70 (d, J = 1.2 Hz, 2H).1.21 (t, J = 7.2 Hz, 3H). Ethyl 2-(4-amino-2,3-difluorophenyl)acetate

To a solution of ethyl 2-(2,3-difluoro-4-nitrophenyl)acetate (3.95 g, 16.1 mmol) in EtOH/H2O (200 mL, 3:1) iron (2699 mg, 48.3 mmol) and NH4Cl (8618 mg, 161 mmol) were added and the mixture was stirred 2 h at 80 °C. The mixture was filtered, concentrated, and purified by column chromatography (EtOAc/PE = 0/1~1/1, Silica- CS 40 g, 40 mL/min, silica gel, UV 254) to afford the product (3.20 g, 92 %). ESI-MS m/z calcd for [C H F NO ] [M+H]+: 216.1; found: 2 1 10 11 2 2 16.3. H NMR (400 MHz, Chloroform-d) δ 6.80 – 6.76 (m, 1H), 6.52 – 6.47 (m, 1H), 4.16 (q, J = 7.2 Hz, 2H), 3.80 (br s, 2H), 3.56 (d, J = 1.2 Hz, 2H).1.26 (t, J = 7.2 Hz, 3H). Ethyl 2-(4-chloro-2,3-difluorophenyl)acetate

To a cooled (0 °C) solution of ethyl 2-(4-amino-2,3-difluorophenyl)acetate (1.20 g, 5.58 mmol) in concentrated HCl (15 mL) a solution of NaNO2 (423 mg, 6.13 mmol) in water (2 mL) was added and the mixture was stirred 10 min at 0 °C. Then a solution of CuCl (1656 mg, 16.7 mmol) in concentrated HCl (2 mL) was added and the mixture was stirred overnight at rt. The mixture was extracted with EtOAc (3 x 30 mL). The combined organic phases were washed with saturated aq NaHCCL, water, and brine, dried over MgSCU, evaporated, and purified by column chromatography (EtOAc/PE = 0/1— 1/1 , Silica-CS 40 g, 40 mL/min, silica gel, UV 254) to afford the product (700 mg, 54 %). 'HNMR (400 MHz, Chloroform-d) 5 7.16 - 7.12 (m, 1H), 7.01 - 6.97 (m, 1H), 4.18 (q, J= 7.2 Hz, 2H), 3.66 (d, J= 1.6 Hz, 2H), 1.27 (t, J= 7.2 Hz, 3 H).

2-(4-Chloro-2,3-difluorophenyl)acetic acid

To a solution of ethyl 2-(4-chloro-2,3-difluorophenyl)acetate (700 mg, 2.98 mmol) in MeOH/H₂O (30 mL, 2: 1) NaOH (239 mg, 5.97 mmol) was added and the mixture was stirred 1 h at rt. The mixture was concentrated and dissolved in water (30 mL). The solution was acidified to pH=5 by addition of HC1 (1 M). The formed solid was collected and dried in vacuo to provide the product (450 mg, 73 %). ESLMS m/z calcd for [C₈H₅C1F₂O₂] [M+H]⁺: 207.0; found: 207.1. 'H NMR (400 MHz, Chloroform-d) 5 7.11 - 7.06 (m, 1H), 6.94 - 6.89 (m, 1H), 3.66 (s, 2H).

2-(4-Chloro-2,3-difluorophenyl)-3-(dimethylamino)prop-2-enal

To a cooled (0 °C) solution of DMF (1592 mg, 21.8 mmol) and phosphoryl trichloride (3006 mg, 19.6 mmol) 2-(4-chloro-2,3-difluorophenyl)acetic acid (450 mg, 2.18 mmol) was added and the mixture was stirred overnight at 60-70 °C. After cooling to rt, the mixture was slowly added to a mixture of ice and water with external cooling to keep the temperature below 10 °C. K2CO3 was added slowly until pH reached 11. EtOH (1 mL) was added to control frothing. To the alkaline mixture toluene (30 mL) was added, and the mixture was refluxed for 1.5 h and then cooled to rt. The aqueous phase was extracted with toluene (40 mL). The combined organic phases were washed with water, dried over Na₂SO4, evaporated, and purified by column chromatography (EtOAc/PE = 0/1— 1/0, Silica-CS 10 g, 15 mL/min, silica gel, UV 254) to give the product (249 mg, 47 %). ESLMS m/z calcd for [C11H10CIF2NO] [M+H]⁺: 246.0; found: 246.2. 'HNMR (400 MHz, Chloroform-d) 5 9.09 (s, 1H), 7.18 - 7.14 (m, 1H), 6.99 - 6.94 (m, 2H), 3.25 - 2.55 (m, 6H).

5-Bromo-2-(trifluoromethyl)-3-nitropyridine

A solution of 2,5-dibromo-3-nitropyridine (2.00 g, 7.09 mmol), methyl 2,2-difluoro-2- (fhrorosulfonyl)acetate (2.05 g, 10.6 mmol) and Cui (1.62 g, 8.51 mmol) in DMF (20.0 mL) was stirred 2 h at 100 °C. After cooling to rt, the mixture was poured into water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic phases were washed with water (50 mL) and brine (50 mL), dried over Na2SO4, evaporated, and purified by column chromatography (EtOAc/PE = 0/1— 1/4, Silica-CS 20 g, 20 mL/min, silica gel, UV 254) to give the product (1.8 g, 94 %). ESLMS m/z calcd for [C₆H2BrF₃N2O2] [M]: 269.9; found: 270.0. 'HNMR (400 MHz, Chloroform-d) 5 8.90 (d, J= 1.6 Hz, 1H), 8.30 (d, J= 1.6 Hz, 1H).

5-Bromo-2-(trifluoromethyl)pyridin-3-amine

To a soultion of 5-bromo-2-(trifluoromethyl)-3-nitropyridine (1.8 g, 6.64 mmol) in EtOHH₂O (22 mL, 10: 1) iron (1.86 g, 33.2 mmol) and NH₄C1 (2.13 g, 39.9 mmol) were added and the mixture was stirred 6 h at 85 °C. The mixture was concentrated and purified by column chromatography (PE/EtOAc=l/0~4/l, Silica-CS 20 g, 20 mL/min, silica gel, UV 254) to give the product (1.45 g, 91 %). ESLMS m/z calcd for [C6H₄BrF₃N2] [M+H]⁺: 241.0; found: 240.9. 'H NMR (400 MHz, Chloroform-d) 5 8.01 (d, J= 1.6 Hz, 1H), 7.21 (d, J= 1.6 Hz, 1H), 4.22 (br s, 2H).

[5-Bromo-2-(trifluoromethyl)pyrid-3-yl]hydrazine

To a cooled (-5 °C) solution of 5-bromo-2-(trifluoromethyl)pyridin-3-amine (600 mg, 2.49 mmol) in acetic acid (3.0 mL) concentrated HC1 (9.0 mL) was added followed by dropwise addition of a solution of NaNCL (223 mg, 3.24 mmol) in water (1 mL). The resulting mixture was stirred 45 min at -5 °C. Tin(II) chloride dihydrate (1.69 g, 7.47 mmol) dissolved in concentrated HC1 (3.0 mL) was added dropwise at 0 °C. The resulting mixture was stirred 2 h at -5 °C. Water (30 mL) was added and the pH was adjusted to 8 by dropwise addition of aq NaOH (5 M). The aqueous phase was extracted with EtOAc (2 x 50 mL). The combined organic phases were washed with water (50 mL) and brine (50 mL), dried over ISfeSCL, evaporated, and purified by column chromatography (EtOAc/PE = 0/1— 1/4, Silica-CS 20 g, 20 mL/min, silica gel, UV 254) to afford the product (350 mg, 55 %). ESLMS m/z calcd for [CeHsBrFsNs] [M+H]⁺: 256.0; found: 256.1. ^XH NMR (400 MHz, Chloroform-d) 5 7.98 (s, 2H), 5.93 (s, 1H), 3.64 (br s, 2H).

3-|5-(3-Azido-4.6-6M)enzylidene-3-deoxy-|Ll)-«alactopyranosyl)-3-methyl-l//- l,2,4-triazol-l-yl]-5-bromo-2-(trifluoromethyl)pyridine

To a solution of 2,6-anhydro-4-azido-5,7-O-benzylidene-4-deoxy-D-glycero-L-manno- heptonamide (340 mg, 1.06 mmol) in 1,4-dioxane (15.0 mL) A A-di methyl acetamide dimethyl acetal (156 mg, 1.17 mmol) was added and the mixture was stirred 3 h at 50 °C. The mixture was evaporated, and the residue was dissolved in acetic acid (10 mL). To this solution [5-bromo-2-(trifluoromethyl)pyrid-3-yl]hydrazine (326 mg, 1.27 mmol) was added and the mixture was stirred 2 h at 70 °C. The mixture was evaporated and partitioned between water (20 mL) and DCM (20 mL). The aqueous phase was extracted with DCM (2 x 20 mL). The combined organic phases were washed with water (20 mL) and brine (20 mL), dried over Na2SO4, evaporated, and purified by column chromatography (PE/EtOAc=5/l~l/2, Silica-CS 20 g, 30 mL/min, silica gel, UV 254). The obtained material was purified by reversed-phase chromatography (MeCN/EEO =1/20-1/1, C-18 column, 20 mL/min, UV 254) to afford the product (190 mg, 31 %). ESLMS m/z calcd for ^H^BrFsNvC ] [M+H]⁺: 582.1; found: 581.8. 'H NMR (400 MHz, Chloroform-d) 5 8.74 (d, J = 2.0 Hz, 1H), 7.99 (d, J= 2.0 Hz, 1H), 7.40 - 7.25 (m, 5H), 5.40 (s, 1H), 4.62 (s, 1H), 4.39 (d, J= 8.8 Hz, 1H), 4.32 (t, J= 92 Hz, 1H), 4.13 (d, J = 2.8 Hz, 1H), 3.80 (dd, J= 12.4, 1.6 Hz, 1H), 3.44 (dd, J = 12.4, 1.2 Hz, 1H), 3.37 (dd, J= 10.0, 3.2 Hz, 1H), 3.26 (d, J= 0.8 Hz, 1H), 2.37 (s, 3H).

3-[5-(3-Amino-4,6-O-benzylidene-3-deoxy-p-D-galactopyranosyl)-3-methyl-LH- l,2,4-triazol-l-yl]-5-bromo-2-(trifluoromethyl)pyridine

To a solution of 3-[5-(3-azido-4,6-O-benzylidene-3-deoxy-P-D-galactopyranosyl)-3- methyl-U/-l,2,4-triazol-l-yl]-5-bromo-2-(trifluoromethyl)pyridine (190 mg, 0.33 mmol) in THF/water (12 mL, 5:1) triphenylphosphine (428 mg, 1.63 mmol) was added and the mixture was stirred 6 h at 50 °C. The mixture was concentrated and purified by column chromatography (DCM/MeOH = 1/0-10/1, Silica-CS 20 g, 30 mL/min, silica gel, UV 254) to give the product (175 mg, 96 %). ESLMS m/z calcd for [C22H2iBrF₃N₅O4] [M+H]⁺: 556.1; found: 555.8. *HNMR (400 MHz, Chloroform-d) 5 8.74 (s, 1H), 8.02 (s, 1H), 7.38 - 7.25 (m, 5H), 5.37 (s, 1H), 4.27 (d, J = 9.2 Hz, 1H), 4.11 - 4.00 (m, 1H), 3.89 - 3.76 (m, 2H), 3.46 (d, J= 12.8 Hz, 1H), 3.26 (s, 1H), 2.79 (d, J= 8.4 Hz, 1H), 2.37 (s, 3H), 1.71 (br s, 2H), 0.87 - 0.71 (m, 1H).

3-{5-{4,6-O-Benzylidene-3-[(2-terLbutoxycarbonyl)hydrazinyl]-3-deoxy-p-D- galactopyranosyl}-3-methyl-lZ7-l,2,4-triazol-l-yl}-5-bromo-2-

(trifluoromethyl)pyridine

To a solution of 3-[5-(3-amino-4,6-O-benzylidene-3-deoxy-P-D-galactopyranosyl)-3- methyl-lJ/-l,2,4-triazol-l-yl]-5-bromo-2-(trifluoromethyl)pyridine (175 mg, 0.32 mmol) in DCM (10 mL) 7V-tert-butyloxycarbonyl-3-(4-cyanophenyl)oxaziridine (93 mg, 0.38 mmol) was added and the mixture was stirred overnight atrt. The mixture was concentrated and purified by column chromatography (PEZEtOAc=4/ 1-0/1, Silica-CS 20 g, 30 mL/min, silica gel, UV 254) to afford the product (85 mg, 40 %). ESI-MS m/z calcd for ^JEoBrFsNeOe] [M+H]⁺: 671.1; found: 670.8. 'H NMR (400 MHz, Chloroform-d) 5 8.67 (d, J= 1.2 Hz, 1H), 8.00 (d, J= 2.0 Hz, 1H), 7.35 - 7.25 (m, 5H), 6.39 (br s, 1H), 5.36 (s, 1H), 4.63 (br s, 1H), 4.46 (br s, 1H), 4.35 (d, J = 9.2 Hz, 1H), 4.22 (d, J= 2.8 Hz, 1H), 4.13 - 4.07 (m, 1H), 3.82 (dd, J = 12.8, 1.6 Hz, 1H), 3.55 (d, J= 13.2 Hz, 1H), 3.25 (s, 1H), 2.99 (dd, J= 9.6, 2.4 Hz, 1H), 2.37 (s, 3H), 1.38 (s, 9H).

Intermediate 23

5-Chloro-2-cyclopropyl-3-nitropyridine

To a solution of 2,5-dichloro-3-nitropyridine (6.0 g, 31.1 mmol) in 1,4-dioxane (120 mL) and H2O (24 mL) potassium cyclopropyltrifluoroborate (7.36 g, 46.6 mmol), K2CO3 (12.9 g, 93.3 mmol) and Pd(dppf)C12 (1.14 g, 1.55 mmol) were added and the mixture was stirred 16 h at 100 °C under nitrogen atmosphere. The mixture was partitioned between water (100 mL) and DCM (100 mL) and the aqueous phase was extracted with DCM (2 x 100 mL). The combined organic phases were washed with water (100 mL) and brine (50 mL), dried over ISfeSCL, evaporated, and purified by column chromatography (PE/EtOAc= 10/ 1-2/1, Silica-CS 80 g, 40 mL/min, silica gel, UV 254) to afford the product (3.3 g, 53 %). ¹ H NMR (400 MHz, Chloroform-d) 5 8.50 (d, J= 2.0 Hz, 1H), 8.06 (d, J= 2.4 Hz, 1H), 2.67 - 2.60 (m, 1H), 1.19 - 1.06 (m, 4H). 5-Chloro-2-cyclopropylpyridin-3-amine

To a solution of 5-chloro-2-cyclopropyl-3-nitropyridine (3.3 g, 16.6 mmol) in EtOH (100 mL) iron (4.64 g, 83.1 mmol) and NH4CI (4.44 g, 83.1 mmol) were added and the mixture was stirred 16 h at rt under hydrogen atmosphere. The mixture was filtered and evaporated to afford the product (2.00 g, 71 %). ESI-MS m/z calcd for [C8H9CIN2] [M+H]⁺: 169.0; found: 169.0. 'H NMR (400 MHz, DMSO-d₆) 8 7.57 (d, J = 2.0 Hz, 1H), 6.91 (d, J= 2.4 Hz, 1H), 2.06 - 1.99 (m, 1H), 0.85 - 0.77 (m, 4H).

(5-Chloro-2-cyclopropyl-3-pyridyl)hydrazine

To a solution of 5-chloro-2-cyclopropylpyridin-3-amine (450 mg, 2.67 mmol) in water (7 mL) H2SO4 (7 mL, 98 % w/w) was added. A solution of NaNCL (552 mg, 8.01 mmol) in water (2 mL) was added dropwise at -15 °C and the resulting mixture was stirred 2 h under nitrogen atmosphere at -15°C. Then tin(II) chloride dihydrate (3.61 g, 16.0 mmol) was added by small portion at -15 °C and the mixture was stirred 2 h under nitrogen atmosphere at -15 °C. NaOH (50 mL, 5 M) was added at -15 °C followed by water (50 mL) and DCM (50 mL). The phases were separated, and the aqueous phase was extracted with DCM (2 x 50 mL). The combined organic phases were washed with brine (50 mL), dried over Na2SO4, and evaporated to afford the product (230 mg, 47 %). ESLMS m/z calcd for [C₈HIOC1N₃] [M+H]⁺: 184.1; found: 184.3. 'H NMR (400 MHz, DMSO-d₆) 6 7.61 (d, J= 2.4 Hz, IH), 7.29 (d, J= 2.0 Hz, IH), 7.19 (s, IH), 4.27 (s, 2H), 2.05 - 1.98 (m, IH), 0.85 - 0.81 (m, 4H).

3-[5-(3-Azido-4,6-(?-benzylidene-3-deoxy-p-D-galactopyranosyl)-3-methyl-LH- l,2,4-triazol-l-yl]-5-chloro-2-cyclopropylpyridine

To a solution of 2,6-anhydro-4-azido-5,7-O-benzylidene-4-deoxy-D-glycero-L-manno- heptonamide (410 mg, 1.28 mmol) in 1,4-dioxane (15 mL) N,N-dimethylacetamide dimethyl acetal (188 mg, 1.41 mmol) was added and the mixture was stirred 3 h at 50 °C. The mixture was evaporated and dissolved in MeCN (10 mL) and acetic acid (10 mL). (5-Chloro-2-cyclopropyl-3-pyridyl)hydrazine (282 mg, 1.54 mmol) was added and the mixture was stirred 2 h at 100 °C. The mixture was evaporated and partitioned between water (20 mL) and DCM (20 mL). The aqueous phase was extracted with DCM (2 x 20 mL). The combined organic phases were washed with water (20 mL) and brine (20 mL), dried over Na2SO4, evaporated, and purified by column chromatography (PE/EtOAc=3/1~1/2, Silica-CS 12 g, 40 mL/min, silica gel, UV 254) to afford the product (290 mg, 44 %). ESI-MS m/z calcd for [C₂₄H₂₄ClN₇O₄] [M+H]+: 510.2; found: 510.2.1H NMR (400 MHz, Chloroform-d) δ 8.44 (d, J = 2.0 Hz, 1H), 7.66 (d, J = 2.0 Hz, 1H), 7.47 – 7.45 (m, 2H), 7.36 – 7.34 (m, 3H), 5.53 (s, 1H), 4.86 (t, J = 9.6 Hz, 1H), 4.35 (d, J = 9.2 Hz, 1H), 4.24 (d, J = 2.8 Hz, 1H), 3.95 – 3.80 (m, 2H), 3.42 (dd, J = 10.4, 3.2 Hz, 1H), 3.30 (d, J = 1.2 Hz, 1H), 2.05 (s, 3H), 1.60 – 1.54 (m, 1H), 1.09 – 0.93 (m, 4H). 3-[5-(3-Amino-4,6-O-benzylidene-3-deoxy-β-D-galactopyranosyl)-3-methyl-1H- 1,2,4-triazol-1-yl]-5-chloro-2-cyclopropylpyridine

To a solution of 3-[5-(3-azido-4,6-O-benzylidene-3-deoxy-β-^D-galactopyranosyl)-3- methyl-1H-1,2,4-triazol-1-yl]-5-chloro-2-cyclopropylpyridine (290 mg, 0.57 mmol) in THF (15 mL) and water (1.5 mL) triphenylphosphine (746 mg, 2.84 mmol) was added and the mixture was stirred 6 h at 50 °C. The mixture was concentrated and purified by column chromatography (DCM/MeOH=1/0~10/1, Silica-CS 12 g, 40 mL/min, silica gel, UV 254) to afford the product (275 mg, 82 %). ESI-MS m/z calcd for [C24H26ClN5O4] [M+H]+: 484.2; found: 484.3.1H NMR (400 MHz, Chloroform-d) δ 8.38 (d, J = 2.0 Hz, 1H), 7.61 (d, J = 2.0 Hz, 1H), 7.38 – 7.35 (m, 2H), 7.33 – 7.27 (m, 3H), 5.42 (s, 1H), 4.16 (d, J = 9.2 Hz, 1H), 4.11 – 4.03 (m, 3H), 3.87 (dd, J = 12.4, 1.6 Hz, 1H), 3.78 (dd, J = 12.4, 1.2 Hz, 1H), 3.24 (s, 1H), 2.80 (dd, J = 9.2, 2.4 Hz, 1H), 2.38 (s, 3H), 1.55 – 1.49 (m, 1H), 1.13 – 1.08 (m, 1H), 1.01 – 0.97 (m, 1H), 0.91 – 0.87 (m, 2H). 3-{5-{4,6-O-Benzylidene-3-[(2-tert-butoxycarbonyl)hydrazinyl]-3-deoxy-β-D- galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-5-chloro-2- cyclopropylpyridine

To a solution of 3-[5-(3-amino-4,6-O-benzylidene-3-deoxy-β-D-galactopyranosyl)-3- methyl-1H-1,2,4-triazol-1-yl]-5-chloro-2-cyclopropylpyridine (300 mg, 0.62 mmol) in DCM (5.0 mL) N-tert-butyloxycarbonyl-3-(4-cyanophenyl)oxaziridine (153 mg, 0.62 mmol) was added and the mixture was stirred overnight at rt. The mixture was concentrated and purified by column chromatography (PE/EtOAc=4/1~0/1, Silica-CS 12 g, 20 mL/min, silica gel, UV 254) to afford the product (180 mg, 49 %). ESI-MS m/z calcd for [C29H35ClN6O6] [M+H]+: 599.2; found: 598.8. 1H NMR (400 MHz, Chloroform-d) δ 8.35 (d, J = 2.0 Hz, 1H), 7.60 (d, J = 2.0 Hz, 1H), 7.38 – 7.35 (m, 2H), 7.31 – 7.27 (m, 3H), 6.42 (s, 1H), 5.42 (s, 1H), 4.78 – 4.21 (m, 5H), 3.90 – 3.84 (m, 2H), 3.24 (s, 1H), 2.97 (dd, J = 9.6, 3.2 Hz, 1H), 2.38 (s, 3H), 1.59 – 1.51 (m, 1H), 1.38 (s, 9H), 1.09 – 1.05 (m, 1H), 1.02 – 0.97 (m, 1H), 0.90 – 0.85 (m, 2H). Intermediate 24 4-Chloro-1-cyclopropyl-2-nitrobenzene

A solution of l-bromo-4-chl oro-2 -nitrobenzene (1.50 g, 6.34 mmol), potassium cyclopropyl(trifluoro)borate (1.13 g, 7.61 mmol), tricyclohexylphosphane (178 mg, 0.63 mmol), Pd(Oac)2 (71 mg, 0.32 mmol), K3PO4 (4.03 g, 19.0 mmol) in toluene (20.0 mL) and H2O (1.0 mL) was stirred overnight at 80 °C under nitrogen atmosphere. The mixture was cooled to rt, evaporated, and purified by column chromatography (PE/EtOAc=l/0, silica gel) to afford the product (829 mg, 80 % purity, 53 %). ^JH NMR (400 MHz, Chloroform-d) 5 7.81 (d, J = 2.4 Hz, 1H), 7.45 (dd, J = 8.4, 2.4 Hz, 1H), 7.11 (d, .7= 8,4 Hz, 1H), 2.39 - 2.32 (m, 1H), 1.10 - 1.05 (m, 2H), 0.72 - 0.68 (m, 2H).

5-Chloro-2-cyclopropylaniline

To a solution of 4-chloro-l-cyclopropyl-2 -nitrobenzene (829 mg, 4.19 mmol) in EtOH (10.0 mL) iron (1.41 g, 25.2 mmol) and NH4CI (1.56 g, 29.4 mmol) were added and the mixture was stirred 4 h at 70 °C. The mixture was filtered through a celite pad, evaporated, and purified by column chromatography (EtOAc/PE = 0/1-1/19, Silica-CS 20 g, 30 mL/min, silica gel, UV254) to afford the product (512 mg, 73 %). ESLMS m/z calcd for [C9H10CIN] [M+H]⁺: 168.0; found: 168.4. 'H NMR (400 MHz, Chloroform- d) 5 6.93 (dd, J= 8.4, 0.8 Hz, 1H), 6.65 - 6.63 (m, 2H), 4.01 (br s, 2H), 1.60 - 1.58 (m, 1H), 0.92 - 0.87 (m, 2H), 0.58 - 0.54 (m, 2H).

(5-Chloro-2-cyclopropylphenyl)hydrazine

To a solution of 5-chloro-2-cyclopropylaniline (512 mg, 3.05 mmol) in acetic acid (6 mL) concentrated HC1 (6 mL) was added. A solution of NaNCL (316 mg, 4.58 mmol) in water (1 mL) was added dropwise at -5 °C and the resulting mixture was stirred 1 h at 0 °C. A solution of tin(II) chloride dihydrate (2.07 g, 9.16 mmol) in concentrated HC1 (6 mL) was added dropwise at 0 °C. The mixture was warmed to rt and stirred 1 h. The mixture was basified to pH=10 by addition of aq NaOH (IM) and extracted with EtOAc (2 x 30 mL). The combined organic phases were dried over Na2SO4, evaporated, and purified by column chromatography (EtOAc/PE = 0/1— 1/5, Silica-CS 20 g, 30 mL/min, silica gel, UV 254) to afford the product (273 mg, 49 %). ESI-MS m/z calcd for [C9H11CIN2] [M+H]⁺: 183.1; found: 183.3. ^XH NMR (400 MHz, Chloroform-d) 5 6.90 - 6.88 (m, 2H), 6.62 (dd, J= 8.0, 2.0 Hz, 1H), 5.73 (br s, 1H), 3.49 (br s, 2H), 1.48 - 1.41 (m, 1H), 0.84 - 0.80 (m, 2H), 0.49 - 0.46 (m, 2H).

2,6-Anhydro-4-azido-5,7-O-benzylidene-4-deoxy-D-glycero-L-manno-/V-[l- (dimethylamino)ethylidene]heptonamide

To a solution of 2,6-anhydro-4-azido-5,7-O-benzylidene-4-deoxy-D-glycero-L-manno- heptonamide (2.30 g, 7.18 mmol) in 1,4-dioxane (30 mL) A A-di methyl acetamide dimethyl acetal (1.44 g, 10.8 mmol) was added and the mixture was stirred 2 h at 60 °C. The mixture was evaporated to give the product (3.50 g, 79 % purity, 99 %), which was used without purification in subsequent steps. ESI-MS m/z calcd for [C18H23N5O5] [M+H]⁺: 390.2; found: 390.2. 'H NMR (400 MHz, Chloroform-d) 5 7.54 - 7.51 (m, 2H), 7.38 - 7.33 (m, 3H), 5.58 (s, 1H), 4.47 (dd, J= 12.4, 1.6 Hz, 1H), 4.26 - 4.22 (m, 2H), 4.05 (dd, J= 12.4, 1.6 Hz, 1H), 3.83 (d, J= 9.6 Hz, 1H), 3.51 (d, J= 1.2 Hz, 1H), 3.40 (dd, J= 10.0, 3.2 Hz, 1H), 3.14 (s, 3H), 3.12 (s, 3H), 2.39 (s, 3H). l-[5-(3-Azido-4,6-O-benzylidene-3-deoxy-p-D-galactopyranosyl)-3-methyl-LH- l,2,4-triazol-l-yl]-5-chloro-2-cyclopropylbenzene

To a solution of 2,6-anhydro-4-azido-5,7-O-benzylidene-4-deoxy-D-glycero-L-manno- A-[l-(dimethylamino)ethylidene]heptonamide (400 mg, 1.03 mmol) in 1,4-dioxane (6 mL) and acetic acid (3 mL) (5-chloro-2-cyclopropylphenyl)hydrazine (225 mg, 1.23 mmol) was added and the mixture was stirred 2 h at 70 °C. The mixture was evaporated and purified by column chromatography (EtOAc/PE=0-70%, Silica-CS 20 g, 25 mL/min, silica gel, UV 254) to afford the product (353 mg, 60 % purity, 41 %). ESIMS m/z calcd for [C25H25CIN6O4] [M+H]⁺: 509.2; found: 509.3. 'H NMR (400 MHz, Chloroform-d) 5 7.44 - 7.39 (m, 2H), 7.33 - 7.25 (m, 5H), 6.82 (d, J = 8.4 Hz, 1H), 5.45 (s, 1H), 4.63 (dt, J= 10.0, 2.8 Hz, 1H), 4.17 - 4.16 (m, 2H), 3.86 - 3.78 (m, 2H), 3.33 (dd, J= 10.4, 3.6 Hz, 1H), 3.19 (d, J= 1.2 Hz, 1H), 2.38 (s, 3H), 1.45 - 1.42 (m, 1H), 0.77 - 0.75 (m, 2H), 0.62 - 0.60 (m, 2H). l-[5-(3-Amino-4,6-O-benzylidene-3-deoxy-p-D-galactopyranosyl)-3-methyl-LH- l,2,4-triazol-l-yl]-5-chloro-2-cyclopropylbenzene

To a solution of l-[5-(3-azido-4,6-O-benzylidene-3-deoxy-P-D-galactopyranosyl)-3- methyl-U7-l,2,4-triazol-l-yl]-5-chloro-2-cyclopropylbenzene (353 mg, 60 % purity, 0.42 mmol) in THF (5.0 mL) and water (0.5 mL) triphenylphosphine (546 mg, 2.08 mmol) was added and the mixture was stirred 6 h at 50 °C. The mixture was concentrated and purified by column chromatography (PE/EtOAc=l/0~0/l, Silica-CS 20 g, 25 mL/min, silica gel, UV 254) to afford the product (56 mg, 28 %). ESLMS m/z calcd for [C25H27CI2N4O4] [M+H]⁺: 483.2; found: 483.3. l-{5-{4,6-O-Benzylidene-3-[(2-terCbutoxycarbonyl)hydrazinyl]-3-deoxy-p-D- galactopyranosyl}-3-methyl-lZ7-l,2,4-triazol-l-yl}-5-chloro-2- cyclopropylbenzene

To a solution of l-[5-(3-amino-4,6-O-benzylidene-3-deoxy-P-D-galactopyranosyl)-3- methyl-U/-l,2,4-triazol-l-yl]-5-chloro-2-cyclopropylbenzene (137 mg, 0.28 mmol) in DCM (5 mL) 7V-tert-butyloxycarbonyl-3-(4-cyanophenyl)oxaziridine (90.5 mg, 0.37 mmol) was added and the mixture was stirred overnight at rt. The mixture was concentrated and purified by column chromatography (MeOH/DCM=0/l~l/10, Silica- CS 12 g, 20 mL/min, silica gel, UV 254) to afford the product (104 mg, 62 %). ESIMS m/z calcd for [C30H36CIN5O6] [M+H]⁺: 598.2; found: 598.3.

Intermediate 25

(5-Bromo-2-iodophenyl)hydrazine

To a solution of 5-bromo-2 -iodoaniline (500 mg, 1.68 mmol) in acetic acid (3 mL) HC1 (10 mL, 33% w/w) was added. A solution of NaNCL (232 mg, 3.36 mmol) in water (2 mL) was added dropwise at -5 °C and the resulting mixture was stirred 1 h at -5 °C. Then a solution of tin(II) chloride dihydrate (1.52 g, 6.71 mmol) in concentrated HC1 (5 mL) was added dropwise at -5 °C. The mixture was stirred 2 h at -5 °C. The mixture was basified to pH=10 by addition of aq NaOH (100 mL, 10 % w/w). Water (50 mL) and DCM (100 mL) were added and the aqueous phase was extracted with DCM (2 x 50 mL). The combined organic phases were washed with water (50 mL) and brine (2 x 50 mL), dried over ISfeSCL, evaporated, and purified by column chromatography (EtOAc/PE = 0-30%, Silica-CS 20 g, 30 mL/min, silica gel, UV 254) to afford the product (228 mg, 43 %). ESLMS m/z calcd for [CeEfcBrfN ] [M+H]⁺: 312.9; found: 313.0. 'HNMR (400 MHz, DMSO-d₆) 8 7.48 (d, J= 8.0 Hz, 1H), 7.20 (d, J= 2.0 Hz, 1H), 6.57 (dd, J= 8.0, 2.4 Hz, 1H), 6.23 (s, 1H), 4.29 (br s, 2H). 1-[5-(3-Azido-4,6-O-benzylidene-3-deoxy-β-D-galactopyranosyl)-3-methyl-1H- 1,2,4-triazol-1-yl]-5-bromo-2-iodobenzene

To a solution of 2,6-anhydro-4-azido-5,7-O-benzylidene-4-deoxy-^D-glycero-^L-manno- N-[1-(dimethylamino)ethylidene]heptonamide (280 mg, 0.72 mmol) in 1,4-dioxane (9 mL) a solution of (5-bromo-2-iodophenyl)hydrazine (225 mg, 0.72 mmol) in acetic acid (3 mL) was added and the mixture was stirred 2 h at 60 °C. The mixture was evaporated and partitioned between aq NaHCO3 (100 mL) and DCM (50 mL). The aqueous phase was extracted with DCM (2 x 50 mL). The combined organic phases were washed with water (20 mL) and brine (20 mL), dried over Na2SO4, evaporated, and purified by column chromatography (EtOAc/PE=0-50%, Silica-CS 20 g, 30 mL/min, silica gel, UV 254) to afford the product (202 mg, 44 %). ESI-MS m/z calcd for [C₂₂H₂₀BrIN₆O₄] [M+H]+: 639.2; found: 639.0. 1H NMR (400 MHz, Chloroform-d) δ 7.64 (d, J = 8.4 Hz, 1H), 7.57 (br s, 1H), 7.42 – 7.39 (m, 2H), 7.32 – 7.27 (m, 3H), 7.23 – 7.21 (m, 1H), 5.44 (s, 1H), 4.56 (t, J = 9.6 Hz, 1H), 4.31 – 4.29 (m, 2H), 4.15 (d, J = 2.8 Hz, 1H), 3.84 (dd, J = 12.8, 1.6 Hz, 1H), 3.70 (d, J = 12.4 Hz, 1H), 3.37 (dd, J = 10.4, 3.2 Hz, 1H), 3.23 (d, J = 0.8 Hz, 1H), 2.39 (s, 3H). 1-[5-(3-Amino-4,6-O-benzylidene-3-deoxy-β-D-galactopyranosyl)-3-methyl-1H- 1,2,4-triazol-1-yl]-5-bromo-2-iodobenzene

To a solution of 1-[5-(3-azido-4,6-O-benzylidene-3-deoxy-β-^D-galactopyranosyl)-3- methyl-1H-1,2,4-triazol-1-yl]-5-bromo-2-iodobenzene (202 mg, 0.32 mmol) in THF (10 mL) a solution of triphenylphosphine (414 mg, 1.58 mmol) in water (0.5 mL) was added and the mixture was stirred 6 h at 50 °C. The mixture was concentrated and purified by column chromatography (MeOH/DCM=0~10%, Silica-CS 20 g, 30 mL/min, silica gel, UV 254) to afford the product (152 mg, 78 %). ESI-MS m/z calcd for [C H BrIN O ] [M+H]+: 613.0; found: 6 1 22 22 4 4 13.1. H NMR (400 MHz, DMSO-d6) δ 7.94 (d, J = 8.0 Hz, 1H), 7.66 – 7.58 (m, 1H), 7.51 – 7.48 (m, 1H), 7.47 – 7.40 (m, 5H), 5.55 (s, 1H), 5.18 (dd, J = 5.2 Hz, 1H), 4.05 – 3.91 (m, 4H), 3.74 – 3.68 (m, 1H), 3.47 (d, J = 7.2 Hz, 1H), 2.68 – 2.58 (m, 1H), 2.39 (s, 3H), 1.68 (br s, 2H). 1-{5-{4,6-O-Benzylidene-3-[(2-tert-butoxycarbonyl)hydrazinyl]-3-deoxy-β-D- galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-5-bromo-2-iodobenzene

To a solution of 1-[5-(3-amino-4,6-O-benzylidene-3-deoxy-β-D-galactopyranosyl)-3- methyl-1H-1,2,4-triazol-1-yl]-5-bromo-2-iodobenzene (152 mg, 0.25 mmol) in DCM (10 mL) N-tert-butyloxycarbonyl-3-(4-cyanophenyl)oxaziridine (91.6 mg, 0.37 mmol) was added and the mixture was stirred 12 h at rt. The mixture was concentrated and purified by column chromatography (DCM/EtOAc=0~100%, Silica-CS 20 g, 30 mL/min, silica gel, UV 254) to afford the product (78 mg, 43 %). ESI-MS m/z calcd for [C H BrIN O ] [M+H]+: 728.1; foun 1 27 31 5 6 d: 728.1. H NMR (400 MHz, Chloroform-d) δ 7.65 (d, J = 8.4 Hz, 1H), 7.57 (s, 1H), 7.38 – 7.36 (m, 2H), 7.29 – 7.26 (m, 3H), 7.20 – 7.15 (m, 1H), 6.45 (s, 1H), 5.39 (s, 1H), 4.47 – 4.30 (m, 3H), 4.26 – 4.23 (m, 2H), 3.85 (d, J = 11.6 Hz, 1H), 3.75 (d, J = 12.4 Hz, 1H), 3.21 (s, 1H), 3.01 (d, J = 8.0 Hz, 1H), 2.38 (s, 3H), 1.38 (s, 9H). 5-Bromo-1-{5-{3-[4-(4-chloro-2,3-difluorophenyl)-1H-1,2-pyrazol-1-yl]-3-deoxy- β-D-galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-2-iodobenzene

To a solution of 1-[5-(4,6-O-benzylidene-3-[(2-tert-butoxycarbonyl)hydrazinyl]-3- deoxy-β-D-galactopyranosyl)-3-methyl-1H-1,2,4-triazol-1-yl]-5-bromo-2- iodobenzene (78 mg, 0.11 mmol) in EtOH (6 mL) 2-(4-chloro-2,3-difluorophenyl)-3- (dimethylamino)prop-2-enal (31.6 mg, 0.13 mmol) and concentrated HCl (0.3 mL) were added and the mixture was stirred 2 h at 80 °C. The mixture was concentrated and partitioned between aq NaHCO3 (20 mL) and DCM (30 mL). The aqueous phase was extracted with DCM (2 x 20 mL). The combined organic phases were washed with water (20 mL) and brine (20 mL), dried over Na₂SO₄, evaporated, and purified by column chromatography (DCM/MeOH = 0~10%, Silica-CS 12 g, 30 mL/min, silica gel, UV 254) to afford the product (46 mg, 59 %). ESI-MS m/z calcd for [C₂₄H₂₀BrIF₂N₅O₄] [M+H]+: 721.9; found: 722.0. 1H NMR (400 MHz, DMSO-d₆) δ 8.25 (s, 1H), 8.00 (s, 1H), 7.99 (d, J = 8.4 Hz, 1H), 7.66 – 7.62 (m, 2H), 7.55 (dd, J = 8.4, 2.0 Hz, 1H), 7.47 – 7.43 (m, 1H), 5.41 (d, J = 6.8, Hz, 1H), 5.07 (d, J = 4.8 Hz, 1H), 4.80 – 4.59 (m, 2H), 4.49 (dd, J = 10.4, 2.4 Hz, 1H), 4.15 (d, J = 8.8 Hz, 1H), 3.94 (d, J = 4.4 Hz, 1H), 3.57 – 3.54 (m, 1H), 3.43 – 3.41 (m, 2H), 2.37 (s, 3H). Intermediate 26 6-{5-[3-Deoxy-3-(1H-1,2-pyrazol-1-yl)-β-D-galactopyranosyl]-3-methyl-1H-1,2,4- triazol-1-yl}-2-methylbenzothiazole

A solution of 6-{5-{4,6-O-benzylidene-3-[(2-tert-butoxycarbonyl)hydrazinyl]-3- deoxy-β-D-galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-2-methylbenzothiazole (220 mg, 0.37 mmol) in DCM/TFA (5.0 mL, 10: 1) was stirred 16 h at rt. The mixture was concentrated and dissolved together with 1, 1,3,3-tetraethoxypropane (245 mg, 1.11 mmol) in EtOH (5.0 mL). The mixture was cooled to 0 °C, concentrated HC1 (0.5 mL) was added, and the mixture was stirred 2 h at 0 °C. The pH was adjusted to 5 by addition of saturated aq NaHCCL. The mixture was concentrated and purified by prep HPLC [MeCN/H₂O (10 mmol/L, 0.05 % TFA), X-Select 10 pm 19*250 mm, 20 mL/min, UV 254] to give the product (75 mg, 46 %). ESLMS m/z calcd for [C20H22N6O4S] [M+H]⁺: 443.1; found: 443.0. 'H NMR (400 MHz, Chloroform-d) 5 8.11 (d, J = 2.0 Hz, 1H), 7.99 (d, J= 8.4 Hz, 1H), 7.61 (dd, J= 8.4, 2.0 Hz, 1H), 7.59 (d, J= 2.0 Hz, 1H), 7.52 (d, J= 1.6 Hz, 1H), 6.26 (t, J= 2.0 Hz, 1H), 4.85 (t, J = 10.0 Hz, 1H), 4.46 (d, J = 9.2 Hz, 1H), 4.35 (s, 1H), 4.14 (dd, J= 10.4, 2.4 Hz, 1H), 3.84 (dd, J= 11.6, 6.4 Hz, 1H), 3.69 (dd, J= 12.0, 3.6 Hz, 1H), 3.63 (dd, J = 6.4, 4.4 Hz, 1H), 2.82 (s, 3H) , 2.39 (s, 3H).

6- {5- [3-(4-Bromo- 1H- 1 ,2-pyrazol- l-yl)-3-deoxy-p-D-galactopyranosyl] -3-methyl- 1//-1.2.4-tri:izol-l-yl]-2-iiietliylbeiizothiazole

To a solution of 6-{5-[3-deoxy-3-(lA-l,2-pyrazol-l-yl)-P-D-galactopyranosyl]-3- methyl- 1H- 1, 2, 4-triazol-l-yl} -2 -methylbenzothiazole (75 mg, 0.17 mmol) in THF (5 mL) A-bromosuccinimide (45.3 mg, 0.25 mmol) was added at 0 °C and the mixture was stirred 2 h at 0 °C. The mixture was concentrated and purified by prep HPLC [MeOHH₂O (10 mmol/L, 0.05 % TFA), X-Select 10 pm 19*250 mm, 20 mL/min, UV 254] to give the product (65 mg, 74 %). ESLMS m/z calcd for [C2oH2iBrNe04S] [M+H]⁺: 521.1; found: 521.2. ¹ H NMR (400 MHz, Chloroform-d) 5 8.09 (d, J= 2.0 Hz, 1H), 7.97 (d, J= 8.8 Hz, 1H), 7.64 (s, 1H), 7.59 (dd, J= 8.8, 2.0 Hz, 1H), 7.47 (s, 1H), 4.84 (t, J =10.0 Hz, 1H), 4.42 (d, J= 92 Hz, 1H), 4.34 (s, 1H), 4.10 (dd, J= 10.4, 2.4 Hz, 1H), 3.81 (dd, J = 11.6, 6.8 Hz, 1H), 3.68 - 3.60 (m, 2H), 2.82 (s, 3H) , 2.37 (s, 3H). Intermediate 27

[5-Chloro-2-(trifluoromethoxy)phenyl]hydrazine

To a cooled (-5 °C) solution of 5-chloro-2-(trifluoromethoxy)aniline (1.00 g, 4.73 mmol) in acetic acid (5 mL) concentrated HC1 (10 mL) was added. A solution of NaNCL (489 mg, 7.09 mmol) in water (2 mL) was added. The mixture was stirred 1 h at -5 °C. Then a solution of tin(II) chloride dihydrate (3.2 g, 14.2 mmol) in concentrated HC1 (5 mL) was added dropwise. The mixture was allowed to reach rt and was then stirred 3 h. The mixture was basified using aqueous NaOH (1 M) to adjust pH to 10. The mixture was extracted with EtOAc (2 x 50 mL). The combined organic phases were dried over Na2SO4, evaporated, and purified by column chromatography (DCM/PE = 0/1-4/1, silica-CS 40 g 50 mL/min, silica gel, UV 254 nm) to afford the product (732 mg, 68 %). ESLMS m/z calcd for [C7H6CIF3N2O] [M+H]⁺: 227.0; found: 227.3. 'HNMR (400 MHz, DMSO-de) 8 7.27 (s, 1H), 7.19 (d, J= 2.4 Hz, 1H), 7.13 - 7.09 (m, 1H), 6.59 (dd, J= 8.8, 2.4 Hz, 1H), 4.18 (s, 2H). l-|5-(3-Azido-4.6-6M)enzylidene-3-deoxy-|Ll)-«alactopyranosyl)-3-methyl-l//- l,2,4-triazol-l-yl]-5-chloro-2-(trifluoromethoxy)benzene

To a solution of 2,6-anhydro-4-azido-5,7-(9-benzylidene-4-deoxy-D-glycero-L-manno- A-[l-(dimethylamino)ethylidene]heptonamide (400 mg, 1.03 mmol) in 1,4-dioxane (6 mL) and acetic acid (3 mL) [5-chloro-2-(trifluoromethoxy)phenyl]hydrazine (303 mg, 1.34 mmol) was added and the mixture was stirred 2 h at 60 °C. The mixture was concentrated and purified by column chromatography (EtOAc/PE = 0/1— 1/1, Silica-CS 20 g, 25 mL/min, silica gel, UV 254) to afford the product (344 mg, 61 %). ESLMS m/z calcd for [C23H20CIF3N6O5] [M+H]⁺: 553.1; found:553.3. 'H NMR (400 MHz, Chloroform-d) 5 7.62 (d, J = 2.8 Hz, 1H), 7.46 - 7.42 (m, 3H), 7.35 - 7.32 (m, 3H), 7.28 – 7.26 (m, 1H), 5.50 (s, 1H), 4.76 (s, 1H), 4.55 (t, J = 9.6 Hz, 1H), 4.44 (d, J = 9.2 Hz, 1H), 4.23 (d, J = 2.8 Hz, 1H), 3.91 (dd, J = 12.4, 1.6 Hz, 1H), 3.64 (dd, J = 12.8, 1.6 Hz, 1H), 3.47 (dd, J = 10.0, 3.2 Hz, 1H), 3.35 (d, J = 0.8 Hz, 1H), 2.44 (s, 3H). 1-[5-(3-Amino-4,6-O-benzylidene-3-deoxy-β-D-galactopyranosyl)-3-methyl-1H- 1,2,4-triazol-1-yl]-5-chloro-2-(trifluoromethoxy)benzene

To a solution of 1-[5-(3-azido-4,6-O-benzylidene-3-deoxy-β-^D-galactopyranosyl)-3- methyl-1H-1,2,4-triazol-1-yl]-5-chloro-2-(trifluoromethoxy)benzene (170 mg, 0.31 mmol) in THF (8 mL) and water (2 mL) triphenylphosphine (403 mg, 1.54 mmol) was added and the mixture was stirred overnight at 50 °C. The mixture was concentrated and purified by column chromatography (DCM/MeOH=1/0~10/1, Silica-CS 20 g, 25 mL/min, silica gel, UV 254) to afford the product (149 mg, 92 %). ESI-MS m/z calcd for [C H ClF N + 1 23 22 3 4O5] [M+H] : 527.1; found: 527.2. H NMR (400 MHz, Chloroform- d) δ 7.64 (d, J = 2.8 Hz, 1H), 7.46 – 7.41 (m, 3H), 7.36 – 7.33 (m, 3H), 7.29 (dd, J = 8.8, 1.2 Hz, 1H), 5.47 (s, 1H), 4.31 (d, J = 9.2 Hz, 1H), 4.16 (d, J = 3.2 Hz, 1H), 4.05 (t, J = 9.6 Hz, 1H), 3.92 (dd, J = 12.4, 2.0 Hz, 1H), 3.66 (dd, J = 12.8, 1.2 Hz, 1H), 3.36 (s, 1H), 2.90 (dd, J = 9.6, 3.6 Hz, 1H), 2.43 (s, 3H). 1-[5-(4,6-O-Benzylidene-3-[(2-tert-butoxycarbonyl)hydrazinyl]-3-deoxy-β-D- galactopyranosyl)-3-methyl-1H-1,2,4-triazol-1-yl]-5-chloro-2- (trifluoromethoxy)benzene

To a solution of 1-[5-(3-amino-4,6-O-benzylidene-3-deoxy-β-D-galactopyranosyl)-3- methyl-1H-1,2,4-triazol-1-yl]-5-chloro-2-(trifluoromethoxy)benzene (149 mg, 0.28 mmol) in DCM (5 mL) N-tert-butyloxycarbonyl-3-(4-cyanophenyl)oxaziridine (90.5 mg, 0.37 mmol) was added and the mixture was stirred overnight at rt. The mixture was concentrated and purified by column chromatography (MeOH/DCM=0/1~1/10, Silica- CS 12 g, 20 mL/min, silica gel, UV 254) to afford the product (104 mg, 57 %). ESI- MS m/z calcd for [C28H31ClF3N5O7] [M+H]+: 642.2; found: 642.2.1H NMR (400 MHz, Chloroform-d) δ 7.62 (d, J = 2.8 Hz, 1H), 7.48 – 7.28 (m, 7H), 6.52 (br s, 1H), 5.46 (s, 1H), 4.76 (br s, 1H), 4.55 (br s, 1H), 4.39 – 4.32 (m, 3H), 3.92 (dd, J = 12.4, 1.6 Hz, 1H), 3.72 – 3.68 (m, 1H), 3.34 (s, 1H), 3.13 – 3.10 (m, 1H), 2.43 (s, 3H), 1.46 (s, 9H). Intermediate 30 1-Chloro-2,5-difluoro-4-iodobenzene

Trifluoromethanesulfonic acid (10.0 mL) was added to 2-chloro-1,4-difluorobenzene (1.00 g, 6.73 mmol) at rt and the mixture was cooled to 0 °C. N-Iodosuccinimide (1.44 g, 6.40 mmol) was added in multiple portions. After 10 min, the mixture was allowed to reach rt and was then stirred 2 h. The mixture was poured into ice-water and extracted with hexane (2 x 20 mL). The combined organic phases were washed with brine, dried over Na2SO4, concentrated, and purified by column chromatography (PE, Silica-CS 12 g, 20 mL/min, silica gel, UV 254) to give the product (960 mg, 52 %).1H NMR (400 MHz, Chloroform-d) δ 7.53 (dd, J = 8.0, 5.6 Hz, 1H), 7.14 (dd, J = 7.2, 6.4 Hz, 1H). Diethyl 2-(4-chloro-2,5-difluorophenyl)propanedioate

CuI (27.5 mg, 0.14 mmol), 2-phenylphenol (40.9 mg, 0.24 mmol) and cesium carbonate (1.18 g, 3.61 mmol) were added to a dry flask under nitrogen. Ethyl malonate (770 mg, 4.81 mmol) and 1-chloro-2,5-difluoro-4-iodo-benzene (660 mg, 2.40 mmol) in THF (4 mL) were added to the mixture. The mixture was sealed and heated to 90 °C. After stirring 16 h, the mixture was cooled to rt and then diluted with saturated aq NH4CI. The mixture was extracted with EtOAc (2 x 20 mL). The combined organic phases were dried, filtered through celite, evaporated, and purified by column chromatography (EtOAc/PE = 0/1-3/10, Silica-CS 12 g, 20 mL/min, silica gel, UV 254) to afford the product (284 mg, 38 %). 'H NMR (400 MHz, Chloroform-d) 5 7.30 (dd, J = 9.2, 6.0 Hz, 1H), 7.11 (dd, J= 8.8, 6.0 Hz, 1H), 4.85 (s, 1H), 4.23 - 4.13 (m, 4H), 1.22 (t, J = 7.2 Hz, 6H).

2-(4-Chloro-2,5-difluorophenyl)acetic acid

To a solution of diethyl 2-(4-chloro-2,5-difluorophenyl)propanedioate (100 mg, 0.33 mmol) in EtOH (5.0 mL) and water (1.0 mL) NaOH (65.2 mg, 1.63 mmol) was added and the mixture was stirred overnight at rt. The pH was adjusted to 2 using 2N HC1. The aqueous mixture was extracted with EtOAc (2 x 10 mL). The combined organic phases were washed with brine (10 mL), dried over Na2SO4, and concentrated to give the product (46 mg, 68 %). 'HNMR (400 MHz, DMSO-d₆) 8 12.67 (s, 1H), 7.62 (dd, J= 9.2, 6.4 Hz, 1H), 7.49 (dd, J= 9.6, 6.8 Hz, 1H), 3.66 (s, 2H).

2-(4-Chloro-2,5-difluorophenyl)-3-(dimethylamino)prop-2-enal

To a cooled (0 °C) solution of DMF (97.7 mg, 1.34 mmol) and phosphoryl trichloride (171 mg, 1.11 mmol) 2-(4-chloro-2,5-difluorophenyl)acetic acid (46 mg, 0.22 mmol) was added and the mixture was stirred 3 h at 65 °C. After cooling to rt, the mixture was slowly added to a mixture of ice and water. K2CO3 was added slowly until pH reached 11. Ethanol (1 mL) was added to control frothing. To the alkaline mixture toluene (10 mL) was added, and the mixture was refluxed for 1.5 h and then cooled to rt. The aqueous phase was extracted with EtOAc (10 mL). The combined organic phases were washed with brine, dried over Na2SO4, and evaporated. The residue was recrystallized from hexane to give the product (23 mg, 42 %). ESLMS m/z calcd for [C11H10CIF2NO] [M+H]⁺: 246.0; found: 246.4. ^XH NMR (400 MHz, Chloroform-d) 5 9.07 (s, 1H), 7.14 (dd, J = 8.4, 6.4 Hz, 1H), 7.08 (dd, J= 8.4, 6.4 Hz, 1H), 6.95 (s, 1H), 3.15 - 2.71 (m, 6H).

Intermediate 31 l-Chloro-2-fluoro-4-iodo-5-methoxybenzene

A solution of 2-chloro-l-fluoro-4-m ethoxybenzene (1.00 g, 6.23 mmol) and N- iodosuccinimide (1.33 g, 5.92 mmol) in DCM (10.0 mL) was cooled to 0 °C, and sulfuric acid (336 mg, 3.43 mmol) was added in multiple portions. After 10 minutes, the mixture was allowed to warm to rt and stirred for 2 h. The mixture was poured into ice-water and extracted with hexane. The organic phase was washed with water and brine, dried over anhydrous ISfeSC , concentrated, and purified by silica gel chromatography (100% PE) to afford the product (789 mg, 44 %). ^JH NMR (400 MHz, Chloroform-d) 5 7.49 (d, J= 8.0 Hz, 1H), 6.75 (d, J= 6.4 Hz, 1H), 3.79 (s, 3H).

(4-Chloro-5-fluoro-2-methoxyphenyl)boronic acid

A solution of l-chloro-2-fluoro-4-iodo-5-methoxybenzene (200 mg, 0.70 mmol) and triisopropyl borate (171 mg, 0.91 mmol) in dry THF (2.00 mL) was stirred 5 min at - 78 °C under a nitrogen atmosphere. Then n-butyllithium (179 mg, 2.79 mmol) was slowly added, and the mixture was stirred 1 h at -78 °C. The reaction was quenched with a saturated NH4CI solution and extracted with EtOAc (30 mL). The organic phase was washed with water and brine, dried over Na2SO4, evaporated, and purified by column chromatography on silica gel (PE/EtOAc = 1/1) to give the product (29 mg, 20 %). ¹ H NMR (400 MHz, Chloroform-d) 5 7.53 (d, J= 8.8 Hz, 1H), 6.86 (d, J= 5.6 Hz, 1H), 5.83 (s, 2H), 3.83 (s, 3H). Intermediate 32

4-Chloro-5-fluoro-2-(trifluoromethyl)aniline

To a solution of 5-fluoro-2-(trifluoromethyl)aniline (2.0 g, 11.2 mmol) in DMF (10.0 mL) TV-chl orosuccinimide (2.23 g, 16.7 mmol) was added and the mixture was stirred 12 h at rt. The mixture was diluted with water and extracted with /c/V-butyl methyl ether (2 x 30 mL). The combined organic phases were washed with water and brine, dried over Na2SO4, and concentrated in a rotary evaporator at 10 °C. The residue was purified by column chromatography (EtOAc/PE = 0/1, Silica-CS 40 g, 40 mL/min, silica gel, UV 254) to afford the product (1.05 g, 44 %). 'H NMR (400 MHz, DMSO-d₆) 6 7.48 (d, J= 8.0 Hz, 1H), 6.73 (d, J= 12.0 Hz, 1H), 6.07 (s, 2H). l-Chloro-2-fluoro-4-iodo-5-(trifluoromethyl)benzene

A solution of 4-chloro-5-fluoro-2-(trifluoromethyl)aniline (1.05 g, 4.92 mmol) in concentrated HC1 (20.0 mL) was cooled to below 0 °C. A solution of NaNCL (509 mg, 7.37 mmol) in water (2 mL) was added slowly. After 10 minutes at 0 °C, KI (2449 mg, 14.7 mmol) was added, and the mixture was warmed to rt and stirred overnight. The mixture was extracted with EtOAc (2 x 50 mL). The combined organic phases were washed with NaHSCL (50 mL, IM), water (50 mL), and brine (50 mL), dried over Na2SO4, concentrated, and purified by column chromatography (PE = 100%, Silica-CS 40 g, 40 mL/min, silica gel, UV 254) to afford the product (560 mg, 35 %). ^JH NMR (400 MHz, DMSO-de) 8 8.27 (d, J= 8.8 Hz, 1H), 8.02 (d, J= 7.2 Hz, 1H). l-{5-[3-(4-Borono-LH-l,2-pyrazol-l-yl)-3-deoxy-p-D-galactopyranosyl]-3-methyl- TH- 1 ,2,4-triazol- l-yl}-5-chloro-2-(trifluoromethyl)benzene

To a solution of 5-chloro-l-{5-[3-deoxy-3-(4-iodo-U/-l,2-pyrazol-l-yl)-P-D- galactopyranosyl]-3-methyl-U/-l,2,4-triazol-l-yl}-2-(trifluoromethyl)benzene (95 mg, 0.16 mmol) and bis(pinacolato)diboron (121 mg, 0.48 mmol) in DMSO (4.0 mL) Pd(dppf)C12 (23.2 mg, 0.032 mmol) and potassium acetate (77.7 mg, 0.79 mmol) were added. The mixture was purged three times with nitrogen, and stirred 2 h at 60 °C. The mixture was filtered and purified by reversed-phase chromatography (MeCN/thO (0.05 % TFA) = 1/20-1/2, C-18 column, 20 mL/min, UV 214) to afford the product (60 mg, 61 %). ESI-MS m/z calcd for [C19H20BCIF3N5O6] [M+H]⁺: 518.1; found: 518.3. 'H NMR (400 MHz, Methanol-d₄) 8 7.97 (s, 1H), 7.85 (d, J = 8.4 Hz, 1H), 7.75 (dd, J = 1.2, 8.8 Hz, 1H), 7.72 - 7.63 (m, 2H), 4.71 - 4.54 (m, 1H), 4.29 (dd, J= 10.8, 2.8 Hz, 1H), 4.17 (d, J = 9.2 Hz, 1H), 3.96 (d, J= 2.8 Hz, 1H), 3.62 - 3.48 (m, 3H), 2.33 (s, 3H).

Intermediate 33

5-Fluoro-2-(trifluoromethoxy)aniline

To a solution of 4-fluoro-2 -nitro- l-(trifluorom ethoxy )benzene (1.70 g, 7.55 mmol) in acetic acid (20 mL) iron (1265 mg, 22.7 mmol) was added and the mixture was stirred 2 h at 80 °C. The mixture was filtered, concentrated, and purified by column chromatography (EtOAc/PE = 0/1— 1/1, Silica-CS 40 g, 40 mL/min, silica gel, UV 254) to afford the product (900 mg, 61 %). ¹ H NMR (400 MHz, DMSO-d₆) 5 7.13 - 7.09 (m, 1H), 6.55 (dd, J= 11.2, 3.2 Hz, 1H), 6.32 (td, J= 8.8, 3.2 Hz, 1H), 5.72 (s, 2H).

4-Chloro-5-fluoro-2-(trifluoromethoxy)aniline

To a solution of 5-fluoro-2-(trifluoromethoxy)aniline (900 mg, 4.61 mmol) in DMF (6.0 mL) 7V-chlorosuccinimide (924 mg, 6.92 mmol) was added and the mixture was stirred 16 h at rt. The mixture was diluted with water and extracted with EtOAc. The organic phase was washed with water and brine, dried over Na2SO4, concentrated, and purified by column chromatography (EtOAc/PE = 0/1-1/1, Silica-CS 40 g, 40 mL/min, silica gel, UV 254) to afford the product (850 mg, 80 %). ¹ H NMR (400 MHz, DMSO- d₆) 6 7.37 (dd, J = 7.6, 1.2 Hz, 1H), 6.73 (d, J= 11.6 Hz, 1H), 5.93 (s, 2H). l-Chloro-2-fluoro-4-iodo-5-(trifluoromethoxy)benzene

A solution of 4-chloro-5-fluoro-2-(trifluoromethoxy)aniline (1.50 g, 6.53 mmol) in concentrated HC1 (40.0 mL) was cooled to below 0 °C. A solution of NaNCE (676 mg, 9.80 mmol) in water (2 mL) was added. After 10 minutes at 0 °C, KI (3254 mg, 19.6 mmol) was added, and the mixture was warmed to rt and stirred overnight. The mixture was extracted with EtOAc (2 x 60 mL). The combined organic phases were washed with NaHSOs (50 mL, IM), water (50 mL), and brine (50 mL), dried over Na2SO4, concentrated, and purified by column chromatography (PE = 100%, Silica-CS 40 g, 40 mL/min, silica gel, UV 254) to afford the product (933 mg, 42 %). ¹ H NMR (400 MHz, DMSO-de) 6 8.16 (d, J= 8.4 Hz, 1H), 7.84 (dd, J= 6.4, 1.2 Hz, 1H).

Intermediate 34 l-Bromo-4-chloro-5-fluoro-2-nitrobenzene

To a cooled (0 °C) solution of 4-bromo-l -chi oro-2 -fluorobenzene (10.0 g, 47.7 mmol) and NH4NO3 (5.73 g, 71.6 mmol) in DCM (350 mL) trifluoroacetic anhydride (46.5 mL, 334 mmol) was added over 15 min. The mixture was stirred 15 min at 0 °C then 2 h at rt. The reaction was quenched with saturated aq NaHCCL (560 mL) and the phases were separated. The aqueous phase was extracted with DCM and then EtOAc. The combined organic phases were dried over Na2SO4, concentrated, and purified by column chromatography (EtOAc/PE = 0/1— 1/7, Silica-CS 80 g, 50 mL/min, silica gel, UV 254) to afford the product (4.2 g, 35 %). ¹ H NMR (400 MHz, DMSO-d₆) 6 8.50 (d, J= 6.8 Hz, 1H), 8.21 (d, J= 8.8 Hz, 1H). l-Chloro-2-fluoro-5-nitro-4-(trifluoromethyl)benzene

To a solution of l-bromo-4-chl oro-5 -fluoro-2 -nitrobenzene (4.20 g, 16.5 mmol) in DMF (40 mL) methyl 2, 2-difluoro-2 -fluorosulfonylacetate (6.64 g, 33.0 mmol) and Cui (3.14 g, 16.5 mmol) were added and the mixture was stirred 2 h at 80 °C. The reaction was quenched with saturated aq NaHCCL (200 mL) and extracted with EtOAc (2 x 100 mL). The combined organic phases were washed with brine (100 mL), dried over Na2SO4, concentrated, and purified by column chromatography (EtOAc/PE = 0/1— 1/7, Silica-CS 80 g, 50 mL/min, silica gel, UV 254) to afford the product (3.7 g, 92 %). ^JH NMR (400 MHz, DMSO-d₆) 8 8.65 (d, J= 6.4 Hz, 1H), 8.30 (d, J= 92 Hz, 1H).

5-Chloro-4-fluoro-2-(trifluoromethyl)aniline

To a solution of l-chloro-2-fluoro-5-nitro-4-(trifluoromethyl)benzene (1.80 g, 7.39 mmol) in acetic acid (20 mL) iron (1.24 g, 22.2 mmol) was added and the mixture was stirred 4 h at 80 °C. The mixture was filtered, concentrated, and purified by column chromatography (EtOAc/PE = 0/1— 1/4, Silica-CS 40 g, 50 mL/min, silica gel, UV 254) to afford the product (1.3 g, 82 %). 'HNMR (400 MHz, DMSO-d₆) 6 7.41 (d, J= 9.6 Hz, 1H), 7.00 (d, J= 6.4 Hz, 1H), 5.75 (s, 2H).

[5-Chloro-4-fluoro-2-(trifluoromethyl)phenyl]hydrazine

To a solution of 5-chloro-4-fluoro-2-(trifluoromethyl)aniline (1.30 g, 6.09 mmol) in acetic acid (5 mL) concentrated HC1 (5 mL) was added and the mixture was cooled to -5 °C. A solution of NaNCL (630 mg, 9.13 mmol) in water (2 mL) was added and the mixture was stirred 1 h at 0 °C. A sloution of tin(II) chloride dihydrate (2.75 g, 12.2 mmol) in concentrated HC1 (5 mL) was added slowly at 0 °C. The mixture was warmed to rt and stirred 3 h. The mixture was basified to pH = 10 by addition of NaOH (IM). The mixture was extracted with EtOAc (2 x 50 mL). The combined organic phases were dried over Na₂SO4, concentrated, and purified by column chromatography (DCM/PE = 0/1-4/1, Silica-CS 40 g, 50 mL/min, silica gel, UV 254) to afford the product (433 mg, 31 %). ESI-MS m/z calcd for [C7H₅C1F₄N₂] [M+H]⁺: 229.0; found: 229.1. 'H NMR (400 MHz, DMSO-de) 8 7.51 (d, J= 6.8 Hz, 1H), 7.48 (d, J= 92 Hz, 1H), 6.96 (s, 1H), 4.30 (s, 2H). l-|5-(3-Azido-4.6-6M)eiizylidene-3-deoxy-|Ll)-«alactopyranosyl)-3-nietliyl-l//- l,2,4-triazol-l-yl]-5-chloro-4-fluoro-2-(trifluoromethyl)benzene

To a solution of 2,6-anhydro-4-azido-5,7-O-benzylidene-4-deoxy-D-glycero-L-manno- 7V-[l-(dimethylamino)ethylidene]heptonamide (670 mg, 1.72 mmol) in 1,4-di oxane (20 mL) and acetic acid (10 mL) [5-chloro-4-fluoro-2-(trifluoromethyl)phenyl]hydrazine (393 mg, 1.72 mmol) was added and the mixture was stirred 2 h at 70 °C. The mixture was concentrated and purified by column chromatography (EtOAc/PE = 1/5-2/1, Silica-CS 20 g, 30 mL/min, silica gel, UV 254) to afford the product (455 mg, 65 % purity, 31 %). ESI-MS m/z calcd for [C23H19CIF4N6O4] [M+H]⁺: 555.1; found: 555.2. 'H NMR (400 MHz, Chloroform-d) 5 7.65 (d, J= 6.4 Hz, 1H), 7.51 (d, J= 8.8 Hz, 1H), 7.46 - 7.33 (m, 5H), 5.49 (s, 1H), 4.50 - 4.46 (m, 2H), 4.32 - 4.29 (m, 1H), 4.21 (d, J = 2.8 Hz, 1H), 3.91 (dd, J= 12.4, 1.6 Hz, 1H), 3.68 - 3.64 (m, 1H), 3.42 (dd, J= 10.0, 3.2 Hz, 1H), 3.30 (s, 1H), 2.43 (s, 3H). l-|5-(3-Aiiiiiio-4.6-6M)eiizylidene-3-deoxy-|Ll)-«alactopyranosyl)-3-nietliyl-l//- l,2,4-triazol-l-yl]-5-chloro-4-fluoro-2-(trifluoromethyl)benzene

To a solution of l-[5-(3-azido-4,6-O-benzylidene-3-deoxy-P-D-galactopyranosyl)-3- methyl-lJ/-l,2,4-triazol-l-yl]-5-chloro-4-fluoro-2-(trifluoromethyl)benzene (455 mg, purity 65 %, 0.82 mmol) in THF/water (25 mL, 5: 1) triphenylphosphine (645 mg, 2.46 mmol) was added and the mixture was stirred 16 h at 50 °C. The mixture was concentrated and purified by column chromatography (DCM/MeOH= I/O- 10/1, Silica- CS 12 g, 20 mL/min, silica gel, UV 254) to afford the product (366 mg, 84 %). ESIMS m/z calcd for [C23H21CIF4N4O4] [M+H]⁺: 529.1; found: 529.3. 'HNMR (400 MHz, Chloroform-d) 5 7.68 (d, J= 6.4 Hz, 1H), 7.53 (d, J= 8.8 Hz, 1H), 7.43 - 7.32 (m, 5H), 5.46 (s, 1H), 4.23 (d, J = 9.2 Hz, 1H), 4.13 - 4.11 (m, 1H), 4.02 - 3.89 (m, 2H), 3.69 - 3.65 (m, 1H), 3.30 (s, 1H), 2.86 - 2.82 (m, 1H), 2.43 (s, 3H). l-[5-(4,6-O-Benzylidene-3-[(2-terf-butoxycarbonyl)hydrazinyl]-3-deoxy-p-D- galactopyranosyl)-3-methyl- 1 //- 1 ,2,4-triazol- 1-yl] -5-chloro-4-fluoro-2- (trifluoromethyl)benzene

To a solution of l-[5-(3-amino-4,6-O-benzylidene-3-deoxy-P-D-galactopyranosyl)-3- methyl-U/-l,2,4-triazol-l-yl]-5-chloro-4-fluoro-2-(trifluoromethyl)benzene (366 mg, 0.69 mmol) in DCM (10 mL) 7V-tert-butyloxycarbonyl-3-(4-cyanophenyl)oxaziridine (187 mg, 0.76 mmol) was added and the mixture was stirred overnight at rt. The mixture was concentrated and purified by column chromatography (EtOAc/PE=0/l~l/0, Silica- CS 20 g, 30 mL/min, silica gel, UV 254) to afford the product (272 mg, purity 61 %, 37 %). ESLMS m/z calcd for [C28H30CIF4N5O6] [M+H]⁺: 644.2; found: 644.2. 'HNMR (400 MHz, Chloroform-d) 5 7.59 (d, J= 6.4 Hz, 1H), 7.42 (d, J= 8.0 Hz, 1H), 7.35 - 7.25 (m, 6H), 5.38 (s, 1H), 4.49 - 4.46 (m, 2H), 4.27 - 4.19 (m, 2H), 3.85 (dd, J= 12.4, 1.6 Hz, 1H), 3.67 (d, J= 12.0 Hz, 1H), 3.22 (s, 1H), 2.99 - 2.96 (m, 1H), 2.36 (s, 3H), 1.38 (s, 9H).

Intermediate 35

5-Chloro- 1- {5- [3-deoxy-3-(lH- 1 ,2-pyrazol- l-yl)-P-D-galactopyranosyl)-3-methyl- lH-l,2,4-triazol-l-yl]-4-fluoro-2-(trifluoromethyl)benzene

To a solution of l-[5-(4,6-O-benzylidene-3-[(2-tert-butoxycarbonyl)hydrazinyl]-3- deoxy-P-D-galactopyranosyl)-3-methyl-U/-l,2,4-triazol-l-yl]-5-chloro-4-fluoro-2- (trifluoromethyl)benzene (180 mg, 0.28 mmol) in ethanol (5.0 mL) 1, 1,3,3- tetraethoxypropane (185 mg, 0.84 mmol) was added, followed by concentrated HC1 (0.13 mL). The mixture was stirred 1 h at 80 °C, cooled to rt, and the pH was adjusted to 5 using saturated aq NaHCCL. The mixture was concentrated and purified by reversed-phase chromatography (MeCN/H2O = 1/20-1/1, C-18 column, 20 mL/min, UV 214) to give the product (96 mg, 70 %). ESLMS m/z calcd for [C19H18CIF4N5O4] [M+H]⁺: 492.1; found: 492.1. 'H NMR (400 MHz, Methanol-d₄) 8 7.95 - 7.92 (m, 2H), 7.78 (d, J= 2.4 Hz, 1H), 7.52 (d, J= 2.0 Hz, 1H), 6.33 (t, J= 2.4 Hz, 1H), 4.68 - 4.66 (m, 1H), 4.35 (dd, J= 10.8, 2.8 Hz, 1H), 4.29 (d, J= 9.6 Hz, 1H), 4.04 (d, J= 2.4 Hz, 1H), 3.67 - 3.60 (m, 3H), 2.42 (s, 3H).

5-Chloro- 1- {5- [3-deoxy-3-(4-iodo- 1H- 1 ,2-pyrazol- l-yl)-P-D-galactopyranosyl)-3- methyl-lH-l,2,4-triazol-l-yl]-4-fluoro-2-(trifluoromethyl)benzene

To a solution of 5-chloro-l-{5-[3-deoxy-3-(U7-l,2-pyrazol-l-yl)-P-D- galactopyranosyl)-3 -methyl- \H- 1,2, 4-tri azol- l-yl]-4-fluoro-2-

(trifluoromethyl)benzene (96 mg, 0.20 mmol) in MeCN (20 mL) ceric ammonium nitrate (214 mg, 0.39 mmol) and iodine (495 mg, 1.95 mmol) were added and the mixture was stirred 1 h at rt. The mixture was concentrated and purified by reversed- phase chromatography (MeCN/H2O = 1/20-1/1, C-18 column, 20 mL/min, UV 214) to give the product (101 mg, 84 %). ESLMS m/z calcd for [C19H17CIF4IN5O4] [M+H]⁺: 618.0; found: 618.0. ^XH NMR (400 MHz, Methanol-d₄) 8 7.95 - 7.87 (m, 3H), 7.53 (s, 1H), 4.68 - 4.64 (m, 1H), 4.38 (dd, J= 10.8, 2.8 Hz, 1H), 4.28 (d, J= 9.6 Hz, 1H), 4.01 (d, J= 2.8 Hz, 1H), 3.66 - 3.59 (m, 3H), 2.42 (s, 3H).

Intermediate 36

4,5-Dichloro-2-(trifluoromethyl)aniline

To a solution of l,2-dichloro-4-nitro-5-(trifluoromethyl)benzene (1.10 g, 4.23 mmol) in acetic acid (20 mL) iron (709 mg, 12.7 mmol) was added and the mixture was stirred 4 h at 80 °C. The mixture was filtered, concentrated, and purified by column chromatography (EtOAc/PE = 1/10-2/1, Silica-CS 40 g, 50 mL/min, silica gel, UV 254) to afford the product (833 mg, 86 %). ^JH NMR (400 MHz, Chloroform-d) 5 7.48 (s, 1H), 6.86 (s, 1H), 4.03 (br s, 2H).

[4,5-Dichloro-2-(trifluoromethyl)phenyl]hydrazine

To a solution of 4,5-dichloro-2-(trifluoromethyl)aniline (833 mg, 3.62 mmol) in acetic acid (3 mL) concentrated HC1 (3 mL) was added and the mixture was cooled to -5 °C. A solution of NaNO₂ (300 mg, 4.35 mmol) in water (2 mL) was added and the mixture was stirred 1 h at 0 °C. A sloution of tin(II) chloride dihydrate (1.79 g, 7.95 mmol) in concentrated HC1 (3 mL) was added slowly at 0 °C. The mixture was warmed to rt and stirred 3 h. The mixture was basified to pH = 10 by addition of NaOH (IM). The mixture was extracted with EtOAc (2 x 50 mL). The combined organic phases were dried over Na₂SO4, concentrated, and purified by column chromatography (DCM/PE = 0/1-4/1, Silica-CS 40 g, 50 mL/min, silica gel, UV 254) to afford the product (356mg, 40 %). ESI-MS m/z calcd for [C7H5CI2F3N2] [M+H]⁺: 245.0; found: 245.1. 'H NMR (400 MHz, Chloroform-d) 5 7.53 (s, 1H), 7.48 (s, 1H), 5.85 (s, 1H), 3.66 (s, 2H). l-[5-(3-Azido-4,6-O-benzylidene-3-deoxy-p-D-galactopyranosyl)-3-methyl-LH- l,2,4-triazol-l-yl]-4,5-dichloro-2-(trifluoromethyl)benzene

To a solution of 2,6-anhydro-4-azido-5,7-O-benzylidene-4-deoxy-D-glycero-L-manno- 7V-[l-(dimethylamino)ethylidene]heptonamide (800 mg, 2.05 mmol) in 1,4-di oxane (10 mL) and acetic acid (5 mL) [4,5-dichloro-2-(trifluoromethyl)phenyl]hydrazine (604 mg, 2.47 mmol) was added and the mixture was stirred 2 h at 70 °C. The mixture was concentrated and purified by column chromatography (EtOAc/PE = 1/5-2/1, Silica-CS 20 g, 30 mL/min, silica gel, LTV 254) to afford the product (825 mg, 80 % purity, 56 %). ESI-MS m/z calcd for [C23H19CI2F3N6O4] [M+H]⁺: 571.1; found: 571.2. l-[5-(3-Amino-4,6-O-benzylidene-3-deoxy-p-D-galactopyranosyl)-3-methyl-LH- l,2,4-triazol-l-yl]-4,5-dichloro-2-(trifluoromethyl)benzene

To a solution of l-[5-(3-azido-4,6-O-benzylidene-3-deoxy-P-D-galactopyranosyl)-3- methyl-17/-l,2,4-triazol-l-yl]-4,5-dichloro-2-(trifluoromethyl)benzene (825 mg, purity 80 %, 1.16 mmol) in THF/water (10 mL, 5: 1) triphenylphosphine (1.21 g, 4.62 mmol) was added and the mixture was stirred 16 h at 50 °C. The mixture was concentrated and purified by column chromatography (DCM/MeOH= 1/0-20/1, Silica-CS 12 g, 20 mL/min, silica gel, UV 254) to afford the product (558 mg, 89 %). ESI-MS m/z calcd for [C23H21CI2F3N4O4] [M+H]⁺: 545.1; found: 545.2. ^XH NMR (400 MHz, Chloroform- d) 5 7.76 (s, 1H), 7.64 (s, 1H), 7.37 - 7.34 (m, 2H), 7.33 - 7.28 (m, 3H), 5.39 (s, 1H), 4.16 (d, J = 9.2 Hz, 1H), 4.08 - 4.03 (m, 2H), 3.94 (t, J= 9.2 Hz, 1H), 3.85 (dd, J = 12.4, 1.2 Hz, 1H), 3.60 (d, J = 12.4 Hz, 1H), 3.25 (s, 1H), 2.78 (dd, J = 9.6, 3.2 Hz, 1H), 2.36 (s, 3H). l-[5-(4,6-O-Benzylidene-3-[(2-tert-butoxycarbonyl)hydrazinyl]-3-deoxy-p-D- galactopyranosyl)-3-methyl- 1H- 1 ,2,4-triazol- 1-yl] -4,5-dichloro-2- (trifluoromethyl)benzene

To a solution of l-[5-(3-amino-4,6-O-benzylidene-3-deoxy-P-D-galactopyranosyl)-3- methyl-l//-l,2,4-triazol-l-yl]-4,5-dichloro-2-(trifluoromethyl)benzene (558 mg, 1.02 mmol) in DCM (10 mL) 7V-tert-butyloxycarbonyl-3-(4-cyanophenyl)oxaziridine (277 mg, 1.13 mmol) was added and the mixture was stirred overnight at rt. The mixture was concentrated and purified by column chromatography (EtOAc/PE=l/4~l/0, Silica-CS 12 g, 20 mL/min, silica gel, UV 254) to afford the product (295 mg, 44 %). ESI-MS m/z calcd for [C28H30CI2F3N5O6] [M+H]⁺: 660.2; found: 660.2. 'H NMR (400 MHz, Chloroform-d) 5 7.74 (s, 1H), 7.62 (s, 1H), 7.36 - 7.32 (m, 2H), 7.31 - 7.27 (m, 3H), 6.41 (s, 1H), 5.39 (s, 1H), 4.47 - 4.44 (m, 2H), 4.24 - 4.21 (m, 3H), 3.85 (dd, J= 12.4, 1.6 Hz, 1H), 3.66 (d, J= 12.4 Hz, 1H), 3.23 (s, 1H), 2.98 (t, J = 4.0 Hz, 1H), 2.35 (s, 3H), 1.38 (s, 9H).

Intermediate 37

4,5-Dichloro-l-{5-[3-deoxy-3-( lH-l,2-pyrazol-l-yl)-|J-D-galactopyranosyl)-3- methyl-lEZ-l,2,4-triazol-l-yl]-2-(trifluoromethyl)benzene

To a solution of l-[5-(4,6-O-benzylidene-3-[(2-tert-butoxycarbonyl)hydrazinyl]-3- deoxy-P-D-galactopyranosyl)-3-methyl-U/-l,2,4-triazol-l-yl]-4,5-dichloro-2- (trifluoromethyl)benzene (170 mg, 0.26 mmol) in EtOH (5.0 mL) 1, 1,3,3- tetraethoxypropane (68 mg, 0.31 mmol) was added, followed by concentrated HC1 (0.13 mL). The mixture was stirred 1 h at 80 °C, cooled to rt, and the pH was adjusted to 5 using saturated aq NaHCCL. The mixture was concentrated and purified by reversed-phase chromatography (MeCN/H2O = 1/20-1/1, C-18 column, 20 mL/min, UV 214) to give the product (73 mg, 56 %). ESLMS m/z calcd for [C19H18CI2F3N5O4] [M+H]⁺: 508.1; found: 508.2. ^XH NMR (400 MHz, Methanol-d₄) 8 8.16 (s, 1H), 7.94 (s, 1H), 7.78 (d, J= 2.4 Hz, 1H), 7.52 (d, J= 2.0 Hz, 1H), 6.33 (t, J= 2.4 Hz, 1H), 4.68 - 4.66 (m, lH), 4.36 (dd, J= 10.8, 2.8 Hz, 1H), 4.31 (d , J= 9.6 Hz, 1H), 4.04 (d , J = 2.4 Hz, 1H), 3.67 - 3.60 (m, 3H), 2.42 (s, 3H).

4,5-Dichloro-l-{5-[3-deoxy-3-(4-iodo-lH-l,2-pyrazol-l-yl)-|J-D- galactopyranosyl)-3-methyl- 1H- 1 ,2,4-triazol- 1-yl] -2-(tr ifluoromethyl)benzene

To a solution of 4,5-dichloro-l-{5-[3-deoxy-3-(U7-l,2-pyrazol-l-yl)-P-D- galactopyranosyl)-3 -methyl- 1H- 1, 2, 4-triazol-l-yl]-2-(trifluoromethyl)benzene (73 mg, 0.14 mmol) in MeCN (5 mL) ceric ammonium nitrate (315 mg, 0.57 mmol) and iodine (146 mg, 0.57 mmol) were added and the mixture was stirred 1 h at rt. The mixture was concentrated and purified by reversed-phase chromatography (MeCN/H2O = 1/20-1/1, C-18 column, 20 mL/min, UV 214) to afford the product (56 mg, 62 %). ESLMS m/z calcd for [C19H17CI2F3IN5O4] [M+H]⁺: 634.0; found: 634.0. 'HNMR (400 MHz, Methanol-d₄) 6 8.16 (s, 1H), 7.93 (s, 1H), 7.86 (s, 1H), 7.53 (s, 1H), 4.68 - 4.64 (m, 1H), 4.38 (dd, J= 10.4, 2.8 Hz, 1H), 4.30 (d, J= 9.6 Hz, 1H), 4.02 (d, J= 2.4 Hz, 1H), 3.66 - 3.59 (m, 3H), 2.42 (s, 3H).

Intermediate 40

5-Fluoro-2-methyl-6-nitro-l,3-benzothiazole

To a cooled (0 °C) solution of 5-fluoro-2-methyl-l,3-benzothiazole (2.37 g, 14.2 mmol) in H2SO4 (10.0 mL) KNO3 (1.58 g, 15.6 mmol) was added slowly and the mixture was stirred 2 h at 0 °C. The mixture was poured into cooled (0 °C) aq NaOH (10 M) and extracted with EtOAc (2 x 100 mL). The combined organic phases were dried over Na2SO4 and concentrated to give crude product (3 g), which was used without purification in the next step. ESLMS m/z calcd for [C8H5FN2O2S] [M+H]⁺: 213.0; found: 213.0.

5-Fluoro-2-methyl-l,3-benzothiazol-6-amine

To a solution of crude 5-fluoro-2-methyl-6-nitro-l,3-benzothiazole (3 g) in EtOH/H2O (120 mL, 2: 1) iron (1.74 g, 31.1 mmol) and NH4CI (7.56 g, 141 mmol) were added, and the mixture was stirred 1 h at 80 °C. The mixture was filtered through a short silica column and washed by EtOH. The filtrate was concentrated, poured into water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic phases were washed with brine (50 mL), dried over Na2SO4, concentrated, and purified by column chromatography (PE/EtOAc=l/0~3/l, Silica-CS 40 g, 50 mL/min, silica gel, UV 254) to give the product (1.5 g, 58 %). ESLMS m/z calcd for [C8H7FN2S] [M+H]⁺: 183.0; found: 183.1. 'H NMR (400 MHz, DMSO-d₆) 8 7.55 (d, J= 12.0 Hz, 1H), 7.22 (d, J = 8.4 Hz, 1H), 5.36 (s, 2H), 2.68 (s, 3H).

(5-Fluoro-2-methyl-l,3-benzothiazol-6-yl)hydrazine

To a cooled (-5 °C) solution of 5-fluoro-2-methyl-l,3-benzothiazol-6-amine (1.40 g, 7.68 mmol) in concentrated HC1 (20 mL) and water (20 mL) a solution of NaNCL (795 mg, 11.5 mmol) in water (5 mL) was added dropwise. The resulting mixture was stirred 1 h at 0 °C. Tin(II) chloride dihydrate (3.81 g, 16.9 mmol) dissolved in concentrated HC1 (8 mL) was added dropwise at 0 °C. The resulting mixture was allowed to reach rt and was then stirred 3 h. The pH of the mixture was adjusted to 11 by addition of NaOH (1 M). The mixture was extracted with EtOAc (2 x 100 mL). The combined organic phases were dried over Na2SO₄, evaporated, and purified by column chromatography (EtOAc/DCM = 0/1-1/10, Silica-CS 40 g, 50 mL/min, silica gel, UV 254) to afford the product (510 mg, 34 %). ESLMS m/z calcd for [CsHsFNsS] [M+H]⁺: 198.0; found: 198.2. 'HNMR (400 MHz, Methanol-d₄) 8 7.56 (d, J = 8.0 Hz, 1H), 7.45 (d, J= 12.0 Hz, 1H), 2.74 (s, 3H).

6-|5-(3-Azido-4.6-6M)enzylidene-3-deoxy-|Ll)-«alactopyranosyl)-3-methyl-l//- l,2,4-triazol-l-yl]-5-fluoro-2-methylbenzothiazole

To a solution of 2,6-anhydro-4-azido-5,7-O-benzylidene-4-deoxy-D-glycero-L-manno- A-[l-(dimethylamino)ethylidene]heptonamide (660 mg, 1.69 mmol) in 1,4-dioxane (10 mL) and acetic acid (5 mL) (5-fluoro-2-methyl-l,3-benzothiazol-6-yl)hydrazine (368 mg, 1.86 mmol) was added and the mixture was stirred 2 h at 60 °C. The mixture was concentrated and purified by column chromatography (EtOAc/PE = 0/1-1/1, Silica-CS 20 g, 25 mL/min, silica gel, UV 254) to afford the product (290 mg, 33 %). ESLMS m/z calcd for [C24H22FN7O4S] [M+H]⁺: 524.1; found: 524.0. 'H NMR (400 MHz, Chloroform-d) 5 7.98 (d, J = 6.8 Hz, 1H), 7.72 (d, J = 10.8 Hz, 1H), 7.42 - 7.36 (m, 2H), 7.35 - 7.31 (m, 3H), 5.46 (s, 1H), 4.67 - 4.55 (m, 2H), 4.22 (d, J= 2.8 Hz, 1H), 3.84 (dd, J= 12.6, 1.4 Hz, 1H), 3.56 - 3.47 (m, 2H), 3.37 (s, 1H), 2.86 (s, 3H), 2.48 (s, 3H). 6-[5-(3-Amino-4,6-O-benzylidene-3-deoxy-p-D-galactopyranosyl)-3-methyl-LH- l,2,4-triazol-l-yl]-5-fluoro-2-methylbenzothiazole

To a solution of 6-[5-(3-azido-4,6-O-benzylidene-3-deoxy-P-D-galactopyranosyl)-3- methyl-lJ/-l,2,4-triazol-l-yl]-5-fluoro-2-methylbenzothiazole (290 mg, 0.55 mmol) in THF/water (12 mL, 5: 1) triphenylphosphine (726 mg, 2.77 mmol) was added and the mixture was stirred overnight at 50 °C. The mixture was concentrated and purified by column chromatography (DCM/MeOH = 1/0-10/1, Silica-CS 40 g, 50 mL/min, silica gel, UV 254) to give the product (147 mg, 53 %). ESI-MS m/z calcd for [C24H24FN5O4S] [M+H]⁺: 498.2; found: 498.0. 'H NMR (400 MHz, Chloroform-d) 5 7.99 (d, J = 6.8 Hz, 1H), 7.74 (d, J = 10.8 Hz, 1H), 7.42 - 7.27 (m, 5H), 5.45 (s, 1H), 4.42 (d, J = 9.2 Hz, 1H), 4.21 - 4.10 (m, 2H), 3.86 (d, J = 12.8 Hz, 1H), 3.61 (d, J = 12.4 Hz, 1H), 3.35 (s, 1H), 2.95 (d, J= 8.4 Hz, 1H), 2.86 (s, 3H), 2.39 (s, 3H).

6-{5-{4,6-O-Benzylidene-3-[(2-terf-butoxycarbonyl)hydrazinyl]-3-deoxy-p-D- galactopyranosyl}-3-methyl-lH-l,2,4-triazol-l-yl}-5-fluoro-2- methylbenzothiazole

To a solution of 6-[5-(3-amino-4,6-O-benzylidene-3-deoxy-P-D-galactopyranosyl)-3- methyl-U/-l,2,4-triazol-l-yl]-5-fluoro-2-methylbenzothiazole (147 mg, 0.30 mmol) in DCM (5 mL) 7V-tert-butyloxycarbonyl-3-(4-cyanophenyl)oxaziridine (87.3 mg, 0.36 mmol) was added and the mixture was stirred overnight at rt. The mixture was concentrated and purified by column chromatography (MeOH/DCM = 0/1-1/10, Silica-CS 12 g, 20 mL/min, silica gel, UV 254) to afford the product (115 mg, 64 %). ESLMS m/z calcd for [C29H33FN6O6S] [M+H]⁺: 613.2; found: 613.0. 'H NMR (400 MHz, Chloroform-d) 5 8.00 (d, J= 6.8 Hz, 1H), 7.72 (d, J= 10.8 Hz, 1H), 7.39 - 7.26 (m, 5H), 6.72 (br s, 1H), 5.43 (s, 1H), 4.59 (d, J = 8.8 Hz, 1H), 4.41 - 4.32 (m, 2H), 3.87 (d, J= 12.4 Hz, 1H), 3.66 (d, J= 12.4 Hz, 1H), 3.38 (s, 1H), 3.20 (d, J= 8.4 Hz, 1H), 2.84 (s, 3H), 2.48 (s, 3H), 1.45 (s, 9H).

Intermediate 41

5-Bromo-2-methyl-6-nitro-l,3-benzothiazole

To a cooled (0 °C) solution of 5-bromo-2-methyl-l,3-benzothiazole (1.85 g, 8.11 mmol) in H2SO4 (10 mL) KNO3 (902 mg, 8.92 mmol) was added in small portions. The mixture was stirred 2 h at 0 °C. The mixture was poured into ice cold water and extracted with DCM (2 x 50 mL). The combined organic phases were dried over Na2SC>4, evaporated, and purified by column chromatography (PEZEtOAc = 1/0— 1/1, silica-CS 40 g, 40 mL/min, silica gel, UV 254 nm) to give the product (1.2 g, 54 %). ESLMS m/z calcd for [C₈H₅BrN2O₂S] [M+H]⁺: 272.9; found: 273.0. 'H NMR (400 MHz, Chloroform-d) 5 8.33 (s, 1H), 8.21 (s, 1H), 2.84 (s, 3H).

5-Bromo-2-methyl-l,3-benzothiazol-6-amine

To a solution of 5-bromo-2-methyl-6-nitro-l,3-benzothiazole (1.2 g, 4.39 mmol) in EtOH (15 mL) iron (1.23 g, 22.0 mmol) and NH4CI (1.18 g, 22.0 mmol) were added and the mixture was stirred 2 h at 80 °C. The mixture was filtered, poured into ice cold water and extracted with DCM (3 x 50 mL). The combined organic phases were washed with water and brine, dried over Na2SO4, concentrated, and purified by column chromatography (PE/EtOAc=l/0~l/l, Silica-CS 40 g, 40 mL/min, silica gel, UV 254) to afford the product (900 mg, 84 %). ESLMS m/z calcd for [CsHyBr^S] [M+H]⁺: 243.0; found: 243.0. ^XH NMR (400 MHz, DMSO-d₆) 8 7.91 (s, 1H), 7.28 (s, 1H), 5.46 (br s, 2H), 2.68 (s, 3H). (5-Bromo-2-methyl-l,3-benzothiazol-6-yl)hydrazine

To a cooled (-5 °C) solution of 5-bromo-2-methyl-l,3-benzothiazol-6-amine (800 mg, 3.29 mmol) in water (15 mL) HC1 (15 mL, 33 % wt) was added followed by dropwise addition of a solution of NaNCL (272 mg, 3.95 mmol) in water (2 mL). The mixture was stirred 1 h at -5 °C. Tin(II) chloride dihydrate (1782 mg, 7.90 mmol) dissolved in concentrated HC1 (5 mL) was added dropwise at -5 °C. The resulting mixture was stirred 2 h at -5 °C before NaOH (100 mL, 10 % wt) was added to adjust pH to 7. Water (50 mL) and DCM (100 mL) were added, and the aqueous phase was extracted with DCM (2 x 50 mL). The combined organic phases were washed with water (50 mL) and brine (2 x 50 mL), dried over ISfeSCL, and evaporated to afford the product (350 mg, 41 %). ESLMS m/z calcd for [C₈H₈BrN₃S] [M+H]⁺: 258.0; found: 257.8. 'HNMR (400 MHz, DMSO-de) 8 7.93 (s, 1H), 7.65 (s, 1H), 6.48 (br s, 1H), 4.25 (br s, 2H), 2.70 (s, 3H).

6-|5-(3-Azido-4.6-6M)enzylidene-3-deoxy-|Ll)-«alactopyranosyl)-3-methyl-l//- l,2,4-triazol-l-yl]-5-bromo-2-methylbenzothiazole

To a solution of 2,6-anhydro-4-azido-5,7-O-benzylidene-4-deoxy-D-glycero-L-manno- 7V-[l-(dimethylamino)ethylidene]heptonamide (500 mg, 1.28 mmol) in 1,4-dioxane (10 mL) and acetic acid (3.0 mL) (5-bromo-2-methyl-l,3-benzothiazol-6-yl)hydrazine (348 mg, 1.35 mmol) was added and the mixture was stirred 3 h at 60 °C. The mixture was concentrated, DCM (10 mL) was added and the mixture was washed with aq NaHCCL and brine. The organic phase was dried over ISfeSCU, evaporated, and purified by column chromatography (PE/EtOAc=l/0~0/l, Silica-CS 40 g, 40 mL/min, silica gel, UV 254) to afford the product (360 mg, 48 %). ESI-MS m/z calcd for [C24H22BrN?O4S] [M+H]⁺: 584.1; found: 583.8. 'HNMR (400 MHz, Chloroform-d) 5 8.15 (s, 1H), 7.93 (s, 1H), 7.37 - 7.26 (m, 5H), 5.37 (s, 1H), 4.56 - 4.52 (m, 1H), 4.43 (d, J= 8.0 Hz, 1H), 4.10 (d, J= 2.8 Hz, 1H), 3.72 (d, J = 11.6 Hz, 1H), 3.43 - 3.40 (m, 2H), 3.17 (s, 1H), 2.79 (s, 3H), 2.42 (s, 3H).

6-[5-(3-Amino-4,6-O-benzylidene-3-deoxy-p-D-galactopyranosyl)-3-methyl-LH- l,2,4-triazol-l-yl]-5-bromo-2-methylbenzothiazole

To a solution of 6-[5-(3-azido-4,6-O-benzylidene-3-deoxy-P-D-galactopyranosyl)-3- methyl-U/-l,2,4-triazol-l-yl]-5-bromo-2-methylbenzothiazole (360 mg, 0.62 mmol) in THF/water (10.5 mL, 20: 1) triphenylphosphine (808 mg, 3.08 mmol) was added and the mixture was stirred overnight at 50 °C. The mixture was concentrated and purified by column chromatography (DCM/MeOH = 1/0-10/1, Silica-CS 20 g, 40 mL/min, silica gel, UV 254) to afford the product (300 mg, 87 %). ESI-MS m/z calcd for [C24H24BrN₅O₄S] [M+H]⁺: 558.1; found: 557.8. 'HNMR (400 MHz, DMSO-d₆) 8 8.38 (s, 1H), 8.32 - 8.20 (m, 1H), 7.36 (s, 5H), 5.53 (s, 1H), 5.23 (d, J= 4.0 Hz, 1H), 4.06 - 4.00 (m, 2H), 3.97 (s, 2H), 3.78 - 3.72 (m, 1H), 3.46 - 3.42 (m, 1H), 2.86 (s, 3H), 2.72 - 2.68 (m, 1H), 2.35 (s, 3H).

6-{5-{4,6-O-Benzylidene-3-[(2-terf-butoxycarbonyl)hydrazinyl]-3-deoxy-p-D- galactopyranosyl}-3-methyl-lEZ-l,2,4-triazol-l-yl}-5-bromo-2- methylbenzothiazole

To a solution of 6-[5-(3-amino-4,6-O-benzylidene-3-deoxy-P-D-galactopyranosyl)-3- methyl-U/-l,2,4-triazol-l-yl]-5-bromo-2-methylbenzothiazole (200 mg, 0.36 mmol) in DCM (10 mL) 7V-tert-butyloxycarbonyl-3-(4-cyanophenyl)oxaziridine (106 mg, 0.43 mmol) was added and the mixture was stirred overnight at rt. The mixture was concentrated and purified by column chromatography (DCM/EtOAc=l/0~0/l, Silica- CS 20 g, 40 mL/min, silica gel, UV 254) to afford the product (115 mg, 48 %). ESIMS m/z calcd for ^^BrNeOeS] [M+H]⁺: 673.1; found: 672.8. *H NMR (400 MHz, DMSO-de) 8 8.37 (s, 1H), 8.31 (br s, 1H), 8.24 - 8.20 (m, 1H), 7.42 - 7.36 (m, 5H), 5.48 (s, 1H), 5.16 (d, .7= 4.0 Hz, 1H), 4.54 (br s, 1H), 4.10 - 4.06 (m, 2H), 3.97 - 3.91 (m, 3H), 3.45 - 3.40 (m, 1H), 2.85 (s, 3H), 2.82 - 2.79 (m, 1H), 2.35 (s, 3H), 1.36 (s, 9H).

Intermediate 43

5-(Trifluoromethyl)-2-methyl-6-nitro-l,3-benzothiazole

To a solution of 5-bromo-2-methyl-6-nitro-l,3-benzothiazole (1.0 g, 3.66 mmol) in DMF (10 mL) Cui (837 mg, 4.39 mmol) and methyl 2,2-difluoro-2- fluorosulfonylacetate (1407 mg, 7.32 mmol) were added and the mixture was stirred 3 h at 100 °C under nitrogen. The mixture was cooled to rt, filtered, concentrated, and purified by column chromatography (PE/EtOAc = 0/1— 1/1 , Silica-CS 40 g, 50 mL/min, silica gel, UV 254) to afford the product (830 mg, 86 %). 'H NMR (400 MHz, Chloroform-d) 5 8.41 (s, 1H), 8.31 (s, 1H), 2.88 (s, 3H).

5-(Trifluoromethyl)-2-methyl-l,3-benzothiazol-6-amine

To a solution of 5-(trifluoromethyl)-2-methyl-6-nitro-l,3-benzothiazole (830 mg, 3.17 mmol) in EtOH (25 mL) iron (884 mg, 15.8 mmol), NH4CI (847 mg, 15.8 mmol) and water (1 mL) were added, and the mixture was stirred 12 h at 80 °C. The mixture was cooled to rt, filtered, concentrated, and purified by column chromatography (PE/EtOAc=l/0~l/l, Silica-CS 40 g, 50 mL/min, silica gel, UV 254) to give the product (630 mg, 86 %). ESLMS m/z calcd for [C9H7F3N2S] [M+H]⁺: 233.0; found: 233.3. 'H NMR (400 MHz, Chloroform-d) 5 7.94 (s, 1H), 7.07 (s, 1H), 4.13 (br s, 2H), 2.70 (s, 3H).

[5-(Trifluoromethyl)-2-methyl-l,3-benzothiazol-6-yl]hydrazine

To a cooled (0 °C) solution of 5-(trifluoromethyl)-2-methyl-l,3-benzothiazol-6-amine (630 mg, 2.71 mmol) in concentrated HC1 (15 mL) a solution of NaNCL (281 mg, 4.07 mmol) in water (2 mL) was added dropwise. The resulting mixture was stirred 1 h at 0 °C. Tin(II) chloride dihydrate (1836 mg, 8.14 mmol) dissolved in concentrated HC1 (5 mL) was added dropwise at 0 °C. The resulting mixture was allowed to reach rt and was then stirred 1 h. The pH of the mixture was adjusted to 10 by addition of NaOH (1 M). The mixture was partitioned between water (50 mL) and DCM (100 mL). The aqueous phase was extracted with DCM (2 x 50 mL). The combined organic phases were washed with water (50 mL) and brine (2 x 50 mL), dried over ISfeSCU, evaporated, and purified by column chromatography (EtOAc/PE = 0/1— 1/1, Silica-CS 40 g, 50 mL/min, silica gel, UV 254) to afford the product (270 mg, 40 %). ESLMS m/z calcd for [C9H₈F₃N3S] [M+H]⁺: 248.0; found: 248.3. ^XH NMR (400 MHz, Chloroform-d) 5 7.95 (s, 1H), 7.68 (s, 1H), 5.83 (s, 1H), 3.62 (s, 2H), 2.72 (s, 3H).

6-[5-(3-Azido-4,6-(?-benzylidene-3-deoxy-p-D-galactopyranosyl)-3-methyl-lH- l,2,4-triazol-l-yl]-5-(trifluoromethyl)-2-methylbenzothiazole

To a solution of 2,6-anhydro-4-azido-5,7-O-benzylidene-4-deoxy-D-glycero-L-manno- 7V-[l-(dimethylamino)ethylidene]heptonamide (420 mg, 1.08 mmol) in 1,4-dioxane (12 mL) [5-(trifluoromethyl)-2-methyl-l,3-benzothiazol-6-yl]hydrazine (267 mg, 1.08 mmol) and acetic acid (4 mL) were added and the mixture was stirred 2 h at 60 °C. The mixture was concentrated and partitioned between aq NaHCCL (100 mL) and DCM (50 mL). The aqueous phase was extracted with DCM (2 x 50 mL). The combined organic phases were washed with water (20 mL) and brine (20 mL), dried over ISfeSCU, evaporated, and purified by column chromatography (EtOAc/PE = 0-50%, Silica-CS 20 g, 30 mL/min, silica gel, UV 254) to afford the product (385 mg, 80 % purity, 50 %). ESI-MS m/z calcd for [C25H22F3N7O4S] [M+H]⁺: 574.1; found: 574.0. 'H NMR (400 MHz, Chloroform-d) 5 8.25 (s, 1H), 7.93 (br s, 1H), 7.35 - 7.28 (m, 5H), 5.37 (s, 1H), 4.55 - 4.48 (m, 1H), 4.35 - 4.25 (m, 2H), 4.10 - 4.07 (m, 1H), 3.69 (dd, J= 12.4, 1.2 Hz, 1H), 3.42 (s, 1H), 3.34 (dd, J= 10.4, 3.6 Hz, 1H), 3.11 (s, 1H), 2.82 (s, 3H), 2.39 (s, 3H).

6-[5-(3-Amino-4,6-O-benzylidene-3-deoxy-p-D-galactopyranosyl)-3-methyl-LH- l,2,4-triazol-l-yl]-5-(trifluoromethyl)-2-methylbenzothiazole

To a solution of 6-[5-(3-azido-4,6-O-benzylidene-3-deoxy-P-D-galactopyranosyl)-3- methyl- IT/- l ,2,4-triazol- l -yl]-5-(trifluoromethyl)-2 -methylbenzothiazole (385 mg, purity 80 %, 0.54 mmol) in THF/water (11 mL 11: 1) triphenylphosphine (704 mg, 2.69 mmol) was added and the mixture was stirred 6 h at 50 °C. The mixture was concentrated and purified by column chromatography (DCM/MeOH = 0-10%, Silica- CS 20 g, 30 mL/min, silica gel, UV 254) to give the product (182 mg, 62 %). ESI-MS m/z calcd for [C25H24F3N5O4S] [M+H]⁺: 548.2; found: 548.2. 'H NMR (400 MHz, Chloroform-d) 5 8.26 (s, 1H), 7.96 (s, 1H), 7.35 - 7.29 (m, 5H), 5.34 (s, 1H), 4.16 (d, J= 8.4, Hz, 1H), 4.02 - 3.89 (m, 2H), 3.72 (dd, J= 12.8, 1.6 Hz, 1H), 3.38 (d, J= 11.6, Hz, 1H), 3.12 (s, 1H), 2.82 (s, 3H), 2.76 (dd, J= 10.4, 3.2 Hz, 1H), 2.37 (s, 3H).

6-{5-{4,6-O-Benzylidene-3-[(2-tert-butoxycarbonyl)hydrazinyl]-3-deoxy-p-D- galactopyranosyl}-3-methyl-lEZ-l,2,4-triazol-l-yl}-5-(trifluoromethyl)-2- methylbenzothiazole

To a cooled (-70 °C) solution of 6-[5-(3-amino-4,6-O-benzylidene-3-deoxy-P-D- galactopyranosyl)-3-methyl-U/-l,2,4-triazol-l-yl]-5-(trifluoromethyl)-2- methylbenzothiazole (100 mg, 0.18 mmol) in DCM (10 mL) a solution of tert-butyl 3- (trichloromethyl)oxaziridine-2-carboxylate (71.9 mg, 0.27 mmol) in DCM (2 mL) was added dropwise. After stirring 2 h at -70 °C, the mixture was warmed to rt and stirred 6 h at rt. The mixture was concentrated and purified by column chromatography (DCM/EtOAc = 0-100%, Silica-CS 20 g, 30 mL/min, silica gel, UV 254) to afford the product (35 mg, 29 %). ESLMS m/z calcd for [C30H33F3N6O6S] [M+H]⁺: 663.2; found: 663.2. 'H NMR (400 MHz, DMSO-d₆) 8 8.44 (s, 1H), 8.33 - 8.28 (m, 2H), 7.43 - 7.35 (m, 5H), 5.48 (s, 1H), 5.31 - 5.07 (m, 1H), 4.54 (s, 1H), 4.10 - 4.08 (m, 2H), 4.00 - 3.91 (m, 3H), 3.39 (s, 1H), 2.90 (s, 3H), 2.81 - 2.78 (m, 1H), 2.34 (s, 3H), 1.36 (s, 9H).

Intermediate 44

6- {5- [ 3- Deoxy-3-( 1 H- 1 ,2-pyrazol- l-yl)-P-D-galactopyranosyl] -3-methyl- 1H- 1 ,2,4- triazol-l-yl}-5-fluoro-2-methylbenzothiazole

To a solution of 6-{5-{4,6-O-benzylidene-3-[(2-tert-butoxycarbonyl)hydrazinyl]-3- deoxy-P-D-galactopyranosyl } -3 -methyl- \H- 1 ,2,4-triazol- 1 -yl } -5-fluoro-2- methylbenzothiazole (210 mg, 80 % purity, 0.27 mmol) in EtOH (5.0 mL) 1, 1,3,3- tetraethoxypropane (90.6 mg, 0.41 mmol) and concentrated HC1 (0.25 mL) were added and the mixture was stirred 1 h at 60 °C. The mixture was concentrated and purified by prep HPLC [MeCN/H₂O (10 mmol/L NH4HCO3), X-Select 10 pm 19*250 mm, 20 mL/min, UV 254] to afford the product (53 mg, 38 %). ESLMS m/z calcd for [C20H21FN6O4S] [M+H]⁺: 461.1; found: 461.2. 'H NMR (400 MHz, Methanol -d₄) 8 8.29 (d, J= 7.2 Hz, 1H), 7.88 (d, J= 10.4 Hz, 1H), 7.76 (d, J= 2.4 Hz, 1H), 7.50 (d, J = 2.0 Hz, 1H), 6.32 (t, J= 2.0 Hz, 1H), 4.72 (dd, J= 10.4, 9.6 Hz, 1H), 4.37 - 4.33 (m, 2H), 4.02 (d, J= 2.8 Hz, 1H), 3.72 - 3.61 (m, 3H), 2.89 (s, 3H), 2.45 (s, 3H).

6- {5- [3-Deoxy-3-(4-iodo- 1H- 1 ,2-pyrazol- l-yl)-p-D-galactopyranosyl] -3-methyl- 1H-1 ,2,4-triazol-l-yl}-5-fluoro-2-methylbenzothiazole

To a solution of 6-{5-[3-deoxy-3-(U/-l,2-pyrazol-l-yl)-P-D-galactopyranosyl]-3- methyl- 1H- 1, 2, 4-triazol-l-yl} -5 -fluoro-2 -methylbenzothiazole (53 mg, 0.11 mmol) in MeCN (6.0 mL) ceric ammonium nitrate (63.1 mg, 0.12 mmol) and iodine (292 mg, 1.15 mmol) were added and the mixture was stirred 1 h at 40 °C. The mixture was concentrated and purified by prep HPLC [MeCN/H2O (10 mmol/L NH4HCO3), X- Select 10 pm 19*250 mm, 20 mL/min, UV 254] to give the product (52 mg, 77 %). ESLMS m/z calcd for [C20H20FIN6O4S] [M+H]⁺: 587.0; found: 587.2. 'H NMR (400 MHz, Methanol-d₄) 6 8.28 (d, J= 7.2 Hz, 1H), 7.88 (d, J= 10.0 Hz, 1H), 7.85 (s, 1H), 7.52 (s, 1H), 4.69 (dd, J= 10.4, 9.6 Hz, 1H), 4.38 - 4.34 (m, 2H), 3.99 (d, J= 2.8 Hz, 1H), 3.69 - 3.60 (m, 3H), 2.89 (s, 3H), 2.45 (s, 3H).

Intermediate 49

4-(Methylthio)-2-nitro-l-(trifluoromethyl)benzene

A solution of l-chloro-4-methylsulfanyl-2 -nitrobenzene (600 mg, 2.95 mmol), methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (679 mg, 3.54 mmol) and Cui (673 mg, 3.54 mmol) in DMF (5.0 mL) was stirred 2 h at 100 °C under nitrogen atmosphere. The mixture was cooled to rt, poured into water (20 mL), and extracted with EtOAc (2 x 20 mL). The combined organic phases were washed with water (20 mL) and brine (20 mL), dried over Na₂SO4, evaporated, and purified by column chromatography (PE/EtOAc=l/0~7/l, Silica-CS 20 g, 20 mL/min, silica gel, UV 254) to afford the product (258 mg, 37 %). ¹ H NMR (400 MHz, Chloroform-d) 5 7.61 (d, J= 8.4 Hz, 1H), 7.56 (d, J= 1.2 Hz, 1H), 7.40 (d, J= 8.0 Hz, 1H), 2.50 (s, 3H).

5-(Methylthio)-2-(trifluoromethyl)aniline

A solution of 4-(methylthio)-2-nitro-l-(trifluoromethyl)benzene (258 mg, 1.09 mmol), iron powder (304 mg, 5.44 mmol) and NH4CI (349 mg, 6.53 mmol) in EtOH (10.0 mL) and water (2.0 mL) was stirred 3 h at 85 °C. The mixture was filtered through a celite pad, evaporated, and purified by column chromatography (EtOAc/PE = 0/1 ~ 1/5, Silica- CS 20 g, 20 mL/min, silica gel, UV254) to afford the product (210 mg, 93 %). ESLMS m/z calcd for [C₈H₈F₃NS] [M+H]⁺: 208.0; found: 208.1. 'H NMR (400 MHz, Chloroform-d) 5 7.24 (d, J = 8.4 Hz, 1H), 6.55 (dd, J = 8.4, 0.8 Hz, 1H), 6.48 (s, 1H), 4.03 (br s, 2H), 2.39 (s, 3H).

[5-(Methylthio)-2-(trifluoromethyl)phenyl]hydrazine

To a cooled (-5 °C) solution of 5-(methylthio)-2-(trifluoromethyl)aniline (210 mg, 1.01 mmol) in concentrated HC1 (3.0 mL) a solution of NaNCL (90.9 mg, 1.32 mmol) in water (0.5 mL) was added dropwise and the resulting mixture was stirred 30 min at -5 °C. Then a solution of tin(II) chloride dihydrate (686 mg, 3.04 mmol) in concentrated HC1 (1.0 mL) was added and the mixture was stirred 2 h at -5 °C. Water (20 mL) was added and the mixture was basified to pH=8 by addition of saturated aq NaHCCL. The mixture was extracted with EtOAc (2 x 20 mL). The combined organic phases were washed with water (20 mL) and brine (20 mL), dried over ISfeSCL, evaporated, and purified by column chromatography (EtOAc/PE = 0/1— 1/4, Silica-CS 20 g, 20 mL/min, silica gel, UV 254) to afford the product (105 mg, 47 %). ESLMS m/z calcd for [C8H9F3N2S] [M+H]⁺: 223.0; found: 223.1. *H NMR (400 MHz, Chloroform-d) 5 7.26 (d, J= 8.0 Hz, 1H), 7.12 (s, 1H), 6.56 (d, J= 8.4, 1H), 5.77 (br s, 1H), 3.48 (br s, 2H), 2.44 (s, 3H). l-|5-(3-Azido-4.6-6M)enzylidene-3-deoxy-|Ll)-«alactopyr:inosyl)-3-methyl-l//- l,2,4-triazol-l-yl]-2-(trifluoromethyl)-5-(methylthio)benzene

To a solution of 2,6-anhydro-4-azido-5,7-O-benzylidene-4-deoxy-D-glycero-L-manno- heptonamide (148 mg, 0.46 mmol) in 1,4-dioxane (5.0 mL) AV-dim ethyl acetamide dimethyl acetal (73.9 mg, 0.55 mmol) was added and the mixture was stirred 3 h at 50 °C. The mixture was evaporated, and the residue was dissolved in 1,4-dioxane (6.0 mL) and acetic acid (2.0 mL). To the solution [5-(methylthio)-2- (trifluoromethyl)phenyl]hydrazine (105 mg, 0.47 mmol) was added and the mixture was stirred 2 h at 70 °C. The mixture was evaporated and partitioned between water (20 mL) and DCM (20 mL). The aqueous phase was extracted with DCM (2 x 20 mL). The combined organic phases were washed with water (20 mL) and brine (20 mL), dried over ISfeSCU, evaporated, and purified by column chromatography (EtOAc/PE = 1/5— 2/1 , Silica-CS 20 g, 30 mL/min, silica gel, UV 254) to afford the product (112 mg, 44 %). ESLMS m/z calcd for [C24H23F3N6O4S] [M+H]⁺: 549.1; found: 549.2. *H NMR (400 MHz, Chloroform-d) 5 7.53 (d, J= 8.4 Hz, 1H), 7.46 - 7.25 (m, 7H), 5.42 (s, 1H), 4.48 (t, J = 10.0 Hz, 1H), 4.28 - 4.24 (m, 1H), 4.13 (d, J= 2.8 Hz, 1H), 3.79 (dd, J = 12.4, 1.6 Hz, 1H), 3.53 (dd, J= 12.4, 1.2 Hz, 1H), 3.34 (dd, J= 10.0, 3.2 Hz, 1H), 3.17 (d, J= 0.8 Hz, 1H), 2.37 (s, 3H), 2.32 (s, 3H). l-[5-(3-Amino-4,6-(?-benzylidene-3-deoxy-p-D-galactopyranosyl)-3-methyl-LH- l,2,4-triazol-l-yl]-2-(trifluoromethyl)-5-(methylthio)benzene

To a solution of l-[5-(3-azido-4,6-O-benzylidene-3-deoxy-P-D-galactopyranosyl)-3- methyl-U/-l,2,4-triazol-l-yl]-2-(trifluoromethyl)-5-(methylthio)benzene (112 mg, 0.20 mmol) in THF (5.0 mL) and water (1.0 mL) triphenylphosphine (161 mg, 0.61 mmol) was added and the mixture was stirred overnight at 50 °C. The mixture was concentrated and purified by column chromatography (MeOH/DCM=0/l~l/10, Silica- CS 12 g, 20 mL/min, silica gel, UV 254) to afford the product (85 mg, 80 %). ESI-MS m/z calcd for [C24H25F3N4O4S] [M+H]⁺: 523.2; found: 523.5. 'H NMR (400 MHz, Chloroform-d) 5 7.55 (d, J= 8.4 Hz, 1H), 7.39 - 7.23 (m, 7H), 5.39 (s, 1H), 4.13 (d, J = 9.2 Hz, 1H), 4.07 - 3.98 (m, 2H), 3.81 (dd, J = 12.4, 1.2 Hz, 1H), 3.59 (d, J = 12.4 Hz, 1H), 3.18 (s, 1H), 2.78 (dd, J= 9.2, 2.8 Hz, 1H), 2.36 (s, 3H), 2.35 (s, 3H). l-{5-{4,6-(?-Benzylidene-3-[(2-terCbutoxycarbonyl)hydrazinyl]-3-deoxy-p-D- galactopyranosyl}-3-methyl-lH-l,2,4-triazol-l-yl}-2-(trifluoromethyl)-5-

(methylthio)benzene

To a solution of l-[5-(3-amino-4,6-O-benzylidene-3-deoxy-P-D-galactopyranosyl)-3- methyl-U/-l,2,4-triazol-l-yl]-2-(trifluoromethyl)-5-(methylthio)benzene (85 mg, 0.16 mmol) in DCM (3.0 mL) 7V-tert-butyloxycarbonyl-3-(4-cyanophenyl)oxaziridine (48.1 mg, 0.20 mmol) was added and the mixture was stirred overnight at rt. The mixture was concentrated and purified by column chromatography (PEZEtOAc=4/ 1-0/1, Silica-CS 20 g, 30 mL/min, silica gel, UV 254) to afford the product (20 mg, 19 %). ESLMS m/z calcd for [C29H34F3N5O6S] [M+H]⁺: 638.2; found: 638.3. 'H NMR (400 MHz, Chloroform-d) 5 7.54 (d, J= 8.4 Hz, 1H), 7.38 - 7.22 (m, 7H), 6.45 (br s, 1H), 5.38 (s, 1H), 4.55 (br s, 1H), 4.44 (br s, 1H), 4.31 - 4.17 (m, 3H), 3.81 (dd, J= 12.0, 1.2 Hz, 1H), 3.61 (d, J= 12.4 Hz, 1H), 3.17 (s, 1H), 2.99 (d, J= 8.4 Hz, 1H), 2.36 (s, 3H), 2.34 (s, 3H), 1.38 (s, 9H).

Intermediate 50 l,4-Dibromo-2-fluoro-5-nitrobenzene

To a cooled (0 °C) solution of l,4-bromo-2 -fluorobenzene (3.00 g, 11.8 mmol) and NH4NO3 (1.42 g, 17.7 mmol) in DCM (100 mL) trifluoroacetic anhydride (11.5 mL, 82.7 mmol) was added over 15 min. The mixture was stirred 15 min at 0 °C then 2 h at rt. The reaction was quenched with saturated aq NaHCCL (560 mL) and the phases were separated. The aqueous phase was extracted with DCM and then EtOAc. The combined organic phases were dried over JSfeSCU, concentrated, and purified by column chromatography (EtOAc/PE = 0/1— 1/7, Silica-CS 80 g, 50 mL/min, silica gel, UV 254) to afford the product (2.8 g, 35 %). ^JH NMR (400 MHz, Chloroform-d) 5 8.11 (d, J = 6.4 Hz, 1H), 7.46 (d, J= 7.2 Hz, 1H). l-Bromo-2-fluoro-5-nitro-4-(trifluoromethyl)benzene

To a solution of l,4-dibromo-2-fluoro-5-nitrobenzene (2.80 g, 9.37 mmol) in DMF (25 mL) methyl 2, 2-difluoro-2 -fluorosulfonylacetate (3.6 g, 18.7 mmol) and Cui (1.78 g, 9.37 mmol) were added and the mixture was stirred 2 h at 80 °C. The reaction was quenched with saturated aq NaHCCL (200 mL) and extracted with EtOAc (3 x 100 mL). The combined organic phases were washed with brine (2 x 100 mL), dried over Na2SO4, concentrated, and purified by column chromatography (EtOAc/PE = 0/1— 1/7, Silica- CS 80 g, 50 mL/min, silica gel, UV 254) to afford the product (1.85 g, 69 %). ’H NMR (400 MHz, Chloroform-d) 5 8.16 (d, J= 6.0 Hz, 1H), 7.52 (d, J= 8.0 Hz, 1H).

5-Bromo-4-fluoro-2-(trifluoromethyl)aniline

F^/^CF₃ J T Br^^^NH₂

To a solution of l-bromo-2-fluoro-5-nitro-4-(trifluoromethyl)benzene (2.13 g, 7.40 mmol) in acetic acid (20 mL) iron (1.24 g, 22.2 mmol) was added and the mixture was stirred 4 h at 80 °C. The mixture was concentrated and purified by column chromatography (EtOAc/PE = 0/1— 1/4, Silica-CS 40 g, 50 mL/min, silica gel, UV 254) to afford the product (1.05 g, 55 %). 'HNMR (400 MHz, DMSO-d₆) 8 7.37 (d, J= 9.2 Hz, 1H), 7.15 (d, J = 6.0 Hz, 1H), 5.74 (br s, 2H).

[5-Bromo-4-fluoro-2-(trifluoromethyl)phenyl]hydrazine

To a solution of 5-bromo-4-fluoro-2-(trifluoromethyl)aniline (1.05 g, 4.07 mmol) in acetic acid (5 mL) concentrated HC1 (5 mL) was added and the mixture was cooled to -5 °C. A solution of NaNCL (421 mg, 6.10 mmol) in water (2 mL) was added and the mixture was stirred 1 h at 0 °C. A sloution of tin(II) chloride dihydrate (1.84 g, 8.14 mmol) in concentrated HC1 (5 mL) was added slowly at 0 °C. The mixture was warmed to rt and stirred 3 h. The mixture was basified to pH = 10 by addition of NaOH (IM). The mixture was extracted with EtOAc (2 x 50 mL). The combined organic phases were dried over Na2SO4, concentrated, and purified by column chromatography (DCM/MeOH = 1/0— 4/1 , Silica-CS 40 g, 50 mL/min, silica gel, UV 254) to afford the product (405 mg, 37 %). ESLMS m/z calcd for [C?H5BrF4N2] [M+H]⁺: 273.0; found: 273.0. 'H NMR (400 MHz, DMSO-d₆) 6 7.66 (d, J= 6.0 Hz, 1H), 7.43 (d, J= 8.8 Hz, 1H), 6.93 (br s, 1H), 4.30 (br s, 2H). l-|5-(3-Azido-4.6-6M)enzylidene-3-deoxy-|Ll)-«alactopyranosyl)-3-methyl-l//- l,2,4-triazol-l-yl]-5-bromo-4-fluoro-2-(trifluoromethyl)benzene

To a solution of 2,6-anhydro-4-azido-5,7-O-benzylidene-4-deoxy-D-glycero-L-manno- 7V-[l-(dimethylamino)ethylidene]heptonamide (219 mg, 0.56 mmol) in 1,4-di oxane (5 mL) and acetic acid (1 mL) [5-bromo-4-fluoro-2-(trifluoromethyl)phenyl]hydrazine (160 mg, 0.59 mmol) was added and the mixture was stirred 2 h at 70 °C. The mixture was concentrated and partitioned between aq NaHCCL (20 mL) and EtOAc (20 mL). The aqueous phase was extracted with EtOAc (2 x 20 mL). The combined organic phases were washed with water (20 mL) and brine (20 mL), dried over Na2SO4, evaporated, and purified by column chromatography (PE/EtOAc = 1/0-3/2, Silica-CS 12 g, 15 mL/min, silica gel, UV 254) to afford the product (236 mg, 60 % purity, 42 %). ESLMS m/z calcd for [C23Hi9BrF₄N₆O4] [M+H]⁺: 599.1; found: 599.0. l-|5-(3-Aiiiino-4.6-6M)enzylidene-3-deoxy-|Ll)-«alactopyranosyl)-3-methyl-l//- l,2,4-triazol-l-yl]-5-bromo-4-fluoro-2-(trifluoromethyl)benzene

To a solution of l-[5-(3-azido-4,6-O-benzylidene-3-deoxy-P-D-galactopyranosyl)-3- methyl-17/-l,2,4-triazol-l-yl]-5-bromo-4-fluoro-2-(trifluoromethyl)benzene (236 mg, purity 60 %, 0.39 mmol) in THF/water (2.5 mL, 4:1) triphenylphosphine (310 mg, 1.18 mmol) was added and the mixture was stirred overnight at 50 °C. The mixture was concentrated and purified by column chromatography (DCM/MeOH=l/0~10/l, Silica- CS 20 g, 30 mL/min, silica gel, UV 254) to afford the product (85 mg, 63 %). ESLMS m/z calcd for [C23H2iBrF₄N₄O4] [M+H]⁺: 573.1; found: 573.1. 'H NMR (400 MHz, Chloroform-d) 5 7.84 (d, J= 6 0 Hz 1H) 7 50 (d J= 8 0 Hz, 1H), 7.44 - 7.42 (m, 2H), 7.38 - 7.35 (m, 3H), 5.47 (s, 1H), 4.21 (d, J = 9.2 Hz, 1H), 4.15 - 4.13 (m, 1H), 4.03 (t, J= 9.2 Hz, 1H), 3.92 (dd, J = 12.4, 1.6 Hz, 1H), 3.71 (d, J = 12.8 Hz, 1H), 3.30 (s, 1H), 2.85 (dd, J= 9.2, 2.8 Hz, 1H), 2.42 (s, 3H). l-[5-(4,6-O-Benzylidene-3-[(2-tert-butoxycarbonyl)hydrazinyl]-3-deoxy-p-D- galactopyranosyl)-3-methyl- 1H- 1 ,2,4-triazol- 1-yl] -5-bromo-4-fluoro-2- (trifluoromethyl)benzene

To a solution of l-[5-(3-amino-4,6-O-benzylidene-3-deoxy-P-D-galactopyranosyl)-3- methyl-U/-l,2,4-triazol-l-yl]-5-bromo-4-fluoro-2-(trifluoromethyl)benzene (85 mg, 0.15 mmol) in DCM (5.0 mL) A-ter/-butyloxycarbonyl-3-(4-cyanophenyl)oxaziridine (43.8 mg, 0.18 mmol) was added and the mixture was stirred overnight at rt. The mixture was concentrated and purified by column chromatography (EtOAc/PE = ’Zi-l/O, Silica-CS 12 g, 20 mL/min, silica gel, UV 254) to afford the product (43 mg, 42 %). ESI-MS m/z calcd for ^HsoB^NsOe] [M+H]⁺: 688.1; found: 688.0.

Intermediate 55

2-(2,3-Difluoro-4-methoxyphenyl)-3-(dimethylamino)prop-2-enal

To a cooled (0 °C) solution of DMF (341 mg, 2.23 mmol) and phosphoryl trichloride (341 mg, 2.23 mmol) 2-(2,3-difluoro-4-methoxyphenyl)acetic acid (50 mg, 0.25 mmol) was added and the mixture was stirred 2 h at 60 °C. After cooling to rt, the mixture was slowly added to ice-water (25 mL). K2CO3 was added slowly until pH reached 11. Ethanol (1 mL) was added to control frothing. To the alkaline mixture toluene (10 mL) was added, and the mixture was refluxed for 90 min and then cooled to rt. The aqueous phase was extracted with EtOAc (30 mL). The combined organic phases were washed with brine, dried over Na2SO₄, evaporated, and purified by column chromatography (EtOAc/PE = 1/3, Silica-CS 4 g, 12 mL/min, silica gel, UV 254) to give the product (8 mg, 13 %). ESLMS m/z calcd for [C12H13F2NO2] [M+H]⁺: 242.1; found: 242.2. 'H NMR (400 MHz, Chloroform-d) 5 9.02 (s, 1H), 6.86 - 6.82 (m, 2H), 6.71 - 6.66 (m, 1H), 3.83 (s, 3H), 2.80 (br s, 6H).

Intermediate 56

2,3-Difluoro-4-(trifluoromethoxy)phenylboronic acid

To a cooled (-78 °C) solution of l-bromo-2,3-difluoro-4-(trifluoromethoxy)benzene (250 mg, 0.90 mmol) and triisopropyl borate (255 mg, 1.35 mmol) in THF (5.0 mL) a n-butyllithium solution (0.542 mL, 2.5 M in THF, 1.35 mmol) was added and the mixture was stirred 4 h at -78 °C. The mixture was allowed to reach rt and was then stirred 90 min. HC1 (1 mL, 2 M) was added, and the mixture was stirred 90 min at rt. The mixture was filtered, concentrated, and purified by reversed-phase chromatography (MeCN/H2O = 1/20-2/1, C-18 column, 20 mL/min, UV 214) to afford the product (50 mg, 23 %). ESLMS m/z calcd for [C₇H₄BF₅O3] [M-H]’: 241.0; found: 241.1.

Intermediate 58 l,4-Dibromo-2,3-difluoro-5-nitrobenzene

To a cooled (0 °C) solution of l,4-bromo-2,3-difluorobenzene (5.50 g, 20.2 mmol) in concentrated H2SCU (30 mL) potassium nitrite (2.25 g, 22.3 mmol) was added and the mixture was stirred 2 h at 0 °C. The mixture was slowly added to a mixture of ice-water with external cooling to keep the temperature below 10 °C. The mixture was extracted with EtOAc (2 x 50 mL). The combined organic phases were washed with water (30 mL), aq NaHCOs (2 x 50 mL) and brine (50 mL), dried over Na2SO₄, evaporated, and purified by column chromatography (PE/EtOAc = 1/0— 1/9, Silica-CS 120 g, 90 mL/min, silica gel, UV 254) to afford the product (1.2 g, 54 %). 'H NMR (400 MHz, DMSO-i/,) 6 8.48 (dd, J= 6.0, 2.4 Hz, 1H).

2,5-Dibromo-3,4-difluoroaniline

A mixture of l,4-dibromo-2,3-difluoro-5-nitrobenzene (5.20 g, 16.4 mmol) and iron powder (9.16 g, 164 mmol) in acetic acid (60 mL) was stirred 3 h at 45 °C. The mixture was filtered through a celite pad, evaporated, and purified by column chromatography (PE/EtOAc = 1/0— 1/1, Silica-CS 120 g, 80 mL/min, silica gel, UV 254) to afford the product (4.3 g, 91 %). *H NMR (400 MHz, DMSO-d₆) 8 6.88 (dd, J= 6.0, 2.4 Hz, 1H), 5.75 (s, 2H).

/V-(2,5-Dibromo-3,4-difluorophenyl)acetamide

A solution of 2,5-dibromo-3,4-difluoroaniline (2.10 g, 7.32 mmol) and acetic anhydride (8.23 g, 80.5 mmol) in DCM (11.0 mL) was stirred overnight at rt. The mixture was evaporated and purified by column chromatography (PE/EtOAc = 1/0— 1/2, Silica-CS 80 g, 50 mL/min, silica gel, UV 254) to afford the product (1.84 g, 76 %). ESLMS m/z calcd for [CsHsB^NO] [M+H]⁺: 327.9; found: 328.0. 'H NMR (400 MHz, DMSO- d₆) 6 9.75 (s, 1H), 7.83 (dd, J= 6.4, 2.4 Hz, 1H), 2.10 (s, 3H).

/V-(2,5-Dibromo-3,4-difluorophenyl)thioacetamide

A solution of V-(2,5-dibromo-3,4-difluorophenyl)acetamide (1.64 g, 4.99 mmol) and Lawesson’s reagent (1.61 g, 3.99 mmol) in toluene (10 mL) was stirred 2 h at 100 °C. The mixture was concentrated and purified by column chromatography (PE/EtOAc = 1/0-10/1, Silica-CS 40 g, 30 mL/min, silica gel, UV 254) to afford the product (1.56 g, 91 %). ESI-MS m/z calcd for [CsHsB^NS] [M+H]⁺: 343.9; found: 344.0. 'H NMR (400 MHz, Chloroform-d) 5 8.52 (s, 1H), 8.46 (d, J= 5.2 Hz, 1H), 2.71 (s, 3H).

5-Bromo-6,7-difluoro-2-methyl-l,3-benzothiazole

A solution of V-(2,5-dibromo-3,4-difluorophenyl)thioacetamide (500 mg, 1.45 mmol), Cui (13.8 mg, 0.073 mmol) and 1,10-phenanthroline (13.1 mg, 0.073 mmol) in 1,2- dimethoxy ethane (10 mL) was stirred overnight at 80 °C. The mixture was concentrated and purified by column chromatography (EtOAc/PE = 0/1— 1/4, Silica-CS 20 g, 30 mL/min, silica gel, UV 254) to afford the product (208 mg, 54 %). ESI-MS m/z calcd for [C₈H₄BrF₂NS] [M+H]⁺: 263.9; found: 264.0. 'HNMR (400 MHz, DMSO-d₆) 87.86 (dd, J= 5.2, 2.0 Hz, 1H), 2.77 (s, 3H).

6,7-Difluoro-2-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3- benzothiazole

To a solution of 5-bromo-6,7-difluoro-2-methyl-l,3-benzothiazole (100 mg, 0.38 mmol) in 1,4-dioxane (6.0 mL) Pd(dppf)C12 (55.4 mg, 0.076 mmol), bis(pinacolato)diboron (144 mg, 0.57 mmol) and potassium acetate (111 mg, 1.14 mmol) were added. The mixture was purged three times with argon, and stirred 16 h at 100 °C. The mixture was cooled to rt, poured into water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic phases were washed with water (20 mL) and brine (20 mL), dried over Na2SO₄, concentrated, and purified by column chromatography (EtOAc/PE = 0/1— 1/4, Silica-CS 4 g, 12 mL/min, silica gel, UV 254) to afford the product (100 mg, 90 %). 'H NMR (400 MHz, Chloroform-d) 5 8.06 (dd, J= 3.6, 0.8 Hz, 1H), 2.83 (s, 3H), 1.39 (s, 12H). Intermediate 59

4-Bromo-5,6-difluoro-l,3-benzothiazol-2-amine

To a solution of 2-bromo-3,4-difluoroaniline (900 mg, 4.33 mmol) in acetic acid (10 mL) potassium thiocyanate (1.68 g, 17.3 mmol) was added followed by dropwise addition of bromine (0.443 mL, 8.65 mmol). The mixture was stirred 16 h at rt and concentrated to dryness. Aq NaHCCh (50 mL) was added, and the mixture was extracted with EtOAc (3 x 30 mL). The combined organic phases were washed with brine (30 mL), dried over Na2SO4, evaporated, and purified by column chromatography (EtOAc/PE = 0/1— 1/7, Silica-CS 20 g, 20 mL/min, silica gel, UV 254) to afford the product (466 mg, 41 %). 'HNMR (400 MHz, DMSO-d₆) 6 8.00 (s, 2H), 7.89 (dd, J= 10.0, 7.6 Hz, 1H).

4-Bromo-5,6-difluoro-l,3-benzothiazole

To a solution of 4-bromo-5,6-difluoro-l,3-benzothiazol-2-amine (466 mg, 1.76 mmol) in DMF (4.0 mL) isoamyl nitrite (412 mg, 3.52 mmol) was added and the mixture was stirred 1 h at 80 °C. The mixture was concentrated and dissolved in EtOAc (20 mL). The organic phase was washed with water and brine, dried over ISfeSCU, evaporated, and purified by column chromatography (PE/EtOAc = 1/0-10/1, Silica-CS 20 g, 20 mL/min, silica gel, UV 254) to afford the product (305 mg, 69 %). ^JH NMR (400 MHz, DMSO-de) 8 9.54 (s, 1H), 8.41 (dd, J= 10.0, 7.6 Hz, 1H).

Intermediate 61

2-Methyl-5-(4,4,5,5-tetr amethyl- 1 ,3,2-dioxaborolan-2-yl)-6-nitro- 1 ,3- benzothiazole

To a solution of 5-bromo-2-methyl-6-nitro-l,3-benzothiazole (3.50 g, 12.8 mmol) and bis(pinacolato)diboron (6.51 g, 25.6 mmol) in 1,4-dioxane (50 mL) Pd(dppf)C12 (563 mg, 0.77 mmol) and potassium acetate (3.77 g, 38.4 mmol) were added. The mixture was purged three times with nitrogen, and stirred overnight at 100 °C. The mixture was concentrated and purified by column chromatography (EtOAc/PE = 0/1-1/10, Silica- CS 40 g, 50 mL/min, silica gel, UV 254) to afford the product (2.20 g, 54 %). ESI-MS m/z calcd for [C14H17BN2O4S] [M+H]⁺: 321.1; found: 321.3. 'H NMR (400 MHz, Chloroform-d) 5 8.70 (s, 1H), 8.05 (s, 1H), 2.91 (s, 3H), 1.45 (s, 12H).

2-Methyl-6-nitro- 1 ,3-benzothiazol-5-ol

To a cooled (0 °C) solution of 2-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)-6-nitro-l,3-benzothiazole (2.20 g, 6.87 mmol) in THF (50 mL) NaOH (35 mL, 1 M) was added followed by H2O2 (30.0 %, 3.90 g, 34.4 mmol) and the mixture was stirred 30 min at 0 °C. The mixture was diluted with DCM (100 mL), and neutralized by addition of HC1 (40 mL, 1 M). The organic phase was washed with brine (50 mL), dried over Na2SO4, evaporated, and purified by column chromatography (EtOAc/PE = 0/1— 1/4, Silica-CS 40 g, 40 mL/min, silica gel, UV 254) to afford the product (1.10 g, 76 %). 'HNMR (400 MHz, Chloroform-d) 5 10.52 (s, 1H), 8.63 (s, 1H), 7.65 (s, 1H), 2.88 (s, 3H).

5-Methoxy-2-methyl-6-nitro-l,3-benzothiazole

To a cooled (0 °C) solution of 2-methyl-6-nitro-l,3-benzothiazol-5-ol (550 mg, 2.62 mmol) in anhydrous DMF (6 mL) K2CO3 (1.08 g, 7.85 mmol) and iodomethane (0.652 mL, 10.5 mmol) were added. The mixture was warmed to rt and stirred 16 h. Water was added and the mixture was then extracted with EtOAc (3 x 50 mL). The combined organic phases were washed with brine, dried over Na2SO4, and evaporated to give the product (335 mg, 57 %). ESLMS m/z calcd for [C9H8N2O3S] [M+H]⁺: 225.0; found: 225.2. 'H NMR (400 MHz, Chloroform-d) 5 8.35 (s, 1H), 7.60 (s, 1H), 4.03 (s, 3H), 2.88 (s, 3H). 5-Methoxy-2-methyl-l,3-benzothiazol-6-amine

To a solution of 5-methoxy-2-methyl-6-nitro-l,3-benzothiazole (335 mg, 1.49 mmol) in acetic acid (6 mL) iron (250 mg, 4.48 mmol) was added and the mixture was stirred 4 h at 60 °C. The mixture was filtered, concentrated, and purified by column chromatography (EtOAc/PE = 0/1-1/2, Silica-CS 20 g, 20 mL/min, silica gel, UV 254) to afford the product (245 mg, 84 %). 'H NMR (400 MHz, Chloroform-d) 5 7.35 (s, 1H), 7.05 (s, 1H), 3.92 (s, 3H), 2.75 (s, 3H).

(5-Methoxy-2-methyl-l,3-benzothiazol-6-yl)hydrazine

To a cooled (0 °C) solution of 5-methoxy-2-methyl-l,3-benzothiazol-6-amine (245 mg, 1.26 mmol) in concentrated HC1 (5 mL) a solution of NaNCL (131 mg, 1.89 mmol) in water (1 mL) was added and the mixture was stirred 1 h at 0 °C. A sloution of tin(II) chloride dihydrate (854 mg, 3.78 mmol) in concentrated HC1 (2 mL) was added slowly at 0 °C. The mixture was warmed to rt and stirred 3 h. The mixture was basified to pH = 10 by addition of NaOH (IM). The mixture was extracted with EtOAc (2 x 30 mL). The combined organic phases were dried over Na2SO4, concentrated, and purified by column chromatography (DCM/PE = 0/1-4/1, Silica-CS 40 g, 50 mL/min, silica gel, UV 254) to afford the product (143 mg, 54 %). ESLMS m/z calcd for [C9H11N3OS] [M+H]⁺: 210.1; found: 210.3. 'HNMR (400 MHz, Chloroform-d) 5 7.34 (s, 1H), 7.33 (s, 1H), 3.91 (s, 3H), 2.77 (s, 3H).

6-[5-(3-Azido-4,6-(?-benzylidene-3-deoxy-p-D-galactopyranosyl)-3-methyl-LH- l,2,4-triazol-l-yl]-5-methoxy-2-methylbenzothiazole

To a solution of 2,6-anhydro-4-azido-5,7-O-benzylidene-4-deoxy-D-glycero-L-manno- 7V-[l-(dimethylamino)ethylidene]heptonamide (270 mg, 0.69 mmol) in 1,4-dioxane (6 mL) and acetic acid (3 mL) (5-methoxy-2-methyl-l,3-benzothiazol-6-yl)hydrazine (145 mg, 0.69 mmol) was added and the mixture was stirred 2 h at 60 °C. The mixture was concentrated and purified by column chromatography (EtOAc/PE = 0/1— 1/1, Silica-CS 20 g, 25 mL/min, silica gel, UV 254) to afford the product (165 mg, 45 %). ESI-MS m/z calcd for [C25H25N7O5S] [M+H]⁺: 536.2; found: 536.2. 'H NMR (400 MHz, Chloroform-d) 5 7.85 (s, 1H), 7.51 (s, 1H), 7.42 - 7.41 (m, 2H), 7.35 - 7.32 (m, 3H), 5.47 (s, 1H), 4.62 - 4.61 (m, 1H), 4.41 (d, J = 9.2 Hz, 1H), 4.19 (d, J= 2.8 Hz, 1H), 3.88 - 3.79 (m, 4H), 3.57 - 3.54 (m, 1H), 3.43 - 3.41 (m, 1H), 3.20 (d, J= 0.8 Hz, 1H), 2.84 (s, 3H), 2.45 (s, 3H).

6-[5-(3-Amino-4,6-O-benzylidene-3-deoxy-p-D-galactopyranosyl)-3-methyl-LH- l,2,4-triazol-l-yl]-5-methoxy-2-methylbenzothiazole

To a solution of 6-[5-(3-azido-4,6-O-benzylidene-3-deoxy-P-D-galactopyranosyl)-3- methyl- 177-1, 2, 4-triazol-l-yl]-5-methoxy-2 -methylbenzothiazole (165 mg, 0.31 mmol) in THF/water (6 mL, 5: 1) triphenylphosphine (323 mg, 1.23 mmol) was added and the mixture was stirred overnight at 50 °C. The mixture was concentrated and purified by column chromatography (DCM/MeOH = 1/0-10/1, Silica-CS 20 g, 25 mL/min, silica gel, UV 254) to give the product (107 mg 68 %) ESLMS m/z calcd for [C25H27N5O5S] [M+H]⁺: 510.2; found: 510.1. 'HNMR (400 MHz, Chloroform-d) 5 7.87 (s, 1H), 7.55 (s, 1H), 7.42 - 7.40 (m, 2H), 7.34 - 7.33 (m, 3H), 5.44 (s, 1H), 4.27 (d, J= 92 Hz, 1H), 4.23 - 4.10 (m, 2H), 3.86 - 3.80 (m, 4H), 3.66 - 3.64 (m, 1H), 3.22 (s, 1H), 2.91 - 2.89 (m, 1H) , 2.85 (s, 3H), 2.39 (s, 3H).

6-{5-{4,6-O-Benzylidene-3-[(2-tert-butoxycarbonyl)hydrazinyl]-3-deoxy-p-D- galactopyranosyl}-3-methyl-l/Z-l,2,4-triazol-l-yl}-5-methoxy-2- methylbenzothiazole

To a solution of 6-[5-(3-amino-4,6-O-benzylidene-3-deoxy-P-D-galactopyranosyl)-3- methyl- 177-1, 2, 4-triazol-l-yl]-5-methoxy-2 -methylbenzothiazole (100 mg, 0.20 mmol) in DCM (5 mL) tert-butyl 3-(4-cyanophenyl)oxaziridine-2-carboxylate (72.5 mg, 0.29 mmol) was added and the mixture was stirred overnight at rt. The mixture was concentrated and purified by column chromatography (DCM/MeOH = 1/0-10/1, Silica-CS 12 g, 20 mL/min, silica gel, UV 254). The obtained material was purified reversed-phase chromatography (MeCN/H2O = 1/20-2/1, C-18 column, 20 mL/min, UV 214) to afford the product (24 mg, 30 % purity, 6 %). ESLMS m/z calcd for [C30H36N6O7S] [M+H]⁺: 625.2; found: 625.2.

Intermediate 62

2-Methyl-5-(methylthio)-6-nitro- 1 ,3-benzothiazole

To a cooled (0 °C) solution of 5-fluoro-2-methyl-6-nitro-l,3-benzothiazole (1.51 g, 7.12 mmol) in 1,4-dioxane (70 mL) NaSMe (997 mg, 14.2 mmol) was added and the mixture was stirred 16 h at rt. Water was added and the mixture was extracted with EtOAc (3 x 100 mL). The combined organic phases were washed with brine, dried over Na2SO4, evaporated, and purified by column chromatography (EtOAc/PE = 0/1— 1/4, Silica-CS 40 g, 40 mL/min, silica gel, UV 254) to afford the product (1.29 g, 75 %). ESLMS m/z calcd for [C9H₈N2O₂S2] [M+H]⁺: 241.0; found: 241.1. 'H NMR (400 MHz, DMSO-d₆) 6 9.09 (s, 1H), 7.98 (s, 1H), 2.88 (s, 3H), 2.61 (s, 3H).

2-Methyl-5-(methylthio)- 1 ,3-benzothiazol-6-amine

To a solution of 2-methyl-5-(methylthio)-6-nitro-l,3-benzothiazole (1.20 g, 4.99 mmol) in acetic acid (20 mL) iron (837 mg, 15.0 mmol) was added and the mixture was stirred 4 h at 60 °C. The mixture was filtered, concentrated, and purified by column chromatography (EtOAc/PE = 0/1-1/4, Silica-CS 40 g, 50 mL/min, silica gel, UV 254) to afford the product (806 mg, 77 %). ESI-MS m/z calcd for [C9H10N3S2] [M+H]⁺: 211.0; found: 211.1. ^XH NMR (400 MHz, DMSO-d₆) 8 7.70 (s, 1H), 7.17 (s, 1H), 5.33 (s, 2H), 2.67 (s, 3H), 2.40 (s, 3H).

[2-Methyl-5-(methylthio)- 1 ,3-benzothiazol-6-yl] hydrazine

To a cooled (0 °C) solution of 2-methyl-5-(methylthio)-l,3-benzothiazol-6-amine (806 mg, 3.83 mmol) in concentrated HC1 (15 mL) a solution ofNaNCL (397 mg, 5.75 mmol) in water (2 mL) was added and the mixture was stirred 1 h at 0 °C. A sloution of tin(II) chloride dihydrate (2.59 g, 11.5 mmol) in concentrated HC1 (5 mL) was added slowly at 0 °C. The mixture was warmed to rt and stirred 3 h. The mixture was basified to pH = 10 by addition of NaOH (IM). The mixture was extracted with EtOAc (2 x 50 mL). The combined organic phases were dried over Na2SO4, concentrated, and purified by column chromatography (DCMZEtOAc = 1/0-2/1, Silica-CS 40 g, 50 mL/min, silica gel, UV 254) to afford the product (501 mg, 58 %). ESLMS m/z calcd for [C9H11N3S2] [M+H]⁺: 226.0; found: 226.1. 'HNMR (400 MHz, DMSO-d₆) 6 7.71 (s, 1H), 7.57 (s, 1H), 6.40 (s, 1H), 4.21 (s, 2H), 2.69 (s, 3H), 2.40 (s, 3H).

6-[5-(3-Azido-4,6-O-benzylidene-3-deoxy-p-D-galactopyranosyl)-3-methyl-LH- l,2,4-triazol-l-yl]-2-methyl-5-(methylthio)benzothiazole

To a solution of 2,6-anhydro-4-azido-5,7-O-benzylidene-4-deoxy-D-glycero-L-manno- 7V-[l-(dimethylamino)ethylidene]heptonamide (866 mg, 2.22 mmol) in 1,4-dioxane (10 mL) and acetic acid (3 mL) [2-methyl-5-(methylthio)-l,3-benzothiazol-6-yl]hydrazine (501 mg, 2.22 mmol) was added and the mixture was stirred 2 h at 60 °C. The mixture was concentrated and partitioned between EtOAc (60 mL) and aq NaHCCL (60 mL). The aqueous phase was extracted with EtOAc (2 x 40 mL). The combined organic phases were washed with brine (60 mL), dried over Na2SO4, concentrated, and purified by column chromatography (EtOAc/PE = 1/5— 1/1, Silica-CS 20 g, 30 mL/min, silica gel, UV 254). Further purification by reversed-phase chromatography (MeCN/EEO = 1/20-2/1, C-18 column, 20 mL/min, UV 214) afforded the product (667 mg, 51 %). ESI-MS m/z calcd for [C25H25N7O4S2] [M+H]⁺: 552.1; found: 552.0. 'H NMR (400 MHz, Chloroform-d) 5 7.86 (s, 1H), 7.82 (s, 1H), 7.39 - 7.32 (m, 5H), 5.46 (s, 1H), 4.60 (br s, 1H), 4.41 (d, J = 92 Hz, 1H), 4.17 (d, J= 2.8 Hz, 1H), 3.83 (dd, J= 12.4, 1.6 Hz, 1H), 3.67 (d, J= 13.2 Hz, 1H), 3.40 (dd, J= 10.0, 3.2 Hz, 1H), 3.23 (s, 1H), 2.83 (s, 3H), 2.47 (s, 3H), 2.44 (s, 3H).

6-[5-(3-Amino-4,6-(?-benzylidene-3-deoxy-p-D-galactopyranosyl)-3-methyl-lH- l,2,4-triazol-l-yl]-2-methyl-5-(methylthio)benzothiazole

To a solution of 6-[5-(3-azido-4,6-O-benzylidene-3-deoxy-P-D-galactopyranosyl)-3- methyl-U/-l,2,4-triazol-l-yl]-2-methyl-5-(methylthio)benzothiazole (667 mg, 1.21 mmol) in THF (25 mL) and water (2 mL) triphenylphosphine (951 mg, 3.63 mmol) was added and the mixture was stirred 4 h at 50 °C. The mixture was concentrated and purified by column chromatography (DCM/MeOH = 1/0— 4/1, Silica-CS 20 g, 30 mL/min, silica gel, UV 254). Further purification by reversed-phase chromatography (MeCN/FFO = 1/20-2/1, C-18 column, 20 mL/min, UV 214) afforded the product (407 mg, 64 %). ESLMS m/z calcd for [C25H27N5O4S2] [M+H]⁺: 526.2; found: 526.3. 'H NMR (400 MHz, Chloroform-d) 5 7.82 (s, 1H), 7.76 (s, 1H), 7.30 - 7.26 (m, 5H), 5.37 (s, 1H), 4.20 (d, J = 9.6 Hz, 1H), 4.07 - 4.03 (m, 2H), 3.77 (dd, J= 12.8, 2.0 Hz, 1H), 3.63 (d, J= 12.8 Hz, 1H), 3.16 (s, 1H), 2.78 - 2.71 (m, 4H), 2.39 (s, 3H), 2.38 (s, 3H).

6-{5-{4,6-(?-Benzylidene-3-[(2-tert-butoxycarbonyl)hydrazinyl]-3-deoxy-p-D- galactopyranosyl}-3-methyl-lZ7-l,2,4-triazol-l-yl}-2-methyl-5-

(methylthio)benzothiazole

To a cooled (-78 °C) solution of 6-[5-(3-amino-4,6-O-benzylidene-3-deoxy-P-D- galactopyranosyl)-3-methyl-l//-l,2,4-triazol-l-yl]-2-methyl-5-

(methylthio)benzothiazole (50 mg, 0.095 mmol) inDCM (5 mL) a solution of tert-butyl 3-(trichloromethyl)oxaziridine-2-carboxylate (37.5 mg, 0.14 mmol) in DCM (1 mL) was added and the mixture was stirred 4 h at -78 °C. The mixture was concentrated and purified by reversed-phase chromatography (MeCN/H2O = 1/20-2/1, C-18 column, 20 mL/min, UV 214) to afford the product (10 mg, 16 %). ESLMS m/z calcd for [C30H36N6O6S2] [M+H]⁺: 641.2; found: 641.2. ^XH NMR (400 MHz, Chloroform-d) 5 7.81 (s, 1H), 7.75 (s, 1H), 7.36 - 7.29 (m, 5H), 6.43 - 6.39 (m, 1H), 5.36 (s, 1H), 4.46 - 4.21 (m, 5H), 3.77 (d, J= 11.6 Hz, 1H), 3.66 - 3.62 (m, 1H), 3.15 (s, 1H), 3.00 (br s, 1H), 2.77 (s, 3H), 2.40 (s, 3H), 2.37 (s, 3H), 1.37(s, 9H).

Intermediate 63 6-{5-{2,4,6-Tri-O-acetyl-3-[4-(4-chloro-2,3-difluorophenyl)-lEZ-l,2-pyrazol-l-yl]-

3-deoxy-p-D-galactopyranosyl}-3-methyl-lZ7-l,2,4-triazol-l-yl}-2-methyl-5-

(methylthio)benzothiazole

To a solution of 6-{5-{4,6-O-benzylidene-3-[(2-tert-butoxycarbonyl)hydrazinyl]-3- deoxy-P-D-galactopyranosyl } -3 -methyl- \H- 1 ,2,4-triazol- 1 -yl } -2-methyl-5- (methylthio)benzothiazole (30 mg, 0.047 mmol) in EtOH (10 mL) 2-(4-chloro-2,3- difluorophenyl)-3-(dimethylamino)prop-2-enal (15.0 mg, 0.061 mmol) was added followed by concentrated HC1 (0.2 mL) and the mixture was stirred 2 h at 80 °C. The mixture was concentrated and dissolved in pyridine (2 mL). Acetic anhydride (0.5 mL) was added, and the mixture was stirred 48 h at rt. The mixture was concentrated and purified by chromatography (EtOAc/PE = 1/5-1/0, Silica-CS 4 g, 10 mL/min, silica gel, UV 254). Further purification by reversed-phase chromatography (MeCN/EEO = 1/20-2/1, C-18 column, 20 mL/min, UV 214) afforded the product (12 mg, 34 %). ESIMS m/z calcd for [C33H31CIF2N6O7S2] [M+H]⁺: 761.1; found: 761.0. 'H NMR (400 MHz, Chloroform-d) 5 7.89 - 7.85 (m, 3H), 7.72 (s, 1H), 7.11 - 7.08 (m, 2H), 6.11 (t, J = 11.0, 1H), 5.38 (s, 1H), 4.70 (d, J= 9.6 Hz, 1H), 4.52 (d, J = 92 Hz, 1H), 3.88 - 3.81 (m, 3H), 2.83 (s, 3H), 2.43 - 2.39 (m, 6H), 1.93 (s, 3H), 1.77 - 1.75 (m, 6H).

Intermediate 64

4-Fluoro-6-nitro-l,3-benzothiazol-2-amine

To a cooled (-50 °C) solution of 4-fhioro-l,3-benzothiazol-2-amine (1.0 g, 5.95 mmol) in H2SO4 (10.0 mL) fuming HNO3 (0.3 mL, 6.54 mmol) was added dropwise. The mixture was allowed to warm to rt and was stirred 1 h. The mixture was poured into ice cold water (50 mL) and extracted with EtOAc (2 x 30 mL). The combined organic phases were dried and concentrated to give the product (1.2 g, 95 %). ESI-MS m/z calcd for [C7H4FN3O2S] [M+H]⁺: 214.0; found: 214.0. 'H NMR (400 MHz, DMSO-d₆) 8 8.61 (d, J= 2.0 Hz, 1H), 8.48 (s, 2H), 8.00 (dd, J= 10.4, 2.0 Hz, 1H).

2-Bromo-4-fluoro-6-nitro-l,3-benzothiazole

To a cooled (0 °C) solution of 4-fluoro-6-nitro-l,3-benzothiazol-2-amine (500 mg, 2.35 mmol) and copper(II) bromide (786 mg, 3.52 mmol) in MeCN (10.0 mL) tert-butyl nitrite (363 mg, 3.52 mmol) was added dropwise. The mixture was stirred 1 h at 0 °C and then 1 h at rt. Water (20 mL) was added, and the pH was adjusted to 1 using 2N HC1. The mixture was extracted with DCM (3 x 30 mL). The combined organic phases were dried, concentrated, and purified by column chromatography (PEZEtOAc = 10/1-3/1, Silica-CS 20 g, 30 mL/min, silica gel, UV 254) to afford the product (260 mg, 40 %). 'H NMR (400 MHz, DMSO-d₆) 6 9.07 (d, J = 2.0 Hz, 1H), 8.32 (dd, J = 10.4, 2.0 Hz, 1H).

2-Bromo-4-fluoro-l,3-benzothiazol-6-amine

To a solution of 2-bromo-4-fluoro-6-nitro-l,3-benzothiazole (260 mg, 0.94 mmol) in EtOH/H2O (8.0 mL, v/v 3: 1) iron (262 mg, 4.69 mmol) and NH4CI (251 mg, 4.69 mmol) were added and the mixture was stirred 2 h at 50 °C. The mixture was concentrated and purified by column chromatography (PE/EtOAc= 10/ 1-3/1, Silica-CS 20 g, 30 mL/min, silica gel, UV 254) to give the product (210 mg, 91 %). ESI-MS m/z calcd for [C₇H₄BrFN2S] [M+H]⁺: 246.9; found: 247.1. ^XH NMR (400 MHz, DMSO-d₆) 6 6.87 (d, J= 2.0 Hz, 1H), 6.58 (dd, J= 13.2, 2.0 Hz, 1H), 5.82 (s, 2H).

4-Fluoro-2-methyl-l,3-benzothiazol-6-amine

To a solution of 2-bromo-4-fluoro-l,3-benzothiazol-6-amine (500 mg, 2.02 mmol) and 2,4,6-trimethyl-l,3,5,2,4,6-trioxatriborinane (508 mg, 4.05 mmol) in DMF/H2O (6.0 mL, 5: 1) Pd(dppf)C12 (148 mg, 0.20 mmol) and K2CO3 (839 mg, 6.07 mmol) were added. The mixture was purged three times with nitrogen and stirred 3 h at 70 °C. Water (20 mL) was added, and the mixture was extracted with EtOAc (20 mL). The organic phase was dried, concentrated and purified by column chromatography (PE/EtOAc = 10/1-3/1, Silica-CS 20 g, 30 mL/min, silica gel, UV 254) to give the product (180 mg, 49 %). ESLMS m/z calcd for [C₈H₇FN₂S] [M+H]⁺: 183.0; found: 183.1. *H NMR (400 MHz, DMSO-de) 8 6.82 (d, J = 1.6 Hz, 1H), 6.52 (dd, J = 13.2, 1.6 Hz, 1H), 5.54 (s, 2H), 2.67 (s, 3H).

(4-Fluoro-2-methyl-l,3-benzothiazol-6-yl)hydrazine

To a cooled (-10 °C) solution of 4-fluoro-2-methyl-l,3-benzothiazol-6-amine (180 mg, 0.99 mmol) in concentrated HC1 (10 mL) a solution of NaNCL (81.8 mg, 1.19 mmol) in water (1.0 mL) was added dropwise. The resulting mixture was stirred 30 min at -10 °C. Tin(II) chloride dihydrate (669 mg, 2.96 mmol) dissolved in concentrated HC1 (3.0 mL) was added dropwise. The resulting mixture was allowed to reach rt and was then stirred 2 h. The mixture was poured into saturated aq NaHCCh and extracted with EtOAc (3 x 20 mL). The combined organic phases were washed with brine, dried over Na2SO4, and evaporated to afford the product (170 mg, 65 %). ESLMS m/z calcd for [C₈H₈FN₃S] [M+H]⁺: 198.0; found: 198.1. ^XH NMR (400 MHz, DMSO-d₆) 6 7.17 (s, 1H), 7.07 (d, J= 1.6 Hz, 1H), 6.70 (dd, J= 13.6, 2.0 Hz, 1H), 4.20 (br s, 2H), 2.68 (s, 3H).

6-[5-(3-Azido-4,6-O-benzylidene-3-deoxy-p-D-galactopyranosyl)-3-methyl-LH- l,2,4-triazol-l-yl]-4-fluoro-2-methylbenzothiazole

To a solution of 2,6-anhydro-4-azido-5,7-(9-benzylidene-4-deoxy-D-glycero-L-manno- heptonamide (240 mg, 0.75 mmol) in 1,4-dioxane (9.0 mL) A A -di methyl acetamide dimethyl acetal (110 mg, 0.82 mmol) was added and the mixture was stirred 3 h at 50 °C. The mixture was evaporated, and the residue was dissolved in 1,4-dioxane (9.0 mL) and acetic acid (10 mL). To this solution (4-fluoro-2-methyl-l,3-benzothiazol-6- yl)hydrazine (170 mg, 0.86 mmol) was added and the mixture was stirred 2 h at 60 °C. The mixture was evaporated and partitioned between water (20 mL) and DCM (20 mL). The aqueous phase was extracted with DCM (2 x 20 mL). The combined organic phases were washed with water (20 mL) and brine (20 mL), dried over ISfeSCL, evaporated, and purified by column chromatography (EtOAc/PE = 1/5-2/1, Silica-CS 20 g, 30 mL/min, silica gel, UV 254) to afford the product (280 mg, 71 %). ESLMS m/z calcd for [C24H22FN7O4S] [M+H]⁺: 524.1; found: 524.0. 'H NMR (400 MHz, Chloroform-d) 5 7.81 (s, 1H), 7.45 - 7.36 (m, 3H), 7.34 - 7.25 (m, 3H), 5.52 (s, 1H), 4.78 (t, J= 10.0 Hz, 1H), 4.35 (d, J = 9.2 Hz, 1H), 4.25 (d, J= 3.2 Hz, 1H), 4.03 - 3.94 (m, 2H), 3.43 (s, 1H), 3.39 (dd, J= 10.4, 3.2 Hz, 1H), 2.83 (s, 3H), 2.40 (s, 3H).

6-[5-(3-Amino-4,6-O-benzylidene-3-deoxy-p-D-galactopyranosyl)-3-methyl-LH- l,2,4-triazol-l-yl]-4-fluoro-2-methylbenzothiazole

To a solution of 6-[5-(3-azido-4,6-O-benzylidene-3-deoxy-P-D-galactopyranosyl)-3- methyl-U/-l,2,4-triazol-l-yl]-4-fluoro-2-methylbenzothiazole (280 mg, 0.54 mmol) in THF/water (12 mL, 5: 1) triphenylphosphine (701 mg, 2.67 mmol) was added and the mixture was stirred 6 h at 50 °C. The mixture was concentrated and purified by column chromatography (DCM/MeOH = 1/0-10/1, Silica-CS 12 g, 40 mL/min, silica gel, UV 254) to afford the product (210 mg, 79 %). ESI-MS m/z calcd for [C24H24FN5O4S] [M+H]⁺: 498.2; found: 498.0. 'H NMR (400 MHz, DMSO-d₆) 8 8.16 (d, J = 1.6 Hz, 1H), 7.58 (dd, J= 11.2, 2.0 Hz, 1H), 7.47 - 7.36 (m, 5H), 5.60 (s, 1H), 5.23 (br s, 1H), 4.36 (d, J = 9.2 Hz, 1H), 4.17 - 4.05 (m, 3H), 3.87 (t, J= 9.6 Hz, 1H), 3.67 (s, 1H), 2.86 (s, 3H), 2.72 (dd, J= 10.0, 3.6 Hz, 1H), 2.35 (s, 3H).

6-{5-{4,6-(?-Benzylidene-3-[(2-tert-butoxycarbonyl)hydrazinyl]-3-deoxy-p-D- galactopyranosyl}-3-methyl-lH-l,2,4-triazol-l-yl}-4-fluoro-2- methylbenzothiazole

To a solution of 6-[5-(3-amino-4,6-O-benzylidene-3-deoxy-P-D-galactopyranosyl)-3- methyl-U/-l,2,4-triazol-l-yl]-4-fluoro-2-methylbenzothiazole (210 mg, 0.42 mmol) in DCM (5 mL) 7V-ter/-butyloxycarbonyl-3-(4-cyanophenyl)oxaziridine (114 mg, 0.46 mmol) was added and the mixture was stirred overnight at rt. The mixture was concentrated and purified by column chromatography (PE/EtOAc=4/ 1-0/1, Silica-CS 20 g, 30 mL/min, silica gel, UV 254) to afford the product (140 mg, 54 %). ESLMS m/z calcd for [C29H33FN6O6S] [M+H]⁺: 613.2; found: 613.0. 'H NMR (400 MHz, DMSO-de) 6 8.35 (br s, 1H), 8.15 (d, J= 1.6 Hz, 1H), 7.60 - 7.54 (m, 1H), 7.51 - 7.46 (m, 2H), 7.40 - 7.34 (m, 3H), 5.56 (s, 1H), 5.24 (d, J = 5.2 Hz, 1H), 4.65 - 4.56 (m, 1H), 4.46 (d, J = 9.6 Hz, 1H), 4.22 (d, J= 3.2 Hz, 1H), 4.15 - 4.05 (m, 2H), 3.68 (s, 1H), 2.99 - 2.90 (m, 1H), 2.86 (s, 3H), 2.35 (s, 3H), 1.38 (s, 9H).

Intermediate 65

/V-(2,6-Dibromo-4-nitrophenyl)acetamide

To a solution of 2,6-dibromo-4-nitroaniline (3.5 g, 11.8 mmol) in DMF (40 mL) acetyl chloride (1.3 g, 16.6 mmol) was added and the mixture was stirred overnight at 55 °C. The mixture was poured into crushed ice-water (300 mL). The white solid was filtered, washed with water, and dried to afford the product (3.2 g, 80 %). ESLMS m/z calcd for [C₈H₆Br2N₂O₃] [M+H]⁺: 338.9; found: 338.9. 'H NMR (400 MHz, DMSO-d₆) 8 10.22 (s, 1H), 8.51 (s, 2H), 2.09 (s, 3H).

/V-(2,6-Dibromo-4-nitrophenyl)thioacetamide

To a solution of/V-(2,6-dibromo-4-nitrophenyl)acetamide (3.2 g, 9.47 mmol) in toluene (100 mL) Lawesson’s reagent (3.83 g, 9.47 mmol) was added and the mixture was stirred overnight at 110 °C. The mixture was concentrated and purified by column chromatography (EtOAc/PE = 0/1— 1/1 , Silica-CS 40 g, 50 mL/min, silica gel, UV 254) to give the product (3.1 g, 93 %). ESI-MS m/z calcd for [CsEfcB^lSbChS] [M+H]⁺: 355.0; found: 354.9.

4-Bromo-2-methyl-6-nitro-l,3-benzothiazole

To a solution of A-(2,6-dibromo-4-nitrophenyl)thioacetamide (3.1 g, 8.76 mmol) in 1,2-dimethoxy ethane (40 mL) Cui (83.4 mg, 0.44 mmol), 1,10-phenanthroline (158 mg, 0.88 mmol) and CS2CO3 (4.28 g, 13.1 mmol) were added and the mixture was stirred overnight at 80 °C. The mixture was cooled to rt, filtered over celite and concentrated. The residue was purified by column chromatography (EtOAc/PE = 0/1— 2/1, Silica-CS 40 g, 50 mL/min, silica gel, UV 254) to afford the product (1.8 g, 75 %). ESLMS m/z calcd for [C₈H₅BrN₂O₂S] [M+H]⁺: 272.9; found: 273.0. 'H NMR (400 MHz, DMSO-d₆) 6 9.16 (d, J= 2.0 Hz, 1H), 8.51 (d, J= 2.4 Hz, 1H), 2.92 (s, 3H). 4-Bromo-2-methyl-l,3-benzothiazol-6-amine

To a solution of 4-bromo-2-methyl-6-nitro-l,3-benzothiazole (2.0 g, 7.32 mmol) in EtOH (80 mL) iron (1.22 g, 22.0 mmol), NH4CI (3.92 g, 73.2 mmol) and water (40 mL) were added and the mixture was stirred 1 h at 80 °C. The mixture was cooled, filtered over celite and concentrated. The residue was purified by column chromatography (PE/EtOAc=l/0~l/l, Silica-CS 40 g, 40 mL/min, silica gel, UV 254) to afford the product (1.7 g, 96 %). ESI-MS m/z calcd for [CsEEBrlSbS] [M+H]⁺: 243.0; found: 243.0. 'HNMR (400 MHz, DMSO-d₆) 8 7.00 (d, J= 2.0 Hz, 1H), 6.97 (d, J= 2.0 Hz, 1H), 5.50 (s, 2H), 2.67 (s, 3H).

(4-Bromo-2-methyl-l,3-benzothiazol-6-yl)hydrazine

To a cooled (0 °C) solution of 4-bromo-2-methyl-l,3-benzothiazol-6-amine (800 mg, 3.29 mmol) in HC1 (16 mL), water (8 mL) and acetic acid (8 mL) a solution of NaNCL (199 mg, 2.88 mmol) in water (4 mL) was added over 10 min. The mixture was stirred 1 h at 0 °C. Tin(II) chloride (1.17 g, 6.17 mmol) dissolved in concentrated HC1 (10 mL) was added dropwise at 0 °C. The resulting mixture was warmed to rt and stirred 3 h before aq NaOH (5 M) was added to adjust pH to 8. The mixture was extracted with EtOAc (2 x 250 mL). The combined organic phases were dried over ISfeSCL, evaporated, and purified by column chromatography (EtOAc/DCM=0/l~l/l, Silica-CS 20 g, 25 mL/min, silica gel, UV 254) to afford the product (330 mg, 62 %). ESLMS m/z calcd for [C₈H₈BrN₃S] [M+H]⁺: 258.0; found: 258.0. ’H NMR (400 MHz, DMSO- d₆) 6 7.25 (d, J= 2.0 Hz, 1H), 7.14 - 7.12 (m, 2H), 4.14 (s, 2H), 2.69 (s, 3H).

6-[5-(3-Azido-4,6-O-benzylidene-3-deoxy-p-D-galactopyranosyl)-3-methyl-LH- l,2,4-triazol-l-yl]-4-bromo-2-methylbenzothiazole

To a solution of 2,6-anhydro-4-azido-5,7-(9-benzylidene-4-deoxy-D-glycero-L-manno- 7V-[l-(dimethylamino)ethylidene]heptonamide (200 mg, 0.51 mmol) in 1,4-dioxane (6 mL) and acetic acid (3 mL) (4-bromo-2-methyl-l,3-benzothiazol-6-yl)hydrazine (199 mg, 0.77 mmol) was added and the mixture was stirred 2 h at 60 °C. The mixture was concentrated and purified by column chromatography (DCM/EtOAc=l/0~l/l, Silica- CS 20 g, 25 mL/min, silica gel, UV 254) to afford the product (210 mg, 70 %). ESIMS m/z calcd for ^^BrNyCUS] [M+H]⁺: 584.1; found: 583.8. *H NMR (400 MHz, Chloroform-d) 5 8.04 (br s, 1H), 7.98 (s, 1H), 7.52 - 7.48 (m, 2H), 7.37 - 7.34 (m, 3H), 5.60 (s, 1H), 4.90 - 4.84 (m, 1H), 4.42 - 4.32 (m, 2H), 4.16 - 4.07 (m, 2H), 3.51 - 3.44 (m, 2H), 2.91 (s, 3H), 2.48 (s, 3H).

6-[5-(3-Amino-4,6-O-benzylidene-3-deoxy-p-D-galactopyranosyl)-3-methyl-LH- l,2,4-triazol-l-yl]-4-bromo-2-methylbenzothiazole

To a solution of 6-[5-(3-azido-4,6-O-benzylidene-3-deoxy-P-D-galactopyranosyl)-3- methyl-U/-l,2,4-triazol-l-yl]-4-bromo-2-methylbenzothiazole (210 mg, 0.36 mmol) in THF/water (22 mL, 10: 1) triphenylphosphine (471 mg, 1.80 mmol) was added and the mixture was stirred overnight at 50 °C. The mixture was concentrated and purified by column chromatography (DCM/MeOH = 1/0-10/1, Silica-CS 20 g, 25 mL/min, silica gel, UV 254) to afford the product (130 mg, 65 %). ESLMS m/z calcd for [C24H24BrN₅O₄S] [M+H]⁺: 558 1; found: 557 9 'H NMR (400 MHz, Chloroform-d) 5 7.98 (d, J= 2.0 Hz, 1H), 7.95 (d, J= 2.0 Hz, 1H), 7.43 - 7.39 (m, 2H), 7.31 - 7.28 (m, 3H), 5.50 (s, 1H), 4.29 (t, J= 9.6 Hz, 1H), 4.21 - 4.16 (m, 2H), 4.15 - 4.11 (m, 1H), 4.03 - 3.99 (m, 1H), 3.46 (s, 1H), 2.84 (s, 3H), 2.83 - 2.81 (m, 1H), 2.36 (s, 3H).

6-{5-{4,6-O-Benzylidene-3-[(2-tert-butoxycarbonyl)hydrazinyl]-3-deoxy-p-D- galactopyranosyl}-3-methyl-lZ7-l,2,4-triazol-l-yl}-4-bromo-2- methylbenzothiazole

To a solution of 6-[5-(3-amino-4,6-O-benzylidene-3-deoxy-P-D-galactopyranosyl)-3- methyl-U/-l,2,4-triazol-l-yl]-4-bromo-2-methylbenzothiazole (130 mg, 0.23 mmol) in DCM (5 mL) 7V-tert-butyloxycarbonyl-3-(4-cyanophenyl)oxaziridine (68.8 mg, 0.28 mmol) was added and the mixture was stirred overnight at rt. The mixture was concentrated and purified by column chromatography (DCM/MeOH= I/O- 10/1, Silica- CS 12 g, 20 mL/min, silica gel, UV 254) to afford the product (115 mg, 73 %). ESIMS m/z calcd for [C29H33BrN₆O₆S] [M+H]⁺: 673.1; found: 672.8. *H NMR (400 MHz, Chloroform-d) 5 8.08 (d, J= 1.6 Hz, 1H), 7.97 (d, J= 1.6 Hz, 1H), 7.45 - 7.41 (m, 2H), 7.34 - 7.29 (m, 3H), 5.56 (s, 1H), 4.62 - 4.55 (m, 1H), 4.49 - 4.41 (m, 2H), 4.21 (d, J = 12.4 Hz, 1H), 4.09 - 4.05 (m, 1H), 3.53 (br s, 1H), 3.19 - 3.13 (m, 1H), 2.88 (s, 3H), 2.46 (s, 3H), 1.43 (s, 9H).

Intermediate 66

2-Bromo-6-(trifluoromethyl)-4-nitroaniline

To a solution of 4-nitro-2-(trifluoromethyl)aniline (5.10 g, 24.7 mmol) in DMF (70 mL) 7V-bromosuccinimide (6.61 g, 37.1 mmol) was added and the mixture was stirred overnight at rt. The mixture was concentrated, DCM (10 mL) was added and the mixture was washed with aq NaHCCL (10 mL) and brine (10 mL). The organic phase was dried over Na2SO4, evaporated, and purified by column chromatography (PE/EtOAc=l/0~8/l, Silica-CS 80 g, 80 mL/min, silica gel, UV 254) to afford the product (6.40 g, 91 %). *H NMR (400 MHz, Chloroform-d) 5 8.53 (d, J= 2.8 Hz, 1H), 8.39 (d, J= 2.4 Hz, 1H), 5.42 (s, 2H).

/V-[2-Bromo-6-(trifluoromethyl)-4-nitrophenyl]acetamide

To a solution of 2-bromo-6-(trifluoromethyl)-4-nitroaniline (5.00 g, 17.5 mmol) in pyridine (50 mL) acetic anhydride (7.90 g, 77.4 mmol) and 4-(dimethylamino)pyridine (4.29 g, 35.1 mmol) were added and the mixture was stirred 2 days at 85 °C. The mixture was filtered, and the filtrate was acidified to pH 7-8 using acetic acid. The mixture was extracted with DCM (3 x 50 mL). The combined organic phases were washed with brine (50 mL), dried over Na2SO4, evaporated, and purified by column chromatography (PE/EtOAc=l/0~4/l, Silica-CS 120 g, 80 mL/min, silica gel, UV 254) to afford the product (2.75 g, 48 %). ¹ H NMR (400 MHz, Chloroform-d) 5 8.65 (s, 1H), 8.45 (s, 1H), 7.15 (s, 1H), 2.20 (s, 3H).

/V-[2-Bromo-6-(trifluoromethyl)-4-nitrophenyl]thioacetamide

To a solution of/V-[2-bromo-6-(trifluoromethyl)-4-nitrophenyl]acetamide (1.63 g, 4.98 mmol) in toluene (15 mL) P2S5 (3.32 g, 15.0 mmol) was added and the mixture was stirred 2 h at 90 °C. The mixture was concentrated and purified by column chromatography (EtOAc/PE = 0/1-4/1, Silica-CS 40 g, 50 mL/min, silica gel, UV 254) to give the product (1.1 g, 64 %). 'H NMR (400 MHz, Chloroform-d) 5 8.67 (d, J= 2.0 Hz, 1H), 8.50 (d, J= 2.4 Hz, 1H), 8.27 (s, 1H), 2.72 (s, 3H).

4-(Trifluoromethyl)-2-methyl-6-nitro-l,3-benzothiazole

To a solution of A-[2-bromo-6-(trifluoromethyl)-4-nitrophenyl]thioacetamide (800 mg, 2.33 mmol) in 1,4-dioxane (40 mL) Pd2(dba)s (214 mg, 0.23 mmol), 4,5- bis(diphenylphosphino)-9,9-dimethylxanthene (202 mg, 0.35 mmol) and CS2CO3 (2.28 g, 6.99 mmol) were added. The mixture was purged three times with nitrogen, and stirred 50 min at 90 °C. The mixture was concentrated and purified by column chromatography (EtOAc/PE = 0/1-1/10, Silica-CS 40 g, 40 mL/min, silica gel, UV 254) to afford the product (518 mg, 85 %). ESI-MS m/z calcd for [C9H5F3N2O2S] [M+H]⁺: 263.0; found: 262.6. 'H NMR (400 MHz, Methanol-d₄) 8 8.97 (d, J= 2.4 Hz, 1H), 8.65 (d, J= 2.0 Hz, 1H), 3.01 (s, 3H).

4-(Trifluoromethyl)-2-methyl-l,3-benzothiazol-6-amine

To a solution of 4-(trifluoromethyl)-2-methyl-6-nitro-l,3-benzothiazole (713 mg, 2.72 mmol) in EtOH (12 mL) PtCL (617 mg, 2.72 mmol) was added and the mixture was stirred 1 h at rt. The mixture was filtered over celite, concentrated, and purified by column chromatography (PE/EtOAc= 1/0-20/1, Silica-CS 40 g, 35 mL/min, silica gel, UV 254) to afford the product (398 mg, 63 %). ESI-MS m/z calcd for [C9H7F3N2S] [M+H]⁺: 233.0; found: 233.2. 'H NMR (400 MHz, Chloroform-d) 5 7.21 (d, J = 2.0 Hz, 1H), 7.08 (d, J= 2.0 Hz, 1H), 3.91 (s, 2H), 2.82 (s, 3H).

[4-(Trifluoromethyl)-2-methyl-l,3-benzothiazol-6-yl]hydrazine

To a cooled (-10 °C) solution of 4-(trifluoromethyl)-2-methyl-l,3-benzothiazol-6- amine (398 mg, 1.71 mmol) in concentrated HC1 (6.0 mL) a solution of NaNCL (177 mg, 2.57 mmol) in water (1.5 mL) was added dropwise. The mixture was stirred 30 min at -10 °C. Tin(II) chloride (773 mg, 3.43 mmol) dissolved in concentrated HC1 (1.5 mL) was added dropwise at -10 °C. The resulting mixture was warmed to rt and stirred 2 h before saturated aq NaHCCL was added to adjust pH to 7-8. The mixture was extracted with EtOAc (3 x 20 mL). The combined organic phases were washed with brine, dried over Na2SO4, evaporated, and purified by column chromatography (EtOAc/PE = 0/1— 1/1 , Silica-CS 40 g, 40 mL/min, silica gel, UV 254) to afford the product (200 mg, 47 %). ESI-MS m/z calcd for [C9H8F3N3S] [M+H]⁺: 248.0; found: 247.9. ¹ H NMR (400 MHz, DMSO-d₆) 8 7.53 (d, J= 1.6 Hz, 1H), 7.24 (d, J= 2.0 Hz, 1H), 4.22 (s, 2H), 2.74 (s, 3H).

6-[5-(3-Azido-4,6-O-benzylidene-3-deoxy-p-D-galactopyranosyl)-3-methyl-LH- l,2,4-triazol-l-yl]-4-(trifluoromethyl)-2-methylbenzothiazole

To a solution of 2,6-anhydro-4-azido-5,7-O-benzylidene-4-deoxy-D-glycero-L-manno- A-[l-(dimethylamino)ethylidene]heptonamide (298 mg, 0.77 mmol) in 1,4-dioxane (3 mL) and acetic acid (1 mL) [4-(trifluoromethyl)-2-methyl-l,3-benzothiazol-6- yl]hydrazine (208 mg, 0.84 mmol) was added and the mixture was stirred 2 h at 60 °C. The mixture was concentrated and DCM (10 mL) was added. The organic phase was washed with aq NaHCCL (10 mL) and brine (10 mL), dried over Na2SO4, evaporated, and purified by column chromatography (PE/EtOAc= 10/ 1-0/1, Silica-CS 40 g, 40 mL/min, silica gel, UV 254) to afford the product (372 mg, 85 %). ESLMS m/z calcd for [C25H22F3N7O4S] [M+H]⁺: 574.1; found: 574.2.

6-|5-(3-Ainino-4.6-6M)enzylidene-3-deoxy-|Ll)-«alactopyranosyl)-3-methyl-l//- l,2,4-triazol-l-yl]-4-(trifluoromethyl)-2-methylbenzothiazole

To a solution of 6-[5-(3-azido-4,6-(9-benzylidene-3-deoxy-P-D-galactopyranosyl)-3- methyl-177-l,2,4-triazol-l-yl]-4-(trifluoromethyl)-2 -methylbenzothiazole (372 mg, 0.65 mmol) in THF/water (6 mL, 10: 1) triphenylphosphine (851 mg, 3.24 mmol) was added and the mixture was stirred overnight at 50 °C. The mixture was concentrated and purified by column chromatography (PE/EtOAc=0~30%, Silica-CS 12 g, 12 mL/min, silica gel, UV 254) to afford the product (105 mg, 30 %). ESI-MS m/z calcd for [C25H24F3N5O4S] [M+H]⁺: 548.2; found: 548.2. 'H NMR (400 MHz, Chloroform- d) 5 8.26 (d, J = 1.6 Hz, 1H), 8.07 (s, 1H), 7.41 - 7.40 (m, 2H), 7.29 - 7.26 (m, 3H), 5.50 (s, 1H), 4.32 (t, J= 8.8 Hz, 1H), 4.21 - 4.18 (m, 2H), 4.11 - 4.00 (m, 2H), 3.47 (s, 1H), 2.88 (s, 3H), 2.85 - 2.81 (m, 1H), 2.39 (s, 3H).

6-{5-{4,6-O-Benzylidene-3-[(2-tert-butoxycarbonyl)hydrazinyl]-3-deoxy-p-D- galactopyranosyl}-3-methyl-lZ7-l,2,4-triazol-l-yl}-4-(trifluoromethyl)-2- methylbenzothiazole

To a solution of 6-[5-(3-amino-4,6-O-benzylidene-3-deoxy-P-D-galactopyranosyl)-3- methyl- 177-1, 2, 4-triazol-l-yl]-4-(trifluoromethyl)-2 -methylbenzothiazole (60 mg, 0.11 mmol) in DCM (10 mL) 7V-tert-butyloxycarbonyl-3-(4-cyanophenyl)oxaziridine (40.5 mg, 0.16 mmol) was added and the mixture was stirred overnight at rt. The mixture was concentrated and purified by column chromatography (DCMZEtOAc=4/ 1-0/1, Silica- CS 4 g, 10 mL/min, silica gel UV 254) to afford the product (32 mg, 44 %). ESLMS m/z calcd for [C30H33F3N6O6S] [M+H]⁺: 663.2; found: 662.9. 'H NMR (400 MHz, Chloroform-d) 5 8.26 (d, J= 1.6 Hz, 1H), 8.03 (d, J= 1.6 Hz, 1H), 7.38 - 7.36 (m, 2H), 7.27 - 7.25 (m, 3H), 5.49 (s, 1H), 4.52 (t, J = 9.6 Hz, 1H), 4.33 - 4.30 (m, 2H), 4.17 (dd, J= 12.8, 1.2 Hz, 1H), 4.02 - 3.99 (m, 1H), 3.44 (s, 1H), 3.00 (dd, J = 10.0, 3.2 Hz, 1H), 2.85 (s, 3H), 2.38 (s, 3H), 1.36 (s, 9H).

Intermediate 67

4-Bromo-2,3-difluoro-6-nitroaniline

To a solution of l,2,3-trifluoro-4-nitrobenzene (6.00 g, 33.9 mmol) in MeOH (30 mL) NH3 (30 mL, 7M in MeOH) was added and the mixture was stirred overnight at rt. The mixture was concentrated to afford the product (5.70 g, 97 %). 'H NMR (400 MHz, DMSO-de) 8 7.95 - 7.91 (m, 1H), 7.54 (s, 2H), 6.75 - 6.69 (m, 1H).

4-Bromo-2,3-difluoro-6-nitroaniline

To a solution of 2,3-difluoro-6-nitroaniline (2.0 g, 11.5 mmol) in DMF (15 mL) N- bromosuccinimide (3.07 g, 17.2 mmol) was added and the mixture was stirred 16 h at rt. The mixture was partitioned between aq NaHCOs (20 mL) and EtOAc (20 mL), and the aqueous phase was extracted with EtOAc (2 x 20 mL). The combined organic phases were washed with brine (20 mL), dried over Na2SO4, evaporated, and purified by column chromatography (PE/EtOAc=5/l~l/l, Silica-CS 40 g, 50 mL/min, silica gel, UV 254) to afford the product (1.7 g, 59 %). *H NMR (400 MHz, Chloroform-d) 6 8.16 (dd, J= 6.4, 2.4 Hz, 1H), 6.17 (br s, 2H). l-Bromo-4-chloro-2,3-difluoro-5-nitrobenzene

To a cooled (0 °C) solution of 4-bromo-2,3-difluoro-6-nitroaniline (1.70 g, 6.72 mmol) in MeCN (25 mL) CuCh (1.80 g, 13.4 mmol) was added followed by tert-butyl nitrite (1.39 g, 13.5 mmol) and the mixture was stirred 16 h at rt. Water (20 mL) was added and the mixture was extracted with EtOAc (3 x 30 mL) The combined organic phases were dried, evaporated, and purified by column chromatography (PE/EtOAc= 10/ 1-3/1, Silica-CS 20 g, 30 mL/min, silica gel, UV 254) to afford the product (1.5 g, 82 %). ^JH NMR (400 MHz, Chloroform-d) 5 8.06 (dd, J= 6.0, 2.0 Hz, 1H).

5-Bromo-2-chloro-3,4-difluoroaniline

To a solution of l-bromo-4-chloro-2,3-difhioro-5-nitrobenzene (1.50 g, 5.51 mmol) in acetic acid (15 mL) iron (922 mg, 16.5 mmol) was added and the mixture was stirred 2 h at 65 °C. The mixture was filtered, concentrated, and purified by column chromatography (PE/EtOAc=l/0~l/l, Silica-CS 40 g, 40 mL/min, silica gel, UV 254) to afford the product (1.2 g, 90 %). ESLMS m/z calcd for [CeHsBrQN] [M+H]⁺: 241.9; found: 242.0. ^XH NMR (400 MHz, Chloroform-d) 5 6.73 (dd, J= 5.6, 2.4 Hz, 1H), 4.06 (br s, 2H).

7-Bromo-4-chloro-5,6-difluoro-l,3-benzothiazol-2-amine

To a solution of 5-bromo-2-chloro-3,4-difluoroaniline (500 mg, 2.06 mmol) in acetic acid (10 mL) potassium thiocyanate (802 mg, 8.25 mmol) was added followed by dropwise addition of bromine (0.211 mL, 4.12 mmol). The mixture was stirred 16 h at rt and concentrated to dryness. Aq NaHCCL (30 mL) was added, and the mixture was extracted with EtOAc (3 x 20 mL). The combined organic phases were washed with brine (20 mL), dried over Na2SO4, evaporated, and purified by column chromatography (EtOAc/PE = 0/1— 1/1, Silica-CS 40 g, 40 mL/min, silica gel, LTV 254) to afford the product (299 mg, 48 %). ESI-MS m/z calcd for [C₇H2BrClF2N₂S] [M+H]⁺: 298.9; found: 299.0. ¹ H NMR (400 MHz, DMSO-d₆) 8 8.24 (s, 2H).

7-Bromo-4-chloro-5,6-difluoro-l,3-benzothiazole

To a solution of 7-bromo-4-chloro-5,6-difluoro-l,3-benzothiazol-2-amine (299 mg, 1.00 mmol) in DMF (3 mL) isoamyl nitrite (234 mg, 2.00 mmol) was added and the mixture was stirred 1 h at 80 °C. The mixture was concentrated and dissolved in EtOAc (20 mL). The organic phase was washed with water and brine, dried over Na₂SO4, evaporated, and purified by column chromatography (PE/EtOAc = 1/0— 2/1, Silica-CS 20 g, 20 mL/min, silica gel, UV 254) to afford the product (196 mg, 69 %). 'H NMR (400 MHz, DMSO-de) 6 9.64 (s, 1H).

Intermediate 68

4-Chloro-2,3-difluoro-6-nitroaniline

To a solution of 2,3-difluoro-6-nitroaniline (2.00 g, 11.5 mmol) in DMF (30 mL) A- chlorosuccinimide (3.07 g, 23.0 mmol) was added and the mixture was stirred 36 h at rt. The mixture was poured into water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic phases were washed with water (50 mL) and brine (50 mL), dried over Na₂SO4, evaporated, and purified by column chromatography (PE/EtOAc=l/0~l/l, Silica-CS 40 g, 40 mL/min, silica gel, UV 254) to afford the product (1.70 g, 71 %). 'H NMR (400 MHz, DMSO-d₆) 6 8.09 (dd, J = 7.2, 2.0 Hz, 1H), 7.69 (s, 2H). 2-Bromo-5-chloro-3,4-difluoro-l-nitrobenzene

A mixture of CuBr2 (1.19 g, 5.32 mmol) and tert-butyl nitrite (805 mg, 7.81 mmol) in MeCN (7 mL) was stirred 10 min at 60 °C. A solution of 4-chloro-2,3-difluoro-6- nitroaniline (740 mg, 3.55 mmol) in MeCN (10 mL) was added dropwise and the mixture was stirred 30 min at 60 °C. The mixture was cooled to rt, HC1 (1 M) was added, and the mixture was extracted with EtOAc. The organic phase was dried, evaporated, and purified by column chromatography (PE/EtOAc=l/0~l/l, Silica-CS 40 g, 40 mL/min, silica gel, UV 254) to afford the product (546 mg, 57 %). ^JH NMR (400 MHz, DMSO-de) 8 8.44 (dd, J= 6.4, 2.4 Hz, 1H).

2-Bromo-5-chloro-3,4-difluoroaniline

A solution of 2-bromo-5-chloro-3,4-difluoro-l-nitrobenzene (546 mg, 2.00 mmol) and iron (561 mg, 10.0 mmol) in acetic acid (10.0 mL) was stirred 3 h at 85 °C. The mixture was filtered through a celite pad, concentrated, and purified by column chromatography (PE/EtOAc= I/O- 10/1, Silica-CS 20 g, 20 mL/min, silica gel, UV 254) to afford the product (395 mg, 81 %). 'H NMR (400 MHz, DMSO-d₆) 6 6.76 (dd, J = 6.4, 2.0 Hz, 1H), 5.79 (s, 2H).

4-Bromo-7-chloro-5,6-difluoro-l,3-benzothiazol-2-amine

To a solution of 2-bromo-5-chloro-3,4-difluoroaniline (376 mg, 1.55 mmol) in acetic acid (5 mL) potassium thiocyanate (603 mg, 6.20 mmol) was added followed by dropwise addition of a solution of bromine (0.159 mL, 3.10 mmol) in acetic acid (1 mL). The mixture was stirred 16 h at rt and concentrated to dryness. Aq NaHCCL (100 mL) was added, and the mixture was extracted with EtOAc (3 x 50 mL). The combined organic phases were washed with brine (50 mL), dried over Na2SO4, evaporated, and purified by column chromatography (EtOAc/PE=0/l~l/10, Silica-CS 12 g, 15 mL/min, silica gel, UV 254) to afford the product (112 mg, 24 %). ¹ H NMR (400 MHz, DMSO- d₆) 8 8.27 (s, 2H).

4-Bromo-7-chloro-5,6-difluoro-l,3-benzothiazole

To a solution of 4-bromo-7-chloro-5,6-difluoro-l,3-benzothiazol-2-amine (112 mg, 0.37 mmol) in DMF (2 mL) isoamyl nitrite (87.6 mg, 0.75 mmol) was added and the mixture was stirred 1 h at 80 °C. The mixture was concentrated and dissolved in EtOAc (20 mL). The organic phase was washed with water and brine, dried over Na2SO4, evaporated, and purified by column chromatography (PEZEtOAc= I/O- 10/1, Silica-CS 12 g, 15 mL/min, silica gel, UV 254) to afford the product (46 mg, 43 %). 'H NMR (400 MHz, Chloroform-d) 6 9.07 (s, 1H).

Intermediate 69 l-{5-[3-(4-Borono-LH-l,2-pyrazol-l-yl)-3-deoxy-p-D-galactopyranosyl]-3-methyl- 1H-1 ,2,4-triazol-l-yl}-5-chloro-4-fluoro-2-(trifluoromethyl)benzene

To a solution of 5-chloro-l-{5-[3-deoxy-3-(4-iodo-U/-l,2-pyrazol-l-yl)-P-D- galactopyranosyl)-3 -methyl- 1H- 1,2, 4-tri azol- l-yl]-4-fluoro-2-

(trifluoromethyl)benzene (50 mg, 0.081 mmol) and bis(pinacolato)diboron (87.6 mg, 0.35 mmol) in DMSO (4.0 mL) Pd(dppf)C12 (16.8 mg, 0.023 mmol) and potassium acetate (56.4 mg, 0.58 mmol) were added. The mixture was purged three times with nitrogen, and stirred 3 h at 70 °C. The mixture was filtered and purified by reversed- phase chromatography (MeCN/fhO (0.05 % TFA) = 0-30%, C-18 column, 20 mL/min, UV 214) to afford the product (33 mg, 41 %). ESI-MS m/z calcd for [C19H19BCIF4N5O6] [M+H]⁺: 536.1; found: 536.2.

Intermediate 71

2-(Trifluoromethyl)-5-(methylthio)pyridin-3-amine

To a solution of 5-bromo-2-(trifluoromethyl)pyridin-3-amine (500 mg, 2.07 mmol) in DMF (5 mL) NaSMe (290 mg, 4.15 mmol) was added and the mixture was stirred overnight at rt. The mixture was concentrated and purified by column chromatography (EtOAc/PE = 0/1— 8/1, Silica-CS 20 g, 20 mL/min, silica gel, LTV 254) to afford the product (252 mg, 58 %). 'H NMR (400 MHz, DMSO-d₆) 8 7.83 (d, J = 1.6 Hz, 1H), 6.79 (d, J= 1.2 Hz, 1H), 4.14 (s, 2H), 2.43 (s, 3H).

[2-(Trifluoromethyl)-5-(methylthio)pyrid-3-yl]hydrazine

To a cooled (-5 °C) solution of 2-(trifluoromethyl)-5-(methylthio)pyridin-3-amine (100 mg, 0.48 mmol) in concentrated HC1 (9.0 mL) a solution of NaNCL (50 mg, 0.72 mmol) in water (2.0 mL) was added and the mixture was stirred 1 h at -5 °C. Tin(II) chloride dihydrate (325 mg, 1.44 mmol) dissolved in concentrated HC1 (2.0 mL) was added dropwise at 0 °C. The resulting mixture was stirred 1 h at -5 °C. Water (30 mL) was added and the pH was adjusted to 10 by dropwise addition of aq NaOH (5 M). The aqueous phase was extracted with EtOAc (2 x 50 mL). The combined organic phases were washed with water (50 mL) and brine (50 mL), dried over ISfeSCL, evaporated, and purified by column chromatography (EtOAc/PE = 0/1— 4/1, Silica-CS 20 g, 30 mL/min, silica gel, UV 254) to afford the product (35 mg, 33 %). ESLMS m/z calcd for [C7H₈F₃N₃S] [M+H]⁺: 224 0; found: 224 2 3-[5-(3-Azido-4,6-O-benzylidene-3-deoxy-p-D-galactopyranosyl)-3-methyl-LH- l,2,4-triazol-l-yl]-2-(trifluoromethyl)-5-(methylthio)pyridine

To a solution of 2,6-anhydro-4-azido-5,7-O-benzylidene-4-deoxy-D-glycero-L-manno- 7V-[l-(dimethylamino)ethylidene]heptonamide (371 mg, 0.95 mmol) in 1,4-di oxane (6 mL) and acetic acid (3 mL) [2-(trifluoromethyl)-5-(methylthio)pyrid-3-yl]hydrazine (255 mg, 1.14 mmol) was added and the mixture was stirred 2 h at 60 °C. The mixture was concentrated, DCM (10 mL) was added, and the mixture was washed with aq NaHCCh (10 mL) and brine (10 mL). The organic phase was dried over ISfeSCL, evaporated, and purified by column chromatography (DCM/EtOAc=l/0~l/2, Silica-CS 40 g, 40 mL/min, silica gel, UV 254) to afford the product (312 mg, 33 %). ESLMS m/z calcd for [C23H22F3N7O4S] [M+H]⁺: 550.1; found: 550.2.

3-|5-(3-Aiiiino-4.6-6M)enzylidene-3-deoxy-|Ll)-«alactopyranosyl)-3-methyl-l//- l,2,4-triazol-l-yl]-2-(trifluoromethyl)-5-(methylthio)pyridine

To a solution of 3-[5-(3-azido-4,6-O-benzylidene-3-deoxy-P-D-galactopyranosyl)-3- methyl-U/-l,2,4-triazol-l-yl]-2-(trifluoromethyl)-5-(methylthio)pyridine (312 mg, 0.57 mmol) in THF/water (6 mL, 5: 1) triphenylphosphine (745 mg, 2.84 mmol) was added and the mixture was stirred overnight at 50 °C. The mixture was concentrated and purified by column chromatography (DCM/MeOH= I/O- 10/1, Silica-CS 4 g, 12 mL/min, silica gel, UV 254) to afford the product (105 mg, 35 %). ESLMS m/z calcd for [C23H24F3N5O4S] [M+H]⁺: 524.1; found: 524.2. 'H NMR (400 MHz, Chloroform- d) 5 8.57 (d, J= 2.0 Hz, 1H), 7.58 (d, J= 2.0 Hz, 1H), 7.41 - 7.38 (m, 2H), 7.35 - 7.34 (m, 3H), 5.44 (s, 1H), 4.32 (d, J = 92 Hz, 1H), 4.11 (d, J= 2.8 Hz, 1H) , 3.94 (t, J = 9.2 Hz, 1H), 3.86 (dd, J= 12.8, 1.6 Hz, 1H), 3.49 (d, J = 12.8 Hz, 1H), 3.30 (s, 1H), 2.87 (d, J= 92 Hz, 1H), 2.44 (s, 3H), 2.41 (s, 3H).

3-[5-(4,6-O-Benzylidene-3-[(2-tert-butoxycarbonyl)hydrazinyl]-3-deoxy-p-D- galactopyranosyl)-3-methyl- 1H- 1 ,2,4-triazol- 1-yl] -2-(tr ifluoromethyl)-5- (methylthio)pyridine

To a solution of 3-[5-(3-amino-4,6-O-benzylidene-3-deoxy-P-D-galactopyranosyl)-3- methyl-lJ/-l,2,4-triazol-l-yl]-2-(trifluoromethyl)-5-(methylthio)pyridine (105 mg, 0.20 mmol) in DCM (4 mL) 7V-tert-butyloxycarbonyl-3-(4-cyanophenyl)oxaziridine (59.3 mg, 0.24 mmol) was added and the mixture was stirred overnight at rt. The mixture was concentrated and purified by column chromatography (EtOAc/PE = ’Zi-l/O, Silica-CS 4 g, 12 mL/min, silica gel, UV 254) to afford the product (22 mg, 17 %). ESI-MS m/z calcd for [C28H33F3N6O6S] [M+H]⁺: 639.2; found: 639.2. 'H NMR (400 MHz, Chloroform-d) 5 8.47 (d, J= 1.6 Hz, 1H), 7.51 (d, J= 1.6 Hz, 1H), 7.33 - 7.31 (m, 2H), 7.27 - 7.22 (m, 3H), 5.37 (s, 1H), 4.31 (d, J = 9.2 Hz, 1H), 4.23 (d, J = 2.8 Hz, 1H), 4.14 (t, J = 10.0 Hz, 1H), 3.80 (d, J= 11.2 Hz, 1H), 3.51 - 3.48 (m, 1H), 3.22 (s, 1H), 3.03 - 3.00 (m, 1H), 2.37 (s, 3H), 2.32 (s, 3H), 1.38 (s, 9H).

Intermediate 73

5-Bromo-6-methyl-3-nitropyridin-2-amine

To a cooled (0 °C) solution of 5-bromo-6-methylpyridin-2-amine (5.0 g, 26.7 mmol) in H2SO4 (20 mL) KNO3 (4.05 g, 40.1 mmol) was added in small portions over 10 min. The mixture was warmed to rt and stirred 2 h. The mixture was slowly added to water (150 mL), basified by addition of NaOH (IN) to pH=10, and filtered. The filter cake was washed with water (3 x 50 mL) and dried in vacuo to afford the product (2.52 g, 41 %). ESLMS m/z calcd for [CeHeBrNsCh] [M+H]⁺: 232.0; found: 232.0. 'H NMR (400 MHz, DMSO-de) 8 8.45 (s, 1H), 8.03 (br s, 2H), 2.49 (s, 3H).

2,5-Dibromo-6-methyl-3-nitropyridine

To a solution of 5-bromo-6-methyl-3-nitropyridin-2-amine (2.5 g, 10.8 mmol) in MeCN (30 mL) tert-butyl nitrite (2.22 g, 21.5 mmol) and CuBr2 (2.89 g, 12.9 mmol) were added and the mixture was stirred 2 h at 60 °C. The mixture was concentrated and purified by column chromatography (DCM/PE=0~50%, Silica-CS 80 g, 40 mL/min, silica gel, UV 254) to afford the product (1.60 g, 50 %). 'H NMR (400 MHz, Chloroform-d) 5 8.24 (s, 1H), 2.68 (s, 3H).

5-Bromo-2-(trifluoromethyl)-6-methyl-3-nitropyridine

To a solution of 2,5-dibromo-6-methyl-3-nitropyridine (1.60 g, 5.41 mmol) in DMF (15 mL) methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (1.69 g, 8.78 mmol) and Cui (836 mg, 4.39 mmol) were added and the mixture was stirred 3 h at 90 °C. After cooling to rt, the mixture was poured into saturated aq NaHCCL (200 mL) and extracted with DCM (2 x 100 mL). The combined organic phases were washed with brine (3 xlOO mL), dried over ISfeSCL, evaporated, and purified by column chromatography (DCM/PE=0/l~l/2, Silica-CS 40 g, 40 mL/min, silica gel, UV 254) to afford the product (1.02 g, 66 %). *H NMR (400 MHz, Chloroform-d) 5 8.28 (s, 1H), 2.76 (s, 3H).

5-Bromo-2-(trifluoromethyl)-6-methylpyridin-3-amine

To a solution of 5-bromo-2-(trifluoromethyl)-6-methyl-3-nitropyridine (1.0 g, 3.51 mmol) in EtOH (15 mL) and H2O (3 mL) iron (980 mg, 17.5 mmol) and NH4CI (938 mg, 17.5 mmol) were added and the mixture was stirred 5 h at 80 °C. The mixture was filtered through a celite pad, concentrated, and purified by column chromatography (DCM/PE=0~50%, Silica-CS 40 g, 40 mL/min, silica gel, UV 254) to afford the product (660 mg, 74 %). ESI-MS m/z calcd for [C7H₆BrF₃N2] [M+H]⁺: 255.0; found: 255.9. 'H NMR (400 MHz, Chloroform-d) 5 7.23 (s, 1H), 4.04 (br s, 2H), 2.49 (s, 3H).

[5-Bromo-2-(trifluoromethyl)-6-methylpyrid-3-yl]hydrazine

To a cooled (0 °C) solution of 5-bromo-2-(trifluoromethyl)-6-methylpyridin-3-amine (660 mg, 2.59 mmol) in concentrated HC1 (15 mL) and acetic acid (3 mL) a solution of NaNCL (268 mg, 3.88 mmol) in water (2 mL) was added dropwise. The resulting mixture was stirred 1 h at 0 °C. Tin(II) chloride dihydrate (1.75 g, 7.76 mmol) dissolved in concentrated HC1 (5 mL) was added slowly at 0 °C. The resulting mixture was stirred 2 h at rt. The mixture was basified to pH 10 using aq NaOH (1 M). Water (100 mL) and DCM (100 mL) were added, and the aqueous phase was extracted with DCM (2 x 50 mL). The combined organic phases were washed with water (50 mL) and brine (2 x 50 mL), dried over ISfeSCL, evaporated, and purified by column chromatography (DCM/PE=0~50%, Silica-CS 20 g, 40 mL/min, silica gel, UV 254) to afford the product (350 mg, 50 %). ESLMS m/z calcd for [C7H₇BrF₃N3] [M+H]⁺: 270.0; found: 270.0. 'H NMR (400 MHz, Chloroform-d) 5 7.96 (s, 1H), 5.77 (s, 1H), 3.60 (s, 2H), 2.50 (s, 3H).

3-|5-(3-Azido-4.6-6M)enzylidene-3-deoxy-|Ll)-«alactopyranosyl)-3-methyl-l//- l,2,4-triazol-l-yl]-5-bromo-2-(trifluoromethyl)-6-methylpyridine

To a solution of 2,6-anhydro-4-azido-5,7-O-benzylidene-4-deoxy-D-glycero-L-manno- heptonamide (370 mg, 1.16 mmol) in 1,4-dioxane (10 mL) MA-di methyl acetamide dimethyl acetal (308 mg, 2.31 mmol) was added and the mixture was stirred 12 h at 50 °C. The mixture was evaporated, and the residue was dissolved in 1,4-dioxane (9 mL) and acetic acid (3 mL). To this solution [5-bromo-2(trifluoromethyl)-6-methylpyrid-3- yl]hydrazine (328 mg, 1.21 mmol) was added and the mixture was stirred 2 h at 60 °C. The mixture was cooled to rt, saturated aq NaHCCL (100 mL) was added and the mixture was extracted DCM (3 x 50 mL). The combined organic phases were washed with brine (2 x 50 mL), dried over ISfeSCU, evaporated, and purified by column chromatography (DCM/EtOAc=l/0~l/2, Silica-CS 40 g, 40 mL/min, silica gel, UV 254) to afford the product (350 mg, 70 % purity, 36 %). ESLMS m/z calcd for [C₂3H2iBrF₃N7O4] [M+H]⁺: 596.1; found: 596.1.

3-|5-(3-Aiiiino-4.6-6M)enzylidene-3-deoxy-|Ll)-«alactopyranosyl)-3-methyl-l//- l,2,4-triazol-l-yl]-5-bromo-2-(trifluoromethyl)-6-methylpyridine

To a solution of 3-[5-(3-azido-4,6-O-benzylidene-3-deoxy-P-D-galactopyranosyl)-3- methyl-U/-l,2,4-triazol-l-yl]-5-bromo-2-(trifluoromethyl)-6-methylpyridine (350 mg, 70 % purity, 0.41 mmol) in THF (15 mL) triphenylphosphine (539 mg, 2.05 mmol) and water (1.5 mL) were added and the mixture was stirred 12 h at 50 °C. The mixture was concentrated and purified by column chromatography (DCM/MeOH= I/O- 10/1, Silica- CS 20 g, 40 mL/min, silica gel, UV 254) to give the product (170 mg, 73 %). ESLMS m/z calcd for ^slfeBrFsNsCU] [M+H]⁺: 570.1; found: 570.2. 'H NMR (400 MHz, Chloroform-d) 5 7.99 (s, 1H), 7.34 - 7.28 (m, 5H), 5.37 (s, 1H), 4.22 (d, J = 9.2 Hz, 1H), 4.08 - 4.03 (m, 1H), 3.89 - 3.81 (m, 2H), 3.56 (dd, J= 12.8, 1.2 Hz, 1H), 3.26 (d, J= 0.8 Hz, 1H), 2.78 (dd, J= 9.6, 3.2 Hz, 1H), 2.68 (s, 3H), 2.36 (s, 3H).

3-{5-{4,6-(?-Benzylidene-3-[(2-tert-butoxycarbonyl)hydrazinyl]-3-deoxy-p-D- galactopyranosyl}-3-methyl-lZ7-l,2,4-triazol-l-yl}-5-bromo-2-(trifluoromethyl)- 6-methylpyridine

To a solution of 3-[5-(3-amino-4,6-O-benzylidene-3-deoxy-P-D-galactopyranosyl)-3- methyl-U/-l,2,4-triazol-l-yl]-5-bromo-2-(trifluoromethyl)-6-methylpyridine (170 mg, 0.30 mmol) in DCM (15 mL) 7V-tert-butyloxycarbonyl-3-(4-cyanophenyl)oxaziridine (138 mg, 0.45 mmol) was added and the mixture was stirred overnight at rt. The mixture was concentrated and purified by column chromatography (DCM/EtOAc=0~100%, Silica-CS 20 g, 40 mL/min, silica gel, UV 254) to afford the product (110 mg, 54 %). ESI-MS m/z calcd for ^^BrFsNeOe] [M+H]⁺: 685.2; found: 685.2. 'HNMR (400 MHz, Chloroform-d) 5 7.99 (s, 1H), 7.33 - 7.37 (m, 5H), 6.38 (s, 1H), 5.37 (s, 1H), 4.54 (s, 1H), 4.45 (s, 1H), 4.30 (d, J= 9.2 Hz, 1H), 4.23 (d, J = 2.4 Hz, 1H), 4.15 - 4.11 (m, 1H), 3.83 (dd, J= 12.4, 1.6 Hz, 1H), 3.63 (d, J= 12.4 Hz, 1H), 3.25 (s, 1H), 2.99 - 2.97 (m, 1H), 2.62 (s, 3H), 2.36 (s, 3H), 1.38 (s, 9H).

Intermediate 74

4-Chloro-2-fluoro-6-nitroaniline

To a solution of 2-fluoro-6-nitroaniline (5.00 g, 32.0 mmol) in DMF (30 mL) N- chlorosuccinimide (5.13 g, 38.4 mmol) was added and the mixture was stirred 16 h at rt. The mixture was diluted with water (100 mL) and the precipitate was filtered off. The obtained solid was washed with water and dried in vacuum to afford the product (4.30 g, 71 %). 'H NMR (400 MHz, DMSO-d₆) 8 7.86 (t, J= 2.0 Hz, 1H), 7.69 (dd, J = 6.4, 2.4 Hz, 1H), 7.46 (s, 2H).

2-Bromo-5-chloro-l-fluoro-3-nitrobenzene

A mixture of copper(II) bromide (7.03 g, 31.5 mmol) and tert-butyl nitrite (4.76 g, 46.2 mmol) in MeCN (30 mL) was stirred 10 min at 60 °C. A solution of 4-chloro-2-fluoro- 6-nitroaniline (4.00 g, 21.0 mmol) in MeCN (40 mL) was added and the mixture was stirred 30 min at 60 °C. After cooling to rt, I N HC1 (30 mL) was added, and the mixture was extracted with EtOAc (2 x 30 mL). The combined organic phases were washed with saturated aq NaHCOs and brine, dried, concentrated, and purified by column chromatography (PEZEtOAc = 1/0-10/1, silica-CS 40 g, 40 mL/min, silica gel, UV 254 nm) to afford the product (3.80 g, 71 %). ¹ H NMR (400 MHz, DMSO-d₆) 6 8.17 (t, J = 2.0 Hz, 1H), 8.06 (dd, J= 8.4, 2.4 Hz, 1H).

5-Chloro-l-fluoro-2-(trifluoromethyl)-3-nitrobenzene

A mixture of 2-bromo-5-chloro-l-fluoro-3-nitrobenzene (2.00 g, 7.86 mmol), methyl 2,2-difluoro-2-fluorosulfonylacetate (2.27 g, 11.8 mmol) and Cui (1.79 g, 9.43 mmol) in DMF (20 mL) was stirred 2 h at 90 °C. After cooling to rt, the mixture was poured into water (50 mL) and then extracted with EtOAc (2 x 30 mL). The combined organic phases were washed with water (20 mL) and brine (20 mL), dried over ISfeSCU, concentrated, and purified by column chromatography (EtOAc/PE = 0/1-1/10, Silica- CS 40 g, 40 mL/min, silica gel, UV 254) to afford the product (1.7 g, 89 %). 'H NMR (400 MHz, DMSO-de) 6 8.30 (s, 1H), 8.25 (d, J= 10.8 Hz, 1H).

5-Chloro-3-fluoro-2-(trifluoromethyl)aniline

A solution of 5-chloro-l-fluoro-2-(trifluoromethyl)-3-nitrobenzene (1.91 g, 7.84 mmol) and Fe (2.20 g, 39.2 mmol) in acetic acid (20 mL) was stirred 3 h at 85 °C. The mixture was filtered through a celite pad, concentrated, and purified by column chromatography (EtOAc/PE = 0/1-1/10, Silica-CS 40 g, 40 mL/min, silica gel, UV 254) to afford the product (1.5 g, 90 %). ¹ H NMR (400 MHz, DMSO-d₆) 6 6.73 (s, 1H), 6.61 (d, J= 11.2 Hz, 1H), 6.27 (s, 2H).

[5-Chloro-3-fluoro-2-(trifluoromethyl)phenyl]hydrazine

To a cooled (-5 °C) solution of 5-chloro-3-fluoro-2-(trifluoromethyl)aniline (800 mg, 3.75 mmol) in acetic acid (8 mL) and concentrated HC1 (8 mL) a solution of NaNCL (310 mg, 4.50 mmol) in water (2.0 mL) was added. The mixture was stirred 1 h at -5 °C. Then a solution of tin(II) chloride dihydrate (1.86 g, 8.22 mmol) dissolved in concentrated HC1 (8.0 mL) was added and the mixture was stirred 3 h at -5 °C. The mixture was extracted with tert-butyl methyl ether (20 mL). The aqueous phase was basified to pH=10 by addition of NaOH (1 M) and extracted with EtOAc (2 x 25 mL). The combined organic phases were dried over Na2SO4, evaporated, and purified by column chromatography (PE/EtOAc = 1/0— 5/1, silica-CS 20 g, 20 mL/min, silica gel, UV 254 nm) to afford the product (115 mg, 13 %). 'H NMR (400 MHz, DMSO-d₆) 8 7.45 (s, 1H), 7.30 (s, 1H), 6.68 (dd, J= 11.6, 1.6 Hz, 1H), 4.38 (br s, 2H). l-|5-(3-Azido-4.6-rt-benzylidene-3-deoxy-|Ll)-«alactopyranosyl)-3-niethyl-l//- l,2,4-triazol-l-yl]-5-chloro-3-fluoro-2-(trifluoromethyl)benzene

To a solution of 2,6-anhydro-4-azido-5,7-O-benzylidene-4-deoxy-D-glycero-L-manno- 7V-[l-(dimethylamino)ethylidene]heptonamide (300 mg, 0.77 mmol) in 1,4-dioxane (5 mL) and acetic acid (1.75 mL) [5-chloro-3-fluoro-2-(trifluoromethyl)phenyl]hydrazine (194 mg, 0.85 mmol) was added and the mixture was stirred 3 h at 60 °C. The mixture was concentrated, DCM (20 mL) was added, and the mixture was washed with aq NaHCCL. The organic phase was dried, evaporated, and purified by column chromatography (EtOAc/PE=0/l~l/0, Silica-CS 40 g, 40 mL/min, silica gel, UV 254) to afford the product (173 mg, 41 %). ESLMS m/z calcd for [C23H19CIF4N6O4] [M+H]⁺: 555.1; found: 555.1. l-[5-(3-Amino-4,6-O-benzylidene-3-deoxy-p-D-galactopyranosyl)-3-methyl-LH- l,2,4-triazol-l-yl]-5-chloro-3-fluoro-2-(trifluoromethyl)benzene

To a solution of l-[5-(3-azido-4,6-O-benzylidene-3-deoxy-P-D-galactopyranosyl)-3- methyl-lJ/-l,2,4-triazol-l-yl]-5-chloro-3-fluoro-2-(trifluoromethyl)benzene (173 mg, 0.31 mmol) in THF (5.0 mL) and water (1.0 mL) triphenylphosphine (245 mg, 0.94 mmol) was added and the mixture was stirred overnight at 50 °C. The mixture was concentrated and purified by column chromatography (DCM/MeOH= I/O- 10/1, Silica- CS 12 g, 20 mL/min, silica gel, UV 254) to afford the product (146 mg, 89 %). ESIMS m/z calcd for [C23H21CIF4N4O4] [M+H]⁺: 529.1; found: 529.2. 'HNMR (400 MHz, Chloroform-d) 5 7.29 - 7.14 (m, 7H), 5.36 (s, 1H), 4.26 (d, J = 8.0 Hz, 1H), 4.05 (s, 1H), 3.84 - 3.81 (m, 2H), 3.70 - 3.67 (m, 1H), 3.37 (s, 1H), 3.28 (s, 1H), 2.93 - 2.83 (m, 3H), 2.33 (s, 3H). !-{5-{4,6-(?-Benzylidene-3-[(2-tert-butoxycarbonyl)hydrazinyl]-3-deoxy-p-D- galactopyranosyl}-3-methyl-lH-l,2,4-triazol-l-yl}-5-chloro-3-fluoro-2-

(trifluoromethyl)benzene

To a solution of l-[5-(3-amino-4,6-O-benzylidene-3-deoxy-P-D-galactopyranosyl)-3- methyl-lJ/-l,2,4-triazol-l-yl]-5-chloro-3-fluoro-2-(trifluoromethyl)benzene (146 mg, 0.28 mmol) in DCM (10 mL) 7V-tert-butyloxycarbonyl-3-(4-cyanophenyl)oxaziridine (82 mg, 0.33 mmol) was added and the mixture was stirred overnight at rt. The mixture was concentrated and purified by column chromatography (PEZEtOAc=4/ 1-0/1, Silica- CS 20 g, 25 mL/min, silica gel, UV 254) to afford the product (83 mg, 47 %). ESI-MS m/z calcd for [C28H30CIF4N5O6] [M+H]⁺: 644.2; found: 644.2. 'H NMR (400 MHz, Chloroform-d) 5 7.31 - 7.27 (m, 5H), 7.24 (s, 1H), 7.06 (br s, 1H), 6.44 (br s, 1H), 5.36 (s, 1H), 4.35 (d, J = 9.2 Hz, 1H), 4.21 (d, J = 2.4 Hz, 1H), 4.10 - 4.06 (m, 1H), 3.84 (d, J= 11.2 Hz, 1H), 3.75 - 3.72 (m, 1H), 3.27 (d, J= 0.8 Hz, 1H), 2.98 - 2.96 (m, 1H), 2.35 (s, 3H), 1.38 (s, 9H).

Intermediate 75

2-Bromo-l,5-dichloro-3-nitrobenzene

A mixture of copper(II) bromide (1.62 g, 7.25 mmol) and tert-butyl nitrite (1.10 g, 10.6 mmol) in MeCN (10 mL) was stirred 10 min at 60 °C. A solution of 2,4-dichloro-6- nitroaniline (1.0 g, 4.83 mmol) in MeCN (10 mL) was added and the mixture was stirred 30 min at 60 °C. After cooling to rt, 1 N HC1 (30 mL) was added, and the mixture was extracted with EtOAc (2 x 30 mL). The combined organic phases were washed with saturated aq NaHCCL and brine, dried, concentrated, and purified by column chromatography (PEZEtOAc = 1/0-10/1, silica-CS 20 g, 20 mL/min, silica gel, UV 254 nm) to afford the product (1.3 g, 99 %). ESI-MS m/z calcd for [CeEhBrChNCh] [M]: 268.9; found: 269.0. 'H NMR (400 MHz, Chloroform-d) 5 7.62 (d, J = 2.4 Hz, 1H), 7.56 (d, .7= 2.4 Hz, 1H). l,5-Dichloro-2-(trifluoromethyl)-3-nitrobenzene

A mixture of 2-bromo-l,5-dichloro-3-nitrobenzene (1.59 g, 5.87 mmol), methyl 2,2- difluoro-2 -fluorosulfonylacetate (1.35 g, 7.04 mmol) and Cui (1.34 g, 7.04 mmol) in DMF (20 mL) was stirred 2 h at 100 °C. After cooling to rt, the mixture was poured into water (50 mL) and then extracted with EtOAc (2 x 30 mL). The combined organic phases were washed with water (20 mL) and brine (20 mL), dried over Na2SO4, concentrated, and purified by column chromatography (EtOAc/PE = 0/1-1/10, Silica- CS 40 g, 30 mL/min, silica gel, UV 254) to afford the product (1.4 g, 92 %). ESI-MS m/z calcd for [C7H2CI2F3NO2] [M]: 258.9; found: 259.0. 'H NMR (400 MHz, Chloroform-d) 5 7.65 (d, J= 1.6 Hz, 1H), 7.41 (d, J= 1.6 Hz, 1H).

3,5-Dichloro-2-(trifluoromethyl)aniline

A solution of l,5-dichloro-2-(trifluoromethyl)-3-nitrobenzene (1.28 g, 4.92 mmol), NH4CI (1.58 g, 29.5 mmol) and Fe (1.37 g, 24.6 mmol) in EtOH (20 mL) and water (4.0 mL) was stirred 3 h at 85 °C. The mixture was concentrated and purified by column chromatography (EtOAc/PE = 0/1-1/5, Silica-CS 20 g, 20 mL/min, silica gel, UV 254) to afford the product (780 mg, 69 %). ESI-MS m/z calcd for [C7H4Q2F3N] [M]: 229.0; found: 229.0. ^XH NMR (400 MHz, Chloroform-d) 5 6.75 (dd, J= 2.0, 0.8 Hz, 1H), 6.53 (dd, J= 2.0, 0.8 Hz, 1H), 4.44 (s, 2H).

[3,5-Dichloro-2-(trifluoromethyl)phenyl]hydrazine

To a cooled (-5 °C) solution of 3,5-dichloro-2-(trifluoromethyl)aniline (780 mg, 3.39 mmol) in concentrated HC1 (3.0 mL) a solution of NaNCL (304 mg, 4.41 mmol) in water (1.0 mL) was added. The mixture was stirred 30 min at -5 °C. Then a solution of tin(II) chloride dihydrate (1.53 g, 6.78 mmol) dissolved in concentrated HC1 (1.0 mL) was added and the mixture was stirred 2 h at -5 °C. The mixture was diluted with water (20 mL) and basified to pH=8 by addition of saturated aq NaHCCL. The mixture was extracted with EtOAc (2 x 20 mL). The combined organic phases were washed with water (20 mL) and brine (20 mL), dried over ISfeSCL, evaporated, and purified by column chromatography (PE/EtOAc=l/0~5/l, silica-CS 20 g, 20 mL/min, silica gel, UV 254 nm) to afford the product (332 mg, 40 %). ESLMS m/z calcd for [C7H5Q2F3N2] [M+H]⁺: 245.0; found: 245.1. *H NMR (400 MHz, Chloroform-d) 5 7.36 (d, J= 1.6 Hz, 1H), 6.77 (d, J= 1.6 Hz, 1H), 6.27 (s, 1H), 3.57 (br s, 2H). l-|5-(3-Azido-4.6-6M)eiizylideiie-3-deoxy-|Ll)-«:il:ictopyranosyl)-3-inethyl-l//- l,2,4-triazol-l-yl]-3,5-dichloro-2-(trifluoromethyl)benzene

To a solution of 2,6-anhydro-4-azido-5,7-O-benzylidene-4-deoxy-D-glycero-L-manno- heptonamide (320 mg, 1.00 mmol) in 1,4-dioxane (5.0 mL) A A-di methyl acetamide dimethyl acetal (186 mg, 1.40 mmol) was added and the mixture was stirred 3 h at 50 °C. The mixture was evaporated, and the residue was dissolved in 1,4-dioxane (6.0 mL) and acetic acid (2.0 mL). [3,5-Dichloro-2-(trifluoromethyl)phenyl]hydrazine (269 mg, 1.10 mmol) was added and the mixture was stirred 2 h at 80 °C. The mixture was concentrated, partitioned between water (20 mL) and DCM (20 mL), and the aqueous phase was extracted with DCM (2 x 20 mL). The combined organic phases were washed with water (20 mL) and brine (20 mL), dried, evaporated, and purified by column chromatography (EtOAc/PE=l/5~2/l, Silica-CS 20 g, 30 mL/min, silica gel, UV 254) to afford the product (240 mg, 42 %). ESI-MS m/z calcd for [C23H19CI2F3N6O4] [M+H]⁺: 571.1; found: 571.0. 'HNMR (400 MHz, Chloroform-d) 5 7.48 (s, 1H), 7.35 - 7.25 (m, 6H), 5.40 (s, 1H), 4.44 (s, 1H), 4.39 - 4.29 (m, 2H), 4.14 (d, J= 2.8 Hz, 1H), 3.83 (dd, J = 12.8, 1.2 Hz, 1H), 3.61 (dd, J= 12.8, 0.8 Hz, 1H), 3.36 (dd, J = 9.2, 3.2 Hz, 1H), 3.29 (s, 1H), 2.36 (s, 3H). l-[5-(3-Amino-4,6-O-benzylidene-3-deoxy-p-D-galactopyranosyl)-3-methyl-lZ/- l,2,4-triazol-l-yl]-3,5-dichloro-2-(trifluoromethyl)benzene

To a solution of l-[5-(3-azido-4,6-O-benzylidene-3-deoxy-P-D-galactopyranosyl)-3- methyl-U/-l,2,4-triazol-l-yl]-3,5-dichloro-2-(trifluoromethyl)benzene (240 mg, 0.42 mmol) in THF (10.0 mL) and water (1.0 mL) triphenylphosphine (220 mg, 0.84 mmol) was added and the mixture was stirred overnight at 50 °C. The mixture was concentrated and purified by column chromatography (DCM/MeOH= I/O- 10/1, Silica- CS 12 g, 20 mL/min, silica gel, UV 254) to afford the product (218 mg, 95 %). ESIMS m/z calcd for [C23H21CI2F3N4O4] [M+H]⁺: 545.1; found: 545.2. 'H NMR (400 MHz, Chloroform-d) 5 7.49 (s, 1H), 7.37 (s, 1H), 7.33 - 7.27 (m, 5H), 5.37 (s, 1H), 4.25 (d, J= 9.6 Hz, 1H), 4.04 (s, 1H), 3.88 - 3.77 (m, 2H), 3.68 - 3.58 (m, 1H), 3.32 - 3.23 (m, 1H), 2.84 - 2.72 (m, 1H), 2.35 (s, 3H). l-{5-{4,6-O-Benzylidene-3-[(2-terCbutoxycarbonyl)hydrazinyl]-3-deoxy-p-D- galactopyranosyl}-3-methyl-lEZ-l,2,4-triazol-l-yl}-3,5-dichloro-2-

(trifluoromethyl)benzene

To a solution of l-[5-(3-amino-4,6-(9-benzylidene-3-deoxy-P-D-galactopyranosyl)-3- methyl-17/-l,2,4-triazol-l-yl]-3,5-dichloro-2-(trifluoromethyl)benzene (110 mg, 0.20 mmol) in DCM (10 mL) 7V-tert-butyloxycarbonyl-3-(4-cyanophenyl)oxaziridine (60 mg, 0.24 mmol) was added and the mixture was stirred overnight at rt. The mixture was concentrated and purified by column chromatography (PE/EtOAc=4/ 1-0/1, Silica-CS 20 g, 30 mL/min, silica gel, UV 254) to afford the product (65 mg, 49 %). ESI-MS m/z calcd for [C28H30CI2F3N5O6] [M+H]⁺: 660.2; found: 660.2. 'H NMR (400 MHz, Chloroform-d) 5 7.32 - 7.25 (m, 7H), 6.39 (br s, 1H), 5.36 (s, 1H), 4.60 - 4.44 (m, 1H), 4.36 (d, J= 9.2 Hz, 1H), 4.21 (d, J= 2.4 Hz, 1H), 4.07 - 4.04 (m, 1H), 3.87 - 3.79 (m, 1H), 3.69 (d, J= 12.8 Hz, 1H), 3.28 (s, 1H), 2.98 (dd, J = 10.0, 2.8 Hz, 1H), 2.35 (s, 3H), 1.39 (s, 9H).

Intermediate 76

5-Chloro-2-(trifluoromethyl)-l-methyl-3-nitrobenzene

To a solution of 2-bromo-5-dichloro-l-methyl-3-nitrobenzene (1.1 g, 5.39 mmol) in DMF (15 mL) methyl 2, 2-difluoro-2 -fluorosulfonylacetate (1.69 g, 8.78 mmol) and Cui (836 mg, 4.39 mmol) were added and the mixture was stirred 3 h at 90 °C. After cooling to rt, the reaction mixture was quenched with saturated aq NaHCCL (200 mL) and then extracted with DCM (2 x 100 mL). The combined organic phases were washed with brine (3 x 100 mL), dried over ISfeSCL, concentrated, and purified by column chromatography (DCM/PE = 0/1— 1/2, Silica-CS 40 g, 40 mL/min, silica gel, UV 254) to afford the product (830 mg, 79 %). ESLMS m/z calcd for [C8H5CIF3NO2] [M]: 239.0; found: 239.0. ^XH NMR (400 MHz, Chloroform-d) 5 7.41 (d, J= 0.8 Hz, 1H), 7.34 (d, J = 0.8 Hz, 1H), 2.50 (q, J= 2.4 Hz, 3H). 5-Chloro-2-(trifluoromethyl)-3-methylaniline

To a solution of 5-chloro-2-(trifluoromethyl)-l-methyl-3-nitrobenzene (830 mg, 3.46 mmol) in EtOH (15 mL) and water (3 mL) NH4CI (927 mg, 17.3 mmol) and Fe (967 mg, 17.3 mmol) were added and the mixture was stirred 5 h at 80 °C. The mixture was concentrated and purified by column chromatography (DCM/PE = 0/1— 1/0, Silica-CS 40 g, 40 mL/min, silica gel, UV 254) to afford the product (620 mg, 85 %). ESI-MS m/z calcd for [C₈H₇C1F₃N] [M+H]⁺: 210.0; found: 210.1. 'H NMR (400 MHz, Chloroform-d) 5 6.50 (s, 1H), 6.49 (s, 1H), 4.23 (s, 2H), 2.30 (q, J= 3.2 Hz, 3H).

[5-Chloro-2-(trifluoromethyl)-3-methylphenyl]hydrazine

To a cooled (-5 °C) solution of 5-chloro-2-(trifluoromethyl)-3-methylaniline (730 mg, 3.01 mmol) in concentrated HC1 (8.0 mL) and acetic acid (4.0 mL) a solution of NaNCL (311 mg, 4.51 mmol) in water (2.0 mL) was added dropwise. The mixture was stirred 1 h at -5 °C. Then a solution of tin(II) chloride dihydrate (2.04 g, 9.02 mmol) dissolved in concentrated HC1 (2.0 mL) was added and the mixture was stirred 2 h at -5 °C. The mixture was diluted with water (20 mL) and basified to pH=10 by addition of NaOH (1 M). The mixture was extracted with DCM (3 x 50 mL). The combined organic phases were washed with water (20 mL) and brine (20 mL), dried over Na₃SO4, evaporated, and purified by column chromatography (PE/DCM=l/0~0/l, silica-CS 20 g, 40 mL/min, silica gel, UV 254 nm) to afford the product (270 mg, 40 %). ESLMS m/z calcd for [C₈H₈C1F₃N₂] [M+H]⁺: 225.0; found: 225.1. ^XH NMR (400 MHz, Chloroform- d) 5 7.19 (s, 1H), 6.54 (s, 1H), 6.05 (s, 1H), 3.51 (s, 2H), 2.32 (q, J= 3.6 Hz, 3H). l-[5-(3-Azido-4,6-(?-benzylidene-3-deoxy-p-D-galactopyranosyl)-3-methyl-lH- l,2,4-triazol-l-yl]-5-chloro-2-(trifluoromethyl)-3-methylbenzene

To a solution of 2,6-anhydro-4-azido-5,7-O-benzylidene-4-deoxy-D-glycero-L-manno- heptonamide (400 mg, 1.25 mmol) in 1,4-dioxane (10 mL) M A -di methyl acetamide dimethyl acetal (333 mg, 2.50 mmol) was added and the mixture was stirred 12 h at 50 °C. The mixture was evaporated, and the residue was dissolved in 1,4-dioxane (9.0 mL) and acetic acid (3.0 mL). To this solution [5-chloro-2-(trifluoromethyl)-3- methylphenyl]hydrazine (266 mg, 1.19 mmol) was added and the mixture was stirred 2 h at 60 °C. The reaction mixture was quenched with saturated aq NaHCCL (100 mL) and extracted with DCM (3 x 50 mL). The combined organic phases were washed with brine (2 x 50 mL), dried, evaporated, and purified by column chromatography (EtOAc/DCM=0/ 1-2/1, Silica-CS 40 g, 40 mL/min, silica gel, UV 254) to afford the product (360 mg, 24 %). ESI-MS m/z calcd for [C24H22CIF3N6O4] [M+H]⁺: 551.1; found: 551.2. 'HNMR (400 MHz, Chloroform-d) 5 7.38 - 7.28 (m, 7H), 5.42 (s, 1H), 4.49 - 4.46 (m, 1H), 4.27 - 4.22 (m, 2H), 4.15 - 4.12 (m, 1H), 3.85 - 3.77 (m, 1H), 3.69 - 3.64 (m, 1H), 3.35 (dd, J = 10.0, 3.2 Hz, 1H), 3.24 - 3.22 (m, 1H), 2.48 - 2.44 (m, 3H), 2.36 (s, 3H). l-|5-(3-Aiiiino-4.6-6M)enzylidene-3-deoxy-|Ll)-«alactopyranosyl)-3-methyl-l//- l,2,4-triazol-l-yl]-5-chloro-2-(trifluoromethyl)-3-methylbenzene

To a solution of l-[5-(3-azido-4,6-O-benzylidene-3-deoxy-P-D-galactopyranosyl)-3- methyl-U/-l,2,4-triazol-l-yl]-5-chloro-2-(trifluoromethyl)-3-methylbenzene (240 mg, 0.31 mmol) in THF (10.0 mL) and water (1.0 mL) triphenylphosphine (400 mg, 1.52 mmol) was added and the mixture was stirred 12 h at 50 °C. The mixture was concentrated and purified by column chromatography (DCM/MeOH= I/O- 10/1, Silica- CS 20 g, 40 mL/min, silica gel, UV 254) to afford the product (130 mg, 81 %). ESIMS m/z calcd for [C24H24CIF3N4O4] [M+H]⁺: 525.1; found: 525.2. 'HNMR (400 MHz, DMSO-de) 8 7.46 - 7.37 (m, 7H), 5.44 (s, 1H), 5.22 - 5.17 (m, 1H), 4.27 (d, J = 8.4 Hz, 1H), 4.07 - 3.94 (m, 3H), 3.87 - 3.83 (m, 1H), 3.54 - 3.52 (m, 1H), 2.31 (s, 3H), 2.29 (s, 3H). l-{5-{4,6-O-Benzylidene-3-[(2-tert-butoxycarbonyl)hydrazinyl]-3-deoxy-p-D- galactopyranosyl}-3-methyl-lH-l,2,4-triazol-l-yl}-5-chloro-2-(trifluoromethyl)- 3-methylbenzene

To a solution of l-[5-(3-amino-4,6-O-benzylidene-3-deoxy-P-D-galactopyranosyl)-3- methyl-U/-l,2,4-triazol-l-yl]-5-chloro-2-(trifluoromethyl)-3-methylbenzene (60 mg, 0.080 mmol) in DCM (6.0 mL)7V-tert-butyloxycarbonyl-3-(4-cyanophenyl)oxaziridine (37 mg, 0.12 mmol) was added and the mixture was stirred overnight at rt. The mixture was concentrated and purified by column chromatography (DCM/EtOAc=l/0~0/l, Silica-CS 20 g, 40 mL/min, silica gel, UV 254) to afford the product (40 mg, 70 %). ESLMS m/z calcd for [C29H33CIF3N5O6] [M+H]⁺: 640.2; found: 640.2. ¹ H NMR (400 MHz, Chloroform-d) 6 7.35 - 7.24 (m, 7H), 6.40 (br s, 1H), 5.37 (s, 1H), 4.52 - 4.34 (m, 2H), 4.30 - 4.14 (m, 3H), 3.85 - 3.80 (m, 1H), 3.75 - 3.67 (m, 1H), 3.25 - 3.18 (m, 1H), 2.99 - 2.93 (m, 1H), 2.42 - 2.35 (m, 6H), 1.39 (s, 9H).

Intermediate 77

Methyl 3-amino-5-chloropicolinate

To a solution of 5-chloro-3-nitropicolinonitrile (4.0 g, 21.8 mmol) in EtOH (80 mL) tin(II) chloride dihydrate (27.8 g, 123 mmol) was added and the mixture was refluxed for 3 h. The mixture was evaporated, dissolved in concentrated HC1 (80 mL) and stirred 6 h at 100 °C. The mixture was concentrated to dryness, dissolved in MeOH (150 mL), and cooled to 0 °C. Thionyl chloride (15 mL) was added and the mixture was heated to 90 °C and stirred 16 h. The mixture was concentrated, dissolved in EtOAc (600 mL), and washed with saturated aq NaHCCL (300 mL). The organic phase was dried over Na2SO4, evaporated, and purified by column chromatography (EtOAc/PE=0/l~l/l, Silica-CS 80 g, 50 mL/min, silica gel, UV 254) to give the product (2.1 g, 52 %). ESIMS m/z calcd for [C7H7CIN2O2] [M+H]⁺: 187.0; found: 187.2. 'H NMR (400 MHz, DMSO-de) 8 7.82 (d, J = 2.0 Hz, 1H), 7.33 (d, J = 2.0 Hz, 1H), 6.89 (s, 2H), 3.81 (s, 3H).

Methyl 5-chloro-3-hydrazinylpicolinate

To a cooled (0 °C) solution of methyl 3-amino-5-chloropicolinate (1.90 g, 10.2 mmol) in concentrated HC1 (20 mL) and acetic acid (10 mL) a solution of NaNCL (1.05 g, 15.3 mmol) in water (2 mL) was added. The resulting mixture was stirred 1 h at 0 °C. Tin(II) chloride dihydrate (4.60 g, 20.4 mmol) dissolved in concentrated HC1 (5 mL) was added at 0 °C. The resulting mixture was warmed to rt and stirred 3 h. The pH was adjusted to 10 by addition of aq NaOH (I M). The mixture was extracted with EtOAc (2 x 50 mL). The combined organic phases were dried over Na2SO4, evaporated, and purified by column chromatography (DCM/PE=0/l~3/l, Silica-CS 40 g, 50 mL/min, silica gel, UV 254) to afford the product (303 mg, 15 %). ESLMS m/z calcd for [C7H8CIN3O2] [M+H]⁺: 202.0; found: 202.2. 'HNMR (400 MHz, DMSO-d₆) 6 8.48 (s, 1H), 7.81 (d, J= 2.0 Hz, 1H), 7.78 (d, J= 2.4 Hz, 1H), 4.56 - 4.55 (m, 2H), 3.81 (s, 3H).

3-[5-(3-Azido-4,6-O-benzylidene-3-deoxy-p-D-galactopyranosyl)-3-methyl-LH- l,2,4-triazol-l-yl]-5-chloro-2-(methoxycarbonyl)pyridine

To a solution of 2,6-anhydro-4-azido-5,7-O-benzylidene-4-deoxy-D-glycero-L-manno- 7V-[l-(dimethylamino)ethylidene]heptonamide (580 mg, 1.49 mmol) in 1,4-dioxane (10 mL) and acetic acid (3.0 mL) methyl 5-chloro-3-hydrazinylpicolinate (300 mg, 1.49 mmol) was added and the mixture was stirred 2 h at 60 °C. The mixture was evaporated and partitioned between aq NaHCCL (60 mL) and EtOAc (60 mL). The aqueous phase was extracted with EtOAc (40 mL). The combined organic phases were washed with brine (60 mL), dried over Na2SO4, evaporated, and purified by column chromatography (EtOAc/PE=l/5~l/l, Silica-CS 20 g, 30 mL/min, silica gel, UV 254). The obtained material was purified by reversed-phase chromatography (MeCN/H2O=l/20~2/l, C-18 column, 20 mL/min, UV 214) to afford the product (345 mg, 44 %). ESLMS m/z calcd for [C23H22CIN7O6] [M+H]⁺: 528.1; found: 528.2. ^XH NMR (400 MHz, DMSO-d₆) 8 8.84 (d, J= 2.0 Hz, 1H), 8.32 (d, J= 2.0 Hz, 1H), 7.41 - 7.38 (m, 5H), 5.81 (d, J= 6.4 Hz, 1H), 5.63 (s, 1H), 4.39 (d, J = 92 Hz, 1H), 4.34 (d, J = 3.6 Hz, 1H), 4.22 - 4.16 (m, 1H), 4.06 - 3.97 (m, 2H), 3.64 (s, 3H), 3.61 (s, 1H), 3.55 (dd, J= 10.0, 3.2 Hz, 1H), 2.34 (s, 3H).

3-|5-(3-Ainino-4.6-6M)enzylidene-3-deoxy-|Ll)-«alactopyranosyl)-3-methyl-l//- l,2,4-triazol-l-yl]-5-chloro-2-(methoxycarbonyl)pyridine

To a solution of 3-[5-(3-azido-4,6-O-benzylidene-3-deoxy-P-D-galactopyranosyl)-3- methyl-U/-l,2,4-triazol-l-yl]-5-chloro-2-(methoxycarbonyl)pyridine (354 mg, 0.67 mmol) in THF/water (10 mL, 5: 1) triphenylphosphine (528 mg, 2.01 mmol) was added and the mixture was stirred 16 h at 50 °C. The mixture was concentrated and purified by column chromatography (DCM/MeOH= 1/0- 10/1, Silica-CS 12 g, 20 mL/min, silica gel, UV 254) to afford the product (216 mg, 64 %). ESI-MS m/z calcd for [C23H24CIN5O6] [M+H]⁺: 502.1; found: 502.1. ^XH NMR (400 MHz, Chloroform-d) 5 8.49 (d, J = 3.6 Hz, 1H), 7.87 (d, J = 2.0 Hz, 1H), 7.29 - 7.27 (m, 5H), 5.36 (s, 1H), 4.37 - 4.33 (m, 1H), 4.14 - 4.12 (m, 1H), 3.93 - 3.82 (m, 2H), 3.76 - 3.73 (m, 4H), 3.32 - 3.30 (m, 1H), 3.02 - 3.00 (m, 1H), 2.33 (s, 3H).

3-{5-{4,6-O-Benzylidene-3-[(2-terCbutoxycarbonyl)hydrazinyl]-3-deoxy-p-D- galactopyranosyl}-3-methyl-lZ7-l,2,4-triazol-l-yl}-5-chloro-2- (methoxycarbonyl)pyridine

To a solution of 3-[5-(3-amino-4,6-O-benzylidene-3-deoxy-P-D-galactopyranosyl)-3- methyl-U/-l,2,4-triazol-l-yl]-5-chloro-2-(methoxycarbonyl)pyridine (216 mg, 0.43 mmol) in DCM (10 mL) 7V-tert-butyloxycarbonyl-3-(4-cyanophenyl)oxaziridine (159 mg, 0.65 mmol) was added and the mixture was stirred overnight atrt. The mixture was concentrated and purified by column chromatography (DCM/EtOAc=4/ 1-0/1, Silica- CS 20 g, 30 mL/min, silica gel, UV 254) to afford the product (146 mg, 55 %). ESIMS m/z calcd for [C28H33CIN6O8] [M+H]⁺: 617.2; found: 617.3. 'H NMR (400 MHz, Chloroform-d) 5 8.48 (d, J= 2.0 Hz, 1H), 7.87 (d, J= 2.0 Hz, 1H), 7.30 - 7.27 (m, 5H), 6.44 (m, 1H), 5.37 (s, 1H), 4.36 (d, J= 92 Hz, 1H), 4.23 (s, 1H), 4.10 - 4.08 (m, 1H), 3.88 - 3.77 (m, 2H), 3.74 (s, 3H), 3.29 (s, 1H), 3.02 (dd, J= 10.0, 2.4 Hz, 1H), 2.36 (s, 3H), 1.38 (s, 9H).

3-{5-{3-[4-(4-Chloro-2,3-difluorophenyl)-lZ7-l,2-pyrazol-l-yl]-3-deoxy-p-D- galactopyranosyl}-3-methyl-lZ7-l,2,4-triazol-l-yl}-5-chloro-2- (methoxycarbonyl)pyridine

To a solution of 3-{5-{4,6-O-benzylidene-3-[(2-tert-butoxycarbonyl)hydrazinyl]-3- deoxy-P-D-galactopyranosyl } -3 -methyl- \H- 1 ,2,4-triazol- 1 -yl } -5-chloro-2- (methoxycarbonyl)pyridine (146 mg, 0.24 mmol) in EtOH (5.0 mL) 2-(4-chloro-2,3- difluorophenyl)-3-(dimethylamino)prop-2-enal (81.4 mg, 0.33 mmol) was added followed by concentrated HC1 (0.2 mL) and the mixture was stirred 2 h at 80 °C. The mixture was evaporated and partitioned between aq NaHCCh (20 mL) and EtOAc (30 mL). The aqueous phase was extracted with EtOAc (2 x 20 mL). The combined organic phases were washed with brine (40 mL), dried over Na2SO4, evaporated, and purified by column chromatography (DCM/MeOH= I/O- 10/1, Silica-CS 12 g, 20 mL/min, silica gel, UV 254) to afford the title compound (89 mg, 62 %). ESLMS m/z calcd for [C25H22CI2F2N6O6] [M+H]⁺: 611.1; found: 611.2. ¹H NMR (400 MHz, Chloroform-d) 5 8.70 (d, J= 2.0 Hz, 1H), 7.97 - 7.95 (m, 2H), 7.81 (s, 1H), 7.18 - 7.08 (m, 2H), 4.53 - 4.43 (m, 2H), 4.36 (s, 1H), 4.15 (d, J = 10.0 Hz, 1H), 3.81 (s, 3H), 3.67 - 3.56 (m, 2H), 3.53 - 3.51 (m, 1H), 2.36 (s, 3H).

Intermediate 79 l-Bromo-5-chloro-2-iodo-3-nitrobenzene

To a solution of 2-bromo-4-chloro-6-nitroaniline (2.40 g, 9.54 mmol) in MeCN (40 mL) Cui (2.73 g, 14.3 mmol) and KI (2.38 g, 14.3 mmol) were added. The mixture was cooled to 0 °C and tert-butyl nitrite (1.97 g, 19.1 mmol) was added. The mixture was stirred 1 h at 60 °C. Water (50 mL) was added, and the mixture was extracted with EtOAc (3 x 40 mL). The combined organic phases were dried, concentrated, and purified by column chromatography (PEZEtOAc = 1/0-20/1, silica-CS 20 g, 30 mL/min, silica gel, UV 254 nm) to afford the product (2.1 g, 61 %). 'H NMR (400 MHz, DMSO-de) 8 8.21 (d, J= 2.4 Hz, 1H), 8.11 (d, J= 2.0 Hz, 1H). l-Bromo-5-chloro-2-(trifluoromethyl)-3-nitrobenzene

A mixture of l-bromo-5-chloro-3-nitrobenzene (2.1 g, 5.80 mmol), methyl 2,2- difluoro-2 -fluorosulfonylacetate (1.34 g, 6.95 mmol) and Cui (1.21 g, 6.38 mmol) in DMF (25 mL) was stirred 2 h at 100 °C. After cooling to rt, the mixture was poured into water (50 mL) and then extracted with EtOAc (2 x 30 mL). The combined organic phases were washed with water (20 mL) and brine (20 mL), dried over Na₂SO4, concentrated, and purified by column chromatography (EtOAc/PE = 0/1-1/10, Silica- CS 40 g, 30 mL/min, silica gel, UV 254) to afford the product (1.5 g, 85 %). 'H NMR (400 MHz, DMSO-d₆) 6 8.46 (d, J= 1.2 Hz, 1H), 8.43 (d, J= 1.6 Hz, 1H).

3-Bromo-5-chloro-2-(trifluoromethyl)aniline

To a solution of l-bromo-5-chloro-2-(trifluoromethyl)-3-nitrobenzene (1.5 g, 4.93 mmol) in acetic acid (20 mL) Fe (825 mg, 14.8 mmol) was added and the mixture was stirred 2 h at 60 °C. The mixture was concentrated and purified by column chromatography (EtOAc/PE = 0/1-1/8, Silica-CS 40 g, 50 mL/min, silica gel, UV 254) to afford the product (600 mg, 44 %). ESLMS m/z calcd for [CyH-tBrClFsN] [M+H]⁺: 273.9; found: 274.0. 'H NMR (400 MHz, DMSO-d₆) 6 6.98 (d, J= 1.2 Hz, 1H), 6.93 (d, J= 1.6 Hz, 1H), 6.23 (s, 2H).

[3-Bromo-5-chloro-2-(trifluoromethyl)phenyl]hydrazine

To a cooled (-5 °C) solution of 3-bromo-5-chloro-2-(trifluoromethyl)aniline (600 mg, 2.19 mmol) in concentrated HC1 (9.0 mL) and acetic acid (3 mL) a solution of NaNCL (226 mg, 3.28 mmol) in water (1.0 mL) was added dropwise. The mixture was stirred 30 min at -5 °C. Then a solution of tin(II) chloride dihydrate (987 mg, 4.37 mmol) dissolved in concentrated HC1 (3.0 mL) was added and the mixture was stirred 2 h at -5 °C. The mixture was diluted with water (20 mL) and basified to pH=8 by addition of saturated aq NaHCCL. The mixture was extracted with EtOAc (2 x 20 mL). The combined organic phases were washed with water (20 mL) and brine (20 mL), dried over Na2SO4, evaporated, and purified by column chromatography (PE/DCM = 1/0— 1/3, silica-CS 20 g, 20 mL/min, silica gel, UV 254 nm) to afford the product (502 mg, 79 %). ESLMS m/z calcd for [C7H₅BrClF₃N2] [M+H]⁺: 288.9; found: 289.0. 'H NMR (400 MHz, DMSO-de) 8 7.55 (d, J= 1.6 Hz, 1H), 7.47 (br s, 1H), 7.03 (d, J= 2.0 Hz, 1H), 4.36 (s, 2H). l-|5-(3-Azido-4.6-6M)enzylidene-3-deoxy-|Ll)-«alactopyranosyl)-3-methyl-l//- l,2,4-triazol-l-yl]-3-bromo-5-chloro-2-(trifluoromethyl)benzene

To a solution of 2,6-anhydro-4-azido-5,7-O-benzylidene-4-deoxy-D-glycero-L-manno- 7V-[l-(dimethylamino)ethylidene]heptonamide (660 mg, 1.69 mmol) in 1,4-di oxane (10 mL) and acetic acid (3 mL) [3-bromo-5-chloro-2-(trifluoromethyl)phenyl]hydrazine (491 mg, 1.69 mmol) was added and the mixture was stirred 2 h at 70 °C. The mixture was concentrated, partitioned between water (20 mL) and DCM (20 mL), and the aqueous phase was extracted with DCM (2 x 20 mL). The combined organic phases were washed with water (20 mL) and brine (20 mL), dried, evaporated, and purified by column chromatography (EtOAc/PE=l/5~2/l, Silica-CS 20 g, 30 mL/min, silica gel, UV 254) to afford the product (505 mg, 48 %). ESLMS m/z calcd for [C23Hi₉BrClF₃N6O4] [M+H]⁺: 615.0; found: 615.2. ^XH NMR (400 MHz, Chloroform- d) 5 7.68 (s, 1H), 7.40 (d, J= 1.6 Hz, 1H), 7.35 - 7.28 (m, 5H), 5.40 (s, 1H), 4.41 - 4.37 (m, 1H), 4.34 - 4.29 (m, 1H), 4.14 (d, J= 3.2 Hz, 1H), 3.85 - 3.80 (m, 1H), 3.68

- 3.60 (m, 1H), 3.37(dd, J= 10.0, 3.2 Hz, 1H), 3.30 - 3.26 (m, 1H), 2.37 (s, 3H). l-[5-(3-Amino-4,6-O-benzylidene-3-deoxy-p-D-galactopyranosyl)-3-methyl-LH- l,2,4-triazol-l-yl]-3-bromo-5-chloro-2-(trifluoromethyl)benzene

To a solution of l-[5-(3-azido-4,6-(9-benzylidene-3-deoxy-P-D-galactopyranosyl)-3- methyl-lJ/-l,2,4-triazol-l-yl]-3-bromo-5-chloro-2-(trifluoromethyl)benzene (505 mg, 0.82 mmol) in THF (10.0 mL) and water (1.0 mL) triphenylphosphine (647 mg, 2.46 mmol) was added and the mixture was stirred overnight at 50 °C. The mixture was concentrated and purified by column chromatography (DCM/MeOH= I/O- 10/1, Silica- CS 12 g, 20 mL/min, silica gel, UV 254) to afford the product (212 mg, 44 %). ESIMS m/z calcd for ^fhiBrClFs^CU] [M+H]⁺: 589.0; found: 589.1. 'H NMR (400 MHz, Chloroform-d) 5 7.72 (s, 1H), 7.41 (s, 1H), 7.35 - 7.27 (m, 5H), 5.37 (s, 1H), 4.25 (d, J= 9.2 Hz, 1H), 4.10 - 4.04 (m, 1H), 3.90 - 3.77 (m, 2H), 3.63 - 3.58 (m, 1H), 3.29 - 3.25 (m, 1H), 2.80 - 2.76 (m, 1H), 2.35 (s, 3H). l-{5-{4,6-O-Benzylidene-3-[(2-terf-butoxycarbonyl)hydrazinyl]-3-deoxy-p-D- galactopyranosyl}-3-methyl-lZ7-l,2,4-triazol-l-yl}-3-bromo-5-chloro-2-

(trifluoromethyl)benzene

To a cooled (-78 °C) solution of l-[5-(3-amino-4,6-O-benzylidene-3-deoxy-P-D- galactopyranosyl)-3 -methyl- 1H- 1,2, 4-tri azol- 1-yl] -3 -bromo-5 -chi oro-2 - (trifluoromethyl)benzene (110 mg, 0.19 mmol) in DCM (5.0 mL) a solution of tert- butyl 3-(trichloromethyl)oxaziridine-2-carboxylate (49 mg, 0.19 mmol) in DCM (1 mL) was added dropwise. After stirring 4 h at -78 °C, the mixture was concentrated and purified by reversed-phase chromatography (MeCN/JbO = 1/20-2/1, C-18 column, 20 mL/min, UV 214) to afford the product (70 mg, 53 %). ESI-MS m/z calcd for [C28H3oBrClF3N₅0₆] [M+H]⁺: 704.1; found: 704.0.

3-Bromo-l-{5-{3-[4-(4-chloro-2,3-difluorophenyl)-lZ/-l ,2-pyrazol-l-yl]-3-deoxy- |Ll)-«alactopyranosyl]-3-methyl-l//-l ,2,4-triazol-l-yl}-5-chloro-2- (trifluoromethyl)benzene

To a solution of l-{5-{4,6-O-benzylidene-3-[(2-tert-butoxycarbonyl)hydrazinyl]-3- deoxy-P-D-galactopyranosyl}-3-methyl-lJ7-l,2,4-triazol-l-yl}-3-bromo-5-chloro-2- (trifluoromethyl)benzene (70 mg, 0.099 mmol) in EtOH (5.0 mL) 2-(4-chloro-2,3- difluorophenyl)-3-(dimethylamino)prop-2-enal (34.2 mg, 0.14 mmol) was added followed by concentrated HC1 (0.25 mL) and the mixture was stirred 1 h at 80 °C. The mixture was concentrated and purified by prep HPLC [MeCN/EEO (10 mmol/L NH4HCO3), X-Select 10 pm 19*250 mm, 20 mL/min, UV 254] to afford the product (33 mg, 48 %). ESI-MS m/z calcd for ^sHwBrChFsNsCU] [M+H]⁺: 698.0; found: 698.0. 'H NMR (400 MHz, Methanol-d₄) 8 8.24 - 8.21 (m, 2H), 7.96 (s, 1H), 7.84 - 7.68 (m, 1H), 7.50 - 7.46 (m, 1H), 7.31 - 7.28 (m, 1H), 4.76 - 4.63 (m, 1H), 4.46 - 4.40 (m, 2H), 4.09 (dd, J= 10.0, 2.4 Hz, 1H), 3.70 - 3.56 (m, 3H), 2.43 - 2.42 (m, 3H).

Intermediate 82 l-(2,5-Dichloro-4-nitrophenyl)thiourea

To a solution of 2,5-dichloro-4-nitroaniline (2.10 g, 10.1 mmol) in MeCN (20 mL) benzoyl isothiocyanate (1.74 g, 10.7 mmol) was added and the mixture was stirred 2 h at rt. The mixture was evaporated, and the residue was dissolved in MeOH (20 mL). A solution of 2 N NaOH (20 mL) was added, and the mixture was stirred 2 h at 70 °C. EtOAC (60 mL) was added, and the mixture was washed with water (2 x 20 mL) and brine (2 x 20 mL). The organic phase was dried, concentrated, and purified by column chromatography (EtOAc/PE = 0/1-1/1, Silica-CS 20 g, 20 mL/min, silica gel, UV 254) to afford the product (2.3 g, 85 %). ESLMS m/z calcd for [C7H5Q2N3O2S] [M+H]⁺: 266.0; found: 266.1. 'H NMR (400 MHz, Chloroform-d) 5 8.42 (s, 1H), 8.04 (s, 1H), 7.85 (s, 1H), 6.25 (s, 2H).

4,7-Dichloro-6-nitro-l,3-benzothiazole

To a solution of l-(2,5-dichloro-4-nitrophenyl)thiourea (2.3 g, 8.64 mmol) in CHCI3 (30 mL) Br2 (3.04 g, 19.0 mmol) was added and the mixture was stirred overnight at 70 °C. The mixture was concentrated, and the residue triturated in PE. The solid was collected by filtration, washed with PE, and dried in vacuo. The obtained material was dissolved in THF (30 mL) and isoamyl nitrite (1.34 g, 11.5 mmol) was added. The mixture was stirred overnight at rt. The mixture was concentrated and purified by column chromatography (EtOAc/PE = 0/1— 1/3, Silica-CS 20 g, 30 mL/min, silica gel, UV 254) to afford the product (460 mg, 48 %). ESLMS m/z calcd for [C7H2Q2N2O2S] [M+H]⁺: 248.9; found: 248.6. ^XH NMR (400 MHz, Chloroform-d) 5 9.25 (s, 1H), 8.16 (s, 1H).

4-Chloro-7-(trifluoromethyl)-6-nitro-l,3-benzothiazole

A mixture of 4,7-dichloro-6-nitro-l,3-benzothiazole (460 mg, 1.85 mmol), methyl 2,2- difluoro-2 -fluorosulfonylacetate (1.6 g, 8.31 mmol) and Cui (528 mg, 2.77 mmol) in DMF (10 mL) was stirred 4 h at 130 °C. After cooling to rt, the mixture was poured into water (30 mL) and then extracted with EtOAc (3 x 20 mL). The combined organic phases were washed with water (2 x 20 mL) and brine (2 x 20 mL), dried over Na2SO4, concentrated, and purified by column chromatography (EtOAc/PE = 0/1— 1/3, Silica- CS 20 g, 20 mL/min, silica gel, UV 254) to afford the product (345 mg, 66 %). ESIMS m/z calcd for [C8H2CIF3N2O2S] [M+H]⁺: 282.9; found: 282.6. *H NMR (400 MHz, Chloroform-d) 5 9.37 (s, 1H), 8.00 (s, 1H).

4-Chloro-7-(trifluoromethyl)-l,3-benzothiazol-6-amine

A solution of 4-chloro-7-(trifluoromethyl)-6-nitro-l,3-benzothiazole (345 mg, 1.22 mmol), Fe (341 mg, 6.10 mmol) and NH4CI (392 mg, 7.32 mmol) in EtOH (20 mL) and water (2.0 mL) was stirred 2 h at 85 °C. The mixture was concentrated and purified by column chromatography (EtOAc/PE = 0/1— 1/3, Silica-CS 20 g, 20 mL/min, silica gel, UV 254) to afford the product (235 mg, 76 %). ESLMS m/z calcd for [C8H4CIF3N2S] [M+H]⁺: 253.0; found: 253.2. ^XH NMR (400 MHz, Chloroform-d) 5 8.82 (s, 1H), 6.99 (s, 1H), 4.48 (s, 2H).

[4-Chloro-7-(trifluoromethyl)-l,3-benzothiazol-6-yl]hydrazine

To a cooled (-5 °C) solution of 4-chloro-7-(trifluoromethyl)-l,3-benzothiazol-6-amine (235 mg, 0.93 mmol) in concentrated HC1 (4.0 mL) a solution of NaNCL (77 mg, 1.12 mmol) in water (0.5 mL) was added dropwise. The mixture was stirred 30 min at -5 °C. Then a cooled (0 °C) solution of tin(II) chloride dihydrate (525 mg, 2.33 mmol) dissolved in concentrated HC1 (1.0 mL) was added and the resulting mixture was stirred 2 h at -5 °C. The mixture was diluted with water (20 mL) and basified to pH=12 by addition of NaOH (5 M). The mixture was extracted with EtOAc (2 x 20 mL). The combined organic phases were washed with water (20 mL) and brine (20 mL), dried over Na2SO4, evaporated, and purified by column chromatography (PE/EtOAc = 1/0-3/1, silica-CS 20 g, 20 mL/min, silica gel, UV 254 nm) to afford the product (162 mg, 65 %). ESLMS m/z calcd for [C₈H₅C1F₃N3S] [M+H]⁺: 268.0; found: 268.0. 'H NMR (400 MHz, Chloroform-d) 5 8.75 (s, 1H), 7.77 (s, 1H), 6.06 (s, 1H), 3.74 (s, 2H).

6-[5-(3-Azido-4,6-O-benzylidene-3-deoxy-p-D-galactopyranosyl)-3-methyl-LH- l,2,4-triazol-l-yl]-4-chloro-7-(trifluoromethyl)benzothiazole

To a solution of 2,6-anhydro-4-azido-5,7-O-benzylidene-4-deoxy-D-glycero-L-manno- heptonamide (300 mg, 0.94 mmol) in 1,4-dioxane (5.0 mL) V,A-di methyl acetamide dimethyl acetal (166 mg, 1.12 mmol) was added and the mixture was stirred 3 h at 50 °C. The mixture was evaporated, and the residue was dissolved in 1,4-dioxane (6.0 mL) and acetic acid (2.0 mL). To this solution [4-chloro-7-(trifluoromethyl)-l,3- benzothiazol-6-yl]hydrazine (256 mg, 0.96 mmol) was added and the mixture was stirred 2 h at 70 °C. The mixture was concentrated, partitioned between water (20 mL) and DCM (20 mL), and the aqueous phase was extracted with DCM (2 x 20 mL). The combined organic phases were washed with water (20 mL) and brine (20 mL), dried, evaporated, and purified by column chromatography (EtOAc/PE=l/5~2/l, Silica-CS 20 g, 30 mL/min, silica gel, UV 254) to afford the product (395 mg, 50 %). ESLMS m/z calcd for [C24H19CIF3N7O4S] [M+H]⁺: 594.1; found: 594.2. ^XH NMR (400 MHz, Chloroform-d) 5 9.20 (s, 1H), 7.70 (s, 1H), 7.38 - 7.26 (m, 5H), 5.38 (s, 1H), 4.49 (s, 1H), 4.33 - 4.23 (m, 2H), 4.15 - 4.08 (m, 1H), 3.73 (d, J= 12.8 Hz, 1H), 3.33 (dd, J= 10.0, 3.2 Hz, 1H), 3.17 (s, 1H), 2.39 (s, 3H).

6-|5-(3-Aiiiino-4.6-6M)enzylidene-3-deoxy-|Ll)-«alactopyranosyl)-3-methyl-l//- l,2,4-triazol-l-yl]-4-chloro-7-(trifluoromethyl)benzothiazole

To a solution of 6-[5-(3-azido-4,6-(9-benzylidene-3-deoxy-P-D-galactopyranosyl)-3- methyl-U/-l,2,4-triazol-l-yl]-4-chloro-7-(trifluoromethyl)benzothiazole (395 mg, 0.47 mmol) in THF (10.0 mL) and water (2.0 mL) triphenylphosphine (349 mg, 1.33 mmol) was added and the mixture was stirred 6 h at 50 °C. The mixture was concentrated and purified by column chromatography (DCM/MeOH= 1/0- 10/1, Silica- CS 20 g, 20 mL/min, silica gel, UV 254) to afford the product (202 mg, 54 %). ESIMS m/z calcd for [C24H21CIF3N5O4S] [M+H]⁺: 568.1; found: 568.1. 'H NMR (400 MHz, Chloroform-d) 5 9.20 (s, 1H), 7.73 (s, 1H), 7.39 - 7.25 (m, 5H), 5.35 (s, 1H), 4.18 - 4.17 (m, 1H), 4.05 - 3.92 (m, 2H), 3.75 (d, J = 12.4 Hz, 1H), 3.62 - 3.42 (m, 1H), 3.18 (d, J= 0.8 Hz, 1H), 2.77 (d, J= 7.6 Hz, 1H), 2.38 (s, 3H).

6-{5-{4,6-O-Benzylidene-3-[(2-terf-butoxycarbonyl)hydrazinyl]-3-deoxy-p-D- galactopyranosyl}-3-methyl-l/Z-l,2,4-triazol-l-yl}-4-chloro-7-

(trifluoromethyl)benzothiazole

To a solution of 6-[5-(3-amino-4,6-(9-benzylidene-3-deoxy-P-D-galactopyranosyl)-3- methyl-lJ/-l,2,4-triazol-l-yl]-4-chloro-7-(trifluoromethyl)benzothiazole (100 mg, 0.18 mmol) in DCM (10 mL) 7V-tert-butyloxycarbonyl-3-(4-cyanophenyl)oxaziridine (52 mg, 0.21 mmol) was added and the mixture was stirred overnight at rt. The mixture was concentrated and purified by column chromatography (PE/EtOAc=4/ 1-0/1, Silica- CS 12 g, 30 mL/min, silica gel, UV 254) to afford the product (48 mg, 40 %). ESI-MS m/z calcd for [C29H30CIF3N6O6S] [M+H]⁺: 683 2; found: 683.1. ^XH NMR (400 MHz, Chloroform-d) 5 9.17 (s, 1H), 7.71 (s, 1H), 7.33 - 7.24 (m, 5H), 6.40 (s, 1H), 5.34 (s, 1H), 4.57 - 4.16 (m, 4H), 3.77 (d, J= 12.0 Hz, 1H), 3.58 (d, J= 11.6 Hz, 1H), 3.18 (s, 1H), 2.96 (d, J= 7.2 Hz, 1H), 2.39 (s, 3H), 1.38 (s, 9H).

Intermediate 83

(5-Chloro-2-methylphenyl)hydrazine

To a cooled (-5 °C) solution of 5-chloro-2 -methylaniline (1.00 g, 7.09 mmol) in acetic acid (5.0 mL) concentrated HC1 (15 mL) was added followed by dropwise addition of a solution of NaNCL (734 mg, 10.6 mmol) in water (2.0 mL). The mixture was stirred 30 min at -5 °C. A solution of tin(II) chloride dihydrate (3.19 g, 14.2 mmol) dissolved in concentrated HC1 (8.0 mL) was added and the mixture was stirred 2 h at -5 °C. The mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic phases were washed with water (30 mL), dried over Na2SO4, evaporated, and purified by reversed-phase chromatography [MeCN/FLO (10 mmol/L TFA), C-18 column, 35 mL/min, UV 214] to afford the product as a HC1 salt (230 mg, 21 %). ESLMS m/z calcd for [C7H9CIN2] [M+H]⁺: 157.1; found: 157.4. 'HNMR (400 MHz, DMSO-de) 8 10.27 (s, 2H), 8.10 (br s, 1H), 7.14 (dd, J = 7.6, 0.8 Hz, 1H), 6.99 (d, J= 2.0 Hz, 1H), 6.92 (dd, J= 8.0, 2.0 Hz, 1H), 2.15 (s, 3H). l-[5-(3-Azido-4,6-O-benzylidene-3-deoxy-p-D-galactopyranosyl)-3-methyl-LH- l,2,4-triazol-l-yl]-5-chloro-2-methylbenzene

To a solution of 2,6-anhydro-4-azido-5,7-O-benzylidene-4-deoxy-D-glycero-L-manno- heptonamide (300 mg, 0.94 mmol) in 1,4-dioxane (5 mL) A A-di methyl acetamide dimethyl acetal (249 mg, 1.87 mmol) was added and the mixture was stirred 3 h at 50 °C. The mixture was evaporated, and the residue was dissolved in 1,4-dioxane (6 mL) and acetic acid (2 mL). To this solution (5-chloro-2-methylphenyl)hydrazine (220 mg, 1.40 mmol) was added and the mixture was stirred 4 h at 80 °C. The mixture was concentrated, partitioned between water (30 mL) and DCM (30 mL), and the aqueous phase was extracted with DCM (2 x 30 mL). The combined organic phases were washed with water (20 mL) and brine (20 mL), dried, evaporated, and purified by column chromatography (EtOAc/PE=l/5~3/l, Silica-CS 20 g, 30 mL/min, silica gel, UV 254) to afford the product (360 mg, 96 %). ESLMS m/z calcd for [C23H23CIN6O4] [M+H]⁺: 483.2; found: 483.4. l-[5-(3-Amino-4,6-O-benzylidene-3-deoxy-p-D-galactopyranosyl)-3-methyl-LH- l,2,4-triazol-l-yl]-5-chloro-2-methylbenzene

To a solution of l-[5-(3-azido-4,6-O-benzylidene-3-deoxy-P-D-galactopyranosyl)-3- methyl- IT/- l , 2, 4-triazol-l-yl]-5-chloro-2 -methylbenzene (210 mg, 0.44 mmol) in THF (6.0 mL) and water (1.2 mL) triphenylphosphine (456 mg, 1.74 mmol) was added and the mixture was stirred overnight at 50 °C. The mixture was concentrated and purified by column chromatography (DCM/MeOH=l/0~10/l, Silica-CS 12 g, 20 mL/min, silica gel, UV 254) to afford the product (122 mg, 61 %). ESLMS m/z calcd for [C23H25CIN4O4] [M+H]⁺: 457.2; found: 457.4. 'H NMR (400 MHz, Chloroform-d) 5 7.47 - 7.44 (m, 2H), 7.39 - 7.34 (m, 5H), 7.24 (d, J = 8.4 Hz, 1H), 5.49 (s, 1H), 4.21 (t, J = 9.4 Hz, 1H), 4.15 (d, J= 2.4 Hz, 1H), 4.10 (d, J = 9.2 Hz, 1H), 3.95 - 3.89 (m, 2H), 3.29 (d, J= 0.8 Hz, 1H), 2.85 (d, J= 7.6 Hz, 1H), 2.41 (s, 3H), 2.10 (s, 3H). l-{5-{4,6-O-Benzylidene-3-[(2-terLbutoxycarbonyl)hydrazinyl]-3-deoxy-p-D- galactopyranosyl}-3-methyl-lZ7-l,2,4-triazol-l-yl}-5-chloro-2-methylbenzene

To a solution of l-[5-(3-amino-4,6-O-benzylidene-3-deoxy-P-D-galactopyranosyl)-3- methyl-UT-1, 2, 4-triazol-l-yl]-5-chloro-2 -methylbenzene (120 mg, 0.26 mmol) in DCM (7.0 mL) 7V-tert-butyloxycarbonyl-3-(4-cyanophenyl)oxaziridine (97 mg, 0.39 mmol) was added and the mixture was stirred overnight at rt. The mixture was concentrated and purified by column chromatography (PE/EtOAc=4/ 1-0/1, Silica-CS 12 g, 25 mL/min, silica gel, UV 254) to afford the product (82 mg, 55 %). ESI-MS m/z calcd for [C28H34CIN5O6] [M+H]⁺: 572.2; found: 572.5. 'H NMR (400 MHz, Chloroform-d) 5 7.46 - 7.44 (m, 2H), 7.38 - 7.34 (m, 4H), 7.32 (d, J = 2.0 Hz, 1H), 7.23 (d, J= 8.4 Hz, 1H), 6.44 (br s, 1H), 5.49 (s, 1H), 4.44 (t, J= 9.6 Hz, 1H), 4.30 (d, J= 2.8 Hz, 1H), 4.19 (d, J = 9.6 Hz, 1H), 3.95 (s, 2H), 3.30 (s, 1H), 3.05 (d, J= 10.0 Hz, 1H), 2.42 (s, 3H), 2.09 (s, 3H), 1.44 (s, 9H).

Intermediate 84

3-Chloro-4,5-difluorophenol

To an argon purged solution of 5-bromo-l-chloro-2,3-difluorobenzene (2.0 g, 8.8 mmol) and KOH (1.73 g, 31 mmol) in 1,4-dioxane (20 mL) and water (20 mL) Pd2(dba)s (161 mg, 0.18 mmol) and 2-di-terLbutylphosphino-3,4,5,6-tetramethyl- 2’,4’,6’-triisopropyl-l,r-biphenyl (211 mg, 0.44 mmol) were added and the mixture was stirred 16 h at 100 °C. The mixture was cooled to 25 °C and acidified to pH 5 using 1 N HC1. The aqueous phase was extracted with DCM (3 x 45 mL). The combined organic phases were dried over Na2SO4, concentrated, and purified by column chromatography (PE/THF = 97/3, Silica-CS 40 g, 35 mL/min, silica gel, UV 214) to afford the product (750 mg, 52 %). 'H NMR (400 MHz, DMSO-d₆) 8 10.30 (s, 1H), 6.82 - 6.74 (m, 2H). l-Chloro-2,3-difluoro-5-methoxybenzene

A solution of 3-chloro-4,5-difluorophenol (796 mg, 4.8 mmol) and K2CO3 (2 g, 15 mmol) in DMF (10 mL) was stirred 15 min at rt and then cooled to 0 °C. lodomethane (1.03 g, 7.3 mmol) was added dropwise, and the mixture was stirred 90 min at rt. The mixture was diluted with EtOAc (20 mL) and washed with brine. The organic phase was dried over Na2SO4, concentrated, and purified by column chromatography (PE/EtOAc=96/4, Silica-CS 40 g, 35 mL/min, silica gel, UV 254) to afford the product (500 mg, 58 %). ‘H NMR (400 MHz, DMSO-d₆) 57.15 - 7.10 (m, 1H), 7.05 - 7.02 (m, 1H), 3.78 (s, 3H).

2-(4-Chloro-2,3-difluoro-6-methoxyphenyl)-4,4,5,5-tetramethyl-l,3,2- dioxaborolane

To a cooled (-78 °C) solution of lithium diisopropylamide (1.05 mL, 2 M in THF, 2.10 mmol) in THF (5.0 mL) a solution of l-chloro-2,3-difluoro-5-methoxy-benzene (250 mg, 1.40 mmol) in THF (1.0 mL) was added dropwise. The mixture was stirred 1 h at -78 °C before a solution of 2-isopropoxy-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (469 mg, 2.52 mmol) in THF (1.0 mL) was added and the mixture was stirred 30 min at -78 °C. The mixture was poured into aq HC1 (15 mL, IM) and extracted with EtOAc (3 x 10 mL). The combined organic phases were concentrated and purified by column chromatography (PE/EtOAc=95/5, Silica-CS 40 g, 35 mL/min, silica gel, UV 214) to afford the product (200 mg, 47 %). ESLMS m/z calcd for [C13H16BCIF2O3] [M+H]⁺: 305.1; found: 305.2. ‘HNMR (400 MHz, DMSO-d₆) 8 7.05 (dd, J= 5.2, 2.0 Hz, 1H), 3.76 (s, 3H), 1.29 (s, 12H). Intermediate 87

(4-Chloro-5-cyano-2,3-difluorophenyl)boronic acid

To a cooled (-40 °C) solution of lithium diisopropylamide (0.95 mL, 2 M in THF, 1.90 mmol) in THF (3.8 mL) a solution of 2-chl oro-3, 4-difluoroenzonitrile (300 mg, 1.73 mmol) in THF (0.6 mL) was added dropwise. The mixture was stirred 1 h at -40 °C before a solution of 2-isopropoxy-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (354 mg, 1.90 mmol) in THF (0.5 mL) was added and the mixture was stirred 30 min at -40 °C. The mixture was poured into diethyl ether (10 mL) and extracted with water (3 x 8 mL). The combined aqueous phases were purified by prep HPLC (MeCN/H2O (10 mmol/L TFA), X-Select 10pm 19*250 mm, 25 mL/min, UV 214) to afford the product (200 mg, 50 %). 'H NMR (400 MHz, DMSO-d₆) 8 8.80 (s, 2H), 7.97 (dd, J= 5.2, 2.4 Hz, 1H).

Intermediate 88 l,2-Difluoro-5-methyl-3-nitrobenzene

To a solution of 5-bromo-l,2-difluoro-3-nitrobenzene (1.0 g, 4.20 mmol) and methylboronic acid (503 mg, 8.40 mmol) in l,4-dioxane/H2O (13 mL, 3: 1) K2CO3 (1.74 g, 12.6 mmol) and Pd(dppf)C12 (307 mg, 0.42 mmol) were added and the mixture was stirred overnight at 90 °C. The mixture was poured into water (50 mL) and extracted with EtOAc (3 x 25 mL). The combined organic phases were washed with brine (50 mL), dried over ISfeSCU, concentrated, and purified by column chromatography (PEZEtOAc = 1/0-1/8, Silica-CS 40 g, 40 mL/min, silica gel, UV 254) to afford the product (302 mg, 27 %). 'H NMR (400 MHz, Chloroform^/) 5 7.66 (dd, J= 3.2, 2.4 Hz, 1H), 7.34 - 7.27 (m, 1H), 2.43 (s, 3H).

2,3-Difluoro-5-methylaniline

A mixture of l,2-difluoro-5-methyl-3-nitrobenzene (345 mg, 1.99 mmol) and Fe (446 mg, 7.97 mmol) in acetic acid (5.0 mL) was stirred 3 h at 65 °C. The mixture was filtered through a celite pad, concentrated, and purified by column chromatography (EtOAc/PE = 0/1—1/4, Silica-CS 20 g, 25 mL/min, silica gel, UV 254) to afford the product (150 mg, 51 %). 'H NMR (400 MHz, DMSO-d₆) 8 6.32 (d, J = 7.6 Hz, 1H), 6.27 - 6.22 (m, 1H), 5.36 (s, 2H), 2.10 (s, 3H).

4-Chloro-2,3-difluoro-5-methylaniline

To a solution of 2,3-difluoro-5-methylaniline (400 mg, 2.79 mmol) in DMF (5 mL) N- chlorosuccinimide (336 mg, 2.52 mmol) was added and the mixture was stirred overnight at rt. The mixture was poured into water (50 mL) and extracted with EtOAc (3 x 30 mL). The combined organic phases were washed with water (50 mL) and brine (50 mL), dried over Na2SO4, concentrated, and purified by silica gel chromatography (PEZEtOAc = 1/0-1/10, Silica-CS 20 g, 25 mL/min, silica gel, UV 254) to afford the product (196 mg, 40 %). 'H NMR (400 MHz, DMSO-d₆) 6 6.50 (dd, J = 8.8, 1.6 Hz, 1H), 5.57 (s, 2H), 2.16 (s, 3H).

2-Chloro-3,4-difluoro-5-iodo-l-methylbenzene

A solution of NaNO₂ (175 mg, 2.53 mmol) and KI (514 mg, 3.1 mmol) in H₂O (1 mL) was added dropwise to a solution of 4-chloro-2,3-difluoro-5-methylaniline (100 mg, 0.56 mmol) and p-toluenesulfonic acid monohydrate (533 mg, 3.10 mmol) in MeCN (2 mL) at 0°C. The mixture was stirred 16 h at rt. The mixture was poured into water (20 mL) and extracted with EtoAc (3 x 15 mL). The combined organic phases were washed with brine (30 mL), dried over ISfeSCU, concentrated, and purified by column chromatography (PE/EtOAc = 1/0-1/20, Silica-CS 20 g, 25 mL/min, silica gel, UV 254) to afford the product (89 mg, 54 %). ¹ H NMR (400 MHz, DMSO-d₆) 8 7.73 - 7.71 (m, 1H), 2.29 (s, 3H).

3- {5- [3-(4-Borono- 1H- 1 ,2-pyrazol- l-yl)-3-deoxy-p-D-galactopyranosyl]-3-methyl- 1H- 1 ,2,4-triazol- l-yl}-5-chloro-2-(trifluoromethyl)pyridine

To a solution of 5-chloro-3-{5-[3-deoxy-3-(4-iodo-U/-l,2-pyrazol-l-yl)-P-D- galactopyranosyl]-3-methyl-177-l,2,4-triazol-l-yl}-2-(trifluoromethyl)pyridine (100 mg, 0.17 mmol) and bis(pinacolato)diboron (121 mg, 0.48 mmol) in DMSO (4.0 mL) Pd(dppf)C12 (23.2 mg, 0.032 mmol) and potassium acetate (77.7 mg, 0.79 mmol) were added. The mixture was purged three times with nitrogen, and stirred 2 h at 60 °C. The mixture was filtered and purified by reversed-phase chromatography (MeCN/thO (0.05 % TFA) = 1/20-1/2, C-18 column, 20 mL/min, UV 214) to afford the product (35 mg, 39 %). ESI-MS m/z calcd for [CisH^BClFsNeOe] [M+H]⁺: 519.1; found: 519.3.

Intermediate 89

3-[5-(3-Azido-4,6-O-benzylidene-3-deoxy-p-D-galactopyranosyl)-lH-l,2,4-triazol- l-yl]-5-chloro-2-(trifluoromethyl)pyridine

To a solution of 2,6-anhydro-4-azido-5,7-O-benzylidene-4-deoxy-D-glycero-L-manno- heptonamide (600 mg, 1.87 mmol) in MeCN (20 mL) VA -di methyl form am ide dimethyl acetal (446 mg, 3.75 mmol) was added and the mixture was stirred 3 h at 50 °C. The mixture was evaporated, and the residue was dissolved in MeCN (30 mL) and acetic acid (10 mL). [5-Chloro-2-(trifluoromethyl)-3-pyridyl]hydrazine (436 mg, 2.06 mmol) was added and the mixture was stirred overnight at 100 °C. The mixture was concentrated and partitioned between water (30 mL) and DCM (20 mL). The aqueous phase was extracted with DCM (2 x 20 mL). The combined organic phases were washed with water (30 mL) and brine (30 mL), dried over ISfeSCL, evaporated, and purified by column chromatography (EtOAc/PE = 1/5— 1/1, Silica-CS 20 g, 20 mL/min, silica gel, UV 254). The obtained material was purified by reversed-phase chromatography (MeCN/EEO = 1/20-1/1, C-18 column, 30 mL/min, UV 254) to afford the product (206 mg, 21 %). ESLMS m/z calcd for [C21H17CIF3N7O4] [M+H]⁺: 524.1; found: 523.9. 'H NMR (400 MHz, Chloroform-d) 5 8.73 (d, J = 2.0 Hz, 1H), 8.09 (s, 1H), 7.93 (d, J = 1.6 Hz, 1H), 7.44 - 7.36 (m, 5H), 5.49 (s, 1H), 4.55 - 4.52 (m, 2H), 4.42 (t, J= 10.0 Hz, 1H), 4.23 (dd, J = 3.2, 0.8 Hz, 1H), 3.90 (dd, J= 12.8, 1.6 Hz, 1H), 3.55 (dd, J = 12.4, 1.2 Hz, 1H), 3.47 (dd, J= 10.0, 3.2 Hz, 1H), 3.36 (d, J= 0.8 Hz, 1H).

3-[5-(3-Amino-4,6-O-benzylidene-3-deoxy-p-D-galactopyranosyl)-lH-l ,2,4- triazol-l-yl]-5-chloro-2-(trifluoromethyl)pyridine

To a solution of 3-[5-(3-azido-4,6-O-benzylidene-3-deoxy-P-D-galactopyranosyl)-U7- l,2,4-triazol-l-yl]-5-chloro-2-(trifluoromethyl)pyridine (206 mg, 0.39 mmol) in THF (10 mL) and water (1.0 mL) triphenylphosphine (309 mg, 1.18 mmol) was added and the mixture was stirred 6 h at 50 °C. The mixture was concentrated and purified by column chromatography (DCM/MeOH= 1/0- 10/1, Silica-CS 20 g, 40 mL/min, silica gel, UV 254) to afford the product (189 mg, 97 %). ESLMS m/z calcd for [C21H19CIF3N5O4] [M+H]⁺: 498.1; found: 498.0. 'H NMR (400 MHz, DMSO-d₆) 8 8.78 (s, 1H), 8.38 (d, J = 1.6 Hz, 1H), 8.24 (s, 1H), 7.40 - 7.28 (m, 5H), 5.46 (s, 1H), 5.17 (d, J= 5.2 Hz, 1H), 4.37 (d, J= 9.6 Hz, 1H), 4.03 (d, J= 2.4 Hz, 1H), 3.95 (dd, J = 12.0, 1.2 Hz, 1H), 3.81 (d, J = 11.2 Hz, 1H), 3.57 (dd, J = 9.6, 4.4 Hz, 1H), 3.54 (s, 1H), 2.65 (dd, J= 9.2, 2.8 Hz, 1H). 3-{5-{4,6-O-Benzylidene-3-[(2-tert-butoxycarbonyl)hydrazinyl]-3-deoxy-p-D- galactopyranosyl}-TH-l ,2,4-triazol-l-yl}-5-chloro-2-(trifluoromethyl)pyridine

To a solution of 3-[5-(3-amino-4,6-O-benzylidene-3-deoxy-P-D-galactopyranosyl)-UT- l,2,4-triazol-l-yl]-5-chloro-2-(trifluoromethyl)pyridine (50 mg, 0.10 mmol) in DCM (5.0 mL)TV-te/7-butyloxy carbonyl-3 -(4-cyanophenyl)oxaziri dine (37.1 mg, 0.15 mmol) was added and the mixture was stirred 48 h at rt. The mixture was concentrated and purified by column chromatography (PE/EtOAc=4/ 1-0/1, Silica-CS 12 g, 30 mL/min, silica gel, UV 254) to afford the product (42 mg, 68 %). ESI-MS m/z calcd for [C26H28CIF3N6O6] [M+H]⁺: 613.2; found: 613.0. *HNMR (400 MHz, Chloroform-d) 5 8.63 (s, 1H), 8.08 (s, 1H), 7.94 (d, J = 2.0 Hz, 1H), 7.42 - 7.33 (m, 5H), 6.43 (s, 1H), 5.45 (s, 1H), 4.63 - 4.56 (m, 2H), 4.51 (d, J = 9.2 Hz, 1H), 4.31 (d, J = 2.4 Hz, 1H), 4.18 (d, J= 10.0 Hz, 1H), 3.91 (dd, J = 12.8, 1.6 Hz, 1H), 3.67 (d, J = 12.8 Hz, 1H), 3.36 (s, 1H), 3.07 (d, J= 92 Hz, 1H), 1.46 (s, 9H).

Intermediate 90

3-{5-{4,6-O-Benzylidene-3-[(2-tert-butoxycarbonyl)hydrazinyl]-3-deoxy-p-D- galactopyranosyl}-3-methyl-lEZ-l,2,4-triazol-l-yl}-2-(trifluoromethyl)-5- methylpyridine

To a solution of 3-[ 5-[4,6-<9-benzylidene-3-[(2-/c/7-butoxycarbonyl)hydrazinyl]-3- deoxy-P-D-galactopyranosyl } -3 -methyl- \H- 1 ,2,4-triazol- 1 -yl } -5-bromo-2- (trifluoromethyl)pyridine (150 mg, 0.22 mmol) and trimethylboroxine (50% in THF, 140 mg, 1.12 mmol) in l,4-dioxane/H2O (5 mL, 4: 1) Pd(dppf)C12 (49 mg, 0.067 mmol) and K2CO3 (92.6 mg, 0.67 mmol) were added. The mixture was purged three times with nitrogen, and stirred 4 h at 55 °C. The mixture was filtered, and the filtrate was acidified to pH 6-7 using TFA. The mixture was concentrated and purified by column chromatography (MeOH/DCM = 0/1-1/10, Silica-CS 12 g, 40 mL/min, silica gel, UV 254) to afford the product (104 mg, 77 %). ESI-MS m/z calcd for [C28H33F3N6O6] [M+H]⁺: 607.2; found: 607.0. 'HNMR (400 MHz, Chloroform-d) 5 8.52 (s, 1H), 7.67 (s, 1H), 7.40 - 7.34 (m, 6H), 5.42 (s, 1H), 4.53 - 4.52 (m, 1H), 4.44 (d, J= 9.6 Hz, 1H),

4.28 - 4.27 (m, 1H), 4.17 - 4.11 (m, 1H), 3.89 - 3.84 (m, 1H), 3.54 - 3.45 (m, 1H),

3.29 (s, 1H), 3.08 - 3.06 (m, 1H), 2.45 (s , 3H), 2.27 (s, 3H), 1.46 (s, 9H).

Intermediate 92

Methyl 2-chloro-2-{2- [5-chloro-2-(trifluoromethyl)pyridin-3- yl] hydrazineylidene} acetate

To a cooled (0 °C) solution of 5-chloro-2-(trifluoromethyl)pyridin-3-amine (1.18 g, 6.00 mmol) in HC1 (60 mL, 6 M) a solution of NaNCL (435 mg, 6.30 mmol) in water (5 mL) was added dropwise and the mixture was stirred 30 min at 0 °C. A solution of methyl 2-chl oro-3 -oxobutanoate (949 mg, 6.30 mmol) in EtOH (5 mL) was added dropwise over 30 min and the mixture was stirred 30 min at 0 °C. A solution of sodium acetate (1.50 g, 18.3 mmol) in water (5 mL) was added, the mixture was allowed to reach rt and was then stirred 2 h. The formed precipitate was filtered off, washed with water, and dried under vacuum to afford the product (1.2 g, 63 %). ESLMS m/z calcd for [C9H6CI2F3N3O2] [M+H]⁺: 316.0; found: 316.0. 'HNMR (400 MHz, DMSO-d₆) 8 9.69 (s, 1H), 8.50 (d, J= 1.6 Hz, 1H), 8.05 (d, J= 1.2 Hz, 1H), 3.85 (s, 3H).

Methyl 2-amino-2-{2- [5-chloro-2-(trifluoromethyl)pyridin-3- yl] hydrazineylidene} acetate

To a cooled (0 °C) solution of methyl 2-chloro-2-{2-[5-chloro-2-

(trifluoromethyl)pyridin-3-yl]hydrazineylidene}acetate (1.20 g, 3.80 mmol) in THF (5 mL) a solution of NH3 (28.5 mL, 0.4 M in 1,4-dioxane, 11.4 mmol) was added and the mixture was stirred 3 h at rt. The mixture was concentrated, and DCM (20 mL) was added. The solids were filtered off and the filtrate was evaporated to afford the product (955 mg, 85 %). ESLMS m/z calcd for [C9H8CIF3N4O2] [M+H]⁺: 297.0; found: 297.0. ‘H NMR (400 MHz, DMSO-d₆) 8 8.31 (s, 1H), 8.10 (d, J = 2.0 Hz, 1H), 7.98 (d, J = 1.6 Hz, 1H), 6.79 (s, 2H), 3.78 (s, 3H).

Methyl 2,6-anhydro-4-azido-5,7-O-benzylidene-4-deoxy-3-O-methoxymethyl-D- glycero-L-manno-heptonate

To a cooled (0 °C) solution of methyl 2,6-anhydro-4-azido-5,7-O-benzylidene-4- deoxy-D-glycero-L -manno-heptonate (17 g, 50.7 mmol) in THF (150 mL) NaH (60 %, 3.89 g, 101 mmol) was added. After stirring 5 min, bromo(methoxy)methane (12.4 mL, 152 mmol) was added and the mixture was stirred 5 min at 0 °C. The mixture was poured into water (150 mL) and extracted with EtOAc (3 x 90 mL). The combined organic phases were washed with water (100 mL) and brine (100 mL), dried over Na2SO4, concentrated, and purified by column chromatography (EtOAc/PE=l/3~l/l, Silica-CS 120 g, 85 mL/min, silica gel, UV 254) to afford the product (12 g, 62 %). ESLMS m/z calcd for [C17H21N3O7] [M+NH₄]⁺: 397.1; found: 397.4. 'H NMR (400 MHz, Chloroform-d) 6 7.48 - 7.45 (m, 2H), 7.31 - 7.19 (m, 3H), 5.53 (s, 1H), 4.68 (s, 2H), 4.29 - 4.20 (m, 3H), 3.99 (dd, J= 12.8, 1.6 Hz, 1H), 3.85 (d, J= 9.6 Hz, 1H), 3.74 (s, 3H), 3.42 (d, J= 0.8 Hz,lH), 3.33 (s, 3H), 3.26 (dd, J= 10.0, 3.6 Hz, 1H). 2,6-Anhydro-4-azido-5,7-O-benzylidene-4-deoxy-3-O-methoxymethyl-D-glycero-

L-manno-heptonic acid

To a solution of methyl 2,6-anhydro-4-azido-5,7-(9-benzylidene-4-deoxy-3-(9- methoxymethyl-D-glycero-L -manno-heptonate (1.30 g, 3.43 mmol) in MeOH (20 mL) a solution of lithium hydroxide monohydrate (288 mg, 6.85 mmol) in water (10 mL) was added and the mixture was stirred 30 min at rt. The mixture was concentrated and dissolved in water (50 mL). The pH of the mixture was adjusted to 4-5 using 1 M HC1, and the mixture was extracted with EtOAc (2 x 50 mL). The combined organic phases were washed with brine, dried over Na2SO₄, and evaporated to give the product (1 g, 80 %). ESLMS m/z calcd for [C16H19N3O7] [M+NH₄]⁺: 383.2; found: 383.2. 'HNMR (400 MHz, Chloroform-d) 5 7.53 - 7.51 (m, 2H), 7.41 - 7.35 (m, 3H), 5.60 (s, 1H), 4.77 (s, 2H), 4.36 - 4.32 (m, 2H), 4.23 (t, J = 9.6 Hz, 1H), 4.06 (dd, J = 12.8, 1.6 Hz, 1H), 3.96 (d, J= 9.2 Hz, 1H), 3.53 (d, J= 0.8 Hz, 1H), 3.44 (s, 3H), 3.33 (dd, J= 10.0, 3.6 Hz, 1H).

3-[5-(3-Azido-4,6-O-benzylidene-3-deoxy-2-O-methoxymethyl-p-D- galactopyranosyl)-3-(methoxycarbonyl)- 1H- 1 ,2,4-triazol- 1-yl] -5-chloro-2-

(trifluoromethyl)pyridine

To a solution of 2,6-anhydro-4-azido-5,7-(9-benzylidene-4-deoxy-3-(9- methoxymethyl-D-glycero-L-manno-heptonic acid (880 mg, 2.41 mmol) in MeCN (10 mL) 4-(dimethylamino)pyridine (88.3 mg, 0.72 mmol), 2-chloro-l -methylpyridinium iodide (880 mg, 3.44 mmol) and DIPEA (881 mg, 6.82 mmol) were added and the mixture was stirred 10 min at rt. A solution of methyl 2-amino-2-{2-[5-chl oro-2 - (trifluoromethyl)pyridin-3-yl]hydrazineylidene}acetate (879 mg, 2.96 mmol) in MeCN (10 mL) was added and the mixture was stirred 2 h at rt. Acectic acid (20 mL) was added and the mixture was stirred 2 h at 65 °C. The mixture was cooled to rt, concentrated, poured into water (20 mL), and extracted with EtOAc (2 x 25 mL). The combined organic phases were washed with water (20 mL) and brine (20 mL), dried over Na2SO4, concentrated, and purified by column chromatography (EtOAc/PE = 0/1 ~ 1/2, Silica-CS 25 g, 25 mL/min, silica gel, UV 254) to afford the product (350 mg, 83 % purity, 19 %). ESLMS m/z calcd for [C25H23CF3N7O7] [M+H]⁺: 626.1; found: 626.2. ^XH NMR (400 MHz, DMSO-d₆) 8 8.86 (s, 1H), 8.49 (d, J= 2.0 Hz, 1H), 7.42 - 7.30 (m, 5H), 5.59 (s, 1H), 4.77 (d, J = 92 Hz, 1H), 4.56 - 4.50 (m, 2H), 4.45 (d, J = 3.2 Hz, 1H), 4.11 (t, J = 1.6 Hz, 1H), 4.02 - 3.99 (m, 1H), 3.88 (s, 3H), 3.82 (d, J = 12.0 Hz, 1H), 3.62 - 3.59 (m, 2H), 3.13 (s, 3H).

3-[5-(3-Amino-4,6-O-benzylidene-3-deoxy-2-O-methoxymethyl-p-D- galactopyranosyl)-3-(methoxycarbonyl)- 1H- 1 ,2,4-triazol- 1-yl] -5-chloro-2- (trifluoromethyl)pyridine

To a solution of 3-[5-(3-azido-4,6-(9-benzylidene-3-deoxy-2-(9-methoxymethyl-P-D- galactopyranosyl)-3-(methoxycarbonyl)-U7-l,2,4-triazol-l-yl]-5-chloro-2- (trifluoromethyl)pyridine (350 mg, 83 % purity, 0.46 mmol) in THF/water (12 mL, 5:1) triphenylphosphine (365 mg, 1.39 mmol) was added and the mixture was stirred 16 h at 50 °C. The mixture was concentrated and purified by column chromatography (DCM/MeOH= I/O- 10/1, Silica-CS 20 g, 30 mL/min, silica gel, UV 254) to afford the product (250 mg, 89 % purity, 80 %). ESLMS m/z calcd for [C25H25CIF3N5O7] [M+H]⁺: 600.1; found: 600.3. 'HNMR (400 MHz, DMSO-d₆) 6 8.83 - 8.82 (m, 1H), 8.42 (d, J = 1.6 Hz, 1H), 7.42 - 7.30 (m, 5H), 5.47 (s, 1H), 4.67 - 4.62 (m, 2H), 4.53 (d, J= 6.8 Hz, 1H), 4.08 - 4.03 (m, 1H), 3.98 - 3.95 (m, 1H), 3.87 (s, 3H), 3.79 (d, J = 12.4 Hz, 1H), 3.70 - 3.65 (m, 1H), 3.60 (s, 1H), 3.29 (s, 2H), 2.99 (s, 3H), 2.92 - 2.90 (m, 1H). 3-[5-(4,6-O-Benzylidene-3-[(2-terf-butoxycarbonyl)hydrazinyl]-3-deoxy-2-O- methoxymethyl-p-D-galactopyranosyl)-3-(methoxycarbonyl)- 1H- 1 ,2,4-triazol- 1- yl]-5-chloro-2-(trifluoromethyl)pyridine

To a solution of 3-[5-(3-amino-4,6-O-benzylidene-3-deoxy-2-O-methoxymethyl-P-D- galactopyranosyl)-3-(methoxycarbonyl)-U7-l,2,4-triazol-l-yl]-5-chloro-2-

(trifluoromethyl)pyridine (250 mg, 89 % purity, 0.37 mmol) in DCM (25 mL) N-tert- butyloxycarbonyl-3-(4-cyanophenyl)oxaziridine (137 mg, 0.56 mmol) was added and the mixture was stirred overnight at rt. The mixture was concentrated and purified by column chromatography (EtOAc/DCM=l/4~l/l, Silica-CS 12 g, 30 mL/min, silica gel, UV 254) to afford the product (189 mg, 71 %). ESI-MS m/z calcd for [C30H34CIF3N6O9] [M+H]⁺: 715.2; found: 714.9. 'H NMR (400 MHz, DMSO-d₆) 8 8.87 - 8.84 (m, 1H), 8.42 - 8.41 (m, 2H), 7.38 - 7.33 (m, 5H), 5.45 (s, 1H), 4.70 (d, J= 10.0 Hz, 1H), 4.64 - 4.55 (m, 3H), 4.21 (d, J= 2.4 Hz, 1H), 3.99 - 3.98 (m, 1H), 3.87 (s, 3H), 3.81 - 3.78 (m, 2H), 3.58 (s, 1H), 3.02 - 3.01 (m, 4H), 1.36 (s, 9H).

3-{5-{3-[4-(4-Chloro-2,3-difluorophenyl)-lEZ-l,2-pyrazol-l-yl]-3-deoxy-2-O- methoxymethyl-p-D-galactopyranosyl)-3-(methoxycarbonyl)-lZ/-l ,2,4-triazol-l- yl]-5-chloro-2-(trifluoromethyl)pyridine

To a solution of 3-[5-(4,6-O-benzylidene-3-[(2-ter/-butoxycarbonyl)hydrazinyl]-3- deoxy-2-O-methoxymethyl-P-D-galactopyranosyl)-3-(methoxycarbonyl)-U7-l,2,4- triazol-l-yl]-5-chloro-2-(trifhioromethyl)pyridine (189 mg, 0.26 mmol) in MeOH (10.0 mL) 2-(4-chloro-2,3-difluorophenyl)-3-(dimethylamino)prop-2-enal (97.4 mg, 0.040 mmol) was added followed by concentrated HC1 (0.50 mL) and the mixture was stirred 2 h at 80 °C. The mixture was cooled to rt and neutralized by addition of saturated aq NaHCCh. The mixture was concentrated and purified by column chromatography (MeOH/DCM = 0/1-1/20, Silica-CS 20 g, 30 mL/min, silica gel, UV 254) and then reversed-phase chromatography (MeCN/LLO = 1/20-2/1, C-18 column, 20 mL/min, UV 214) to afford the product (101 mg, 57 %). ESLMS m/z calcd for [C25HI₉C12F₅N6O₆] [M+H]⁺: 665.1; found: 665.0. 'H NMR (400 MHz, Methanol-d₄) 8 8.99 (d, J= 2.0 Hz, 1H), 8.44 (s, 1H), 8.25 (d, J= 1.6 Hz, 1H), 7.96 (s, 1H), 7.50 - 7.45 (m, 1H), 7.30 - 7.26 (m, 1H), 4.78 (t, J= 10.4 Hz, 1H), 4.54 (d, J= 9.6 Hz, 1H), 4.45 (dd, J = 10.4, 2.8 Hz, 1H), 4.07 (d, J= 2.0 Hz, 1H), 4.00 (s, 3H), 3.70 (t, J = 6.0 Hz, 1H), 3.62 - 3.54 (m, 2H).

3-{3- Aminocar bonyl-5-{3-[4-(4-chloro-2, 3-difluorophenyl)- 1EZ-1, 2-pyrazol-l-yl]-

3-deoxy-2-(7-methoxymethyl-|Ll)-«alactopyranosyl)-l//-l .2.4-1 riazol-l-yl|-5- chloro-2-(trifluoromethyl)pyridine

A solution of3-{5-{3-[4-(4-chloro-2,3-difluorophenyl)-lJ/-l,2-pyrazol-l-yl]-3-deoxy- 2-<9-methoxymethyl-P-D-galactopyranosyl)-3-(methoxycarbonyl)-U/-l,2,4-triazol-l- yl]-5-chloro-2-(trifluoromethyl)pyridine (60 mg, 0.090 mmol) in ammonia (5 mL, 7 N in MeOH) was stirred 16 h at rt. The mixture was concentrated and purified by reversed-phase chromatography (MeCN/H2O = 1/20-1/1, C-18 column, 30 mL/min, UV 254) to afford the product (31 mg, 53 %). ESLMS m/z calcd for [C24H18CI2F5N7O5] [M+H]⁺: 650.1; found: 650.0. 'H NMR (400 MHz, Methanol-d₄) 6 8.98 (d, J= 2.0 Hz, 1H), 8.42 (d, J= 1.2 Hz, 1H), 8.25 (d, J= 1.2 Hz, 1H), 7.97 (s, 1H), 7.50 - 7.46 (m, 1H), 7.30 - 7.26 (m, 1H), 4.81 (t, J= 9.6 Hz, 1H), 4.51 (d, J= 9.2 Hz, 1H), 4.46 (dd, J = 10.4, 2.4 Hz, 1H), 4.09 (d, J= 2.4 Hz, 1H), 3.68 (t, J= 6.0 Hz, 1H), 3.56 (d, J= 6.0 Hz, 2H). Intermediate 93

3-[5-(3-Azido-4,6-O-benzylidene-3-deoxy-2-O-methoxymethyl-p-D- galactopyranosyl)-3-carboxy- 1H- 1 ,2,4-triazol- 1-yl] -5-chloro-2- (trifluoromethyl)pyridine

To a solution of 3-[5-(3-azido-4,6-O-benzylidene-3-deoxy-2-O-methoxymethyl-P-D- galactopyranosyl)-3-(methoxycarbonyl)-U7-l,2,4-triazol-l-yl]-5-chloro-2- (trifluoromethyl)pyridine (1.80 g, 2.88 mmol) in MeOH (10 mL) and THF (20 mL) a solution of lithium hydroxide monohydrate (145 mg, 3.45 mmol) in water (10 mL) was added and the mixture was stirred 1 h at rt. HC1 (20 mL, 0.2 M) was added and the mixture was extracted with EtOAc (2 x 50 mL). The combined organic phases were washed with brine (50 mL), dried over ISfeSCU, concentrated, and purified by column chromatography (MeOH/DCM = 0/1-1/15, Silica-CS 40 g, 50 mL/min, silica gel, UV 254) to afford the product (1.15 g, 65 %). ESLMS m/z calcd for [C24H21CIF3N7O7] [M+H]⁺: 612.1; found: 612.2. ^XH NMR (400 MHz, DMSO-d₆) 8 13.87 (br s, 1H), 8.90 (br s, 1H), 8.52 (d, J= 2.0 Hz, 1H), 7.44 - 7.33 (m, 5H), 5.62 (s, 1H), 4.77 (d, J = 92 Hz, 1H), 4.61 - 4.60 (m, 1H), 4.54 (d, J = 6.8 Hz, 1H), 4.47 (d, J = 3.2 Hz, 1H), 4.15 (t, J= 9.6 Hz, 1H), 4.05 - 4.02 (m, 1H), 3.85 (d, J= 13.2 Hz, 1H), 3.65 - 3.60 (m, 2H), 3.17 (s, 3H).

3-{5-(3-Azido-4,6-O-benzylidene-3-deoxy-2-O-methoxymethyl-p-D- galactopyranosyl)-3-{[2-(trimethylsilyl)ethyl]carbamoyl}-l/7-l,2,4-triazol-l-yl}- 5-chloro-2-(trifluoromethyl)pyridine

To a solution of 3-[5-(3-azido-4,6-O-benzylidene-3-deoxy-2-O-methoxymethyl-P-D- galactopyranosyl)-3-carboxy-U7-l,2,4-triazol-l-yl]-5-chloro-2-

(trifluoromethyl)pyridine (1.15 g, 1.88 mmol) in 1,4-dioxane (10.0 mL) diphenyl phosphoryl azide (0.608 mL, 2.82 mmol) and DIPEA (0.524 mL, 3.76 mmol) were added and the mixture was stirred 2 h at 50 °C. 2-(Trimethylsilyl)ethanol (889 mg, 7.52 mmol) was added and the mixture was stirred 2 h at 100 °C. The mixture was concentrated, water (20 mL) was added, and the mixture was extracted with EtOAc (2 x 20 mL). The combined organic phases were dried over ISfeSCU, concentrated, and purified by column chromatography (EtOAc/PE = 0/1— 1/1 , Silica-CS 25 g, 25 mL/min, silica gel, UV 254) to afford the product (721 mg, 53 %). ESLMS m/z calcd for [C29H34ClF₃N₈O7Si] [M+H]⁺: 727.2; found: 727.2. ¹ H NMR (400 MHz, DMSO-d₆) 8 10.28 (s, 1H), 8.89 (s, 1H), 8.41 (d, J= 1.6 Hz, 1H), 7.39 - 7.32 (m, 5H), 5.61 (s, 1H), 4.64 - 4.62 (m, 1H), 4.56 (d, J= 9.6 Hz, 1H), 4.49 (d, J= 6.8 Hz, 1H), 4.43 (d, J= 2.8 Hz, 1H), 4.14 - 4.10 (m, 3H), 4.03 - 3.99 (m, 1H), 3.89 - 3.86 (m 1H), 3.59 - 3.54 (m, 2H), 3.18 (s, 3H), 0.97 - 0.92 (m, 2H), 0.02 (s, 9H).

3-[3-Amino-5-(3-azido-4,6-O-benzylidene-3-deoxy-2-O-methoxymethyl-p-D- galactopyranosyl)- 1H- 1 ,2,4-triazol- 1-yl] -5-chloro-2-(trifluoromethyl)pyridine

To a solution of 3-{5-(3-azido-4,6-O-benzylidene-3-deoxy-2-O-methoxymethyl-P-D- galactopyranosyl)-3-{[2-(trimethylsilyl)ethyl]carbamoyl}-U/-l,2,4-triazol-l-yl}-5- chloro-2-(trifluoromethyl)pyridine (720 mg, 0.99 mmol) in THF (10.0 mL) TBAF (1.98 mL, 1 M in THF, 1.98 mmol) was added and the mixture was stirred 2 h at 50 °C. Water (30 mL) was added and the mixture was extracted with EtOAc (3 x 30 mL). The combined organic phases were dried, concentrated, and purified by column chromatography (EtOAc/DCM = 0/1— 1/1, Silica-CS 20 g, 30 mL/min, silica gel, UV254) to afford the product (405 mg, 70 %). ESI-MS m/z calcd for [C23H22CIF3N8O5] [M+H]⁺: 583.1; found: 583.2. 'HNMR (400 MHz, DMSO-d₆) 8 8.88 (s, 1H), 8.29 (d, J = 1.6 Hz, 1H), 7.42 - 7.35 (m, 5H), 5.79 (s, 2H), 5.64 (s, 1H), 4.64 (d, J = 6.8 Hz, 1H), 4.51 (d, J = 6.4 Hz, 1H), 4.44 (d, J= 2.8 Hz, 1H), 4.41 (d, J = 9.6 Hz, 1H), 4.18 (t, J= 10.0 Hz, 1H), 4.06 - 4.02 (m, 1H), 3.95 - 3.92 (m, 1H), 3.59 - 3.54 (m, 2H), 3.24 (s, 3H).

3-[5-(3-Azido-4,6-O-benzylidene-3-deoxy-2-O-methoxymethyl-p-D- galactopyranosyl)-3-bromo- 1H- 1 ,2,4-triazol- 1-yl] -5-chloro-2- (trifluoromethyl)pyridine

To a cooled (0 °C) solution of3-[3-amino-5-(3-azido-4,6-O-benzylidene-3-deoxy-2-O- methoxymethyl-P-D-galactopyranosyl)-lZ/-l,2,4-triazol-l-yl]-5-chloro-2- (trifluoromethyl)pyridine (400 mg, 0.69 mmol) in MeCN (10.0 mL) CuBr (197 mg, 1.37 mmol) and CuBr2 (230 mg, 1.03 mmol) were added followed by pentyl nitrite (121 mg, 1.03 mmol). The mixture was stirred 1 h at 0 °C, stirred overnight at rt, and then stirred 4 h at 80 °C. Water (30 mL) was added and the mixture was extracted with EtOAc (3 x 30 mL). The combined organic phases were dried over Na2SO4, concentrated, and purified by column chromatography (EtOAc/PE = 0/1— 1/1, Silica- CS 20 g, 30 mL/min, silica gel, UV254) to afford the prodct (321 mg, 72 %). ESLMS m/z calcd for [C23H2oBrClF₃N70₅] [M+H]⁺: 646.0; found: 646.1. 'H NMR (400 MHz, DMSO-de) 6 8.89 (s, 1H), 8.49 (d, J= 2.0 Hz, 1H), 7.45 - 7.32 (m, 5H), 5.61 (s, 1H), 4.75 (d, J= 9.6 Hz, 1H), 4.58 (s, 2H), 4.46 (d, J= 3.2 Hz, 1H), 4.08 (t, J= 9.6 Hz, 1H), 4.04 - 4.01 (m, 1H), 3.85 (d, J= 12.0 Hz, 1H), 3.66 - 3.63 (m, 2H), 3.18 (s, 3H). 3-[5-(3-Amino-4,6-O-benzylidene-3-deoxy-2-O-methoxymethyl-p-D- galactopyranosyl)-3-bromo- 1H- 1 ,2,4-triazol- 1-yl] -5-chloro-2- (trifluoromethyl)pyridine

To a solution of 3-[5-(3-azido-4,6-O-benzylidene-3-deoxy-2-O-methoxymethyl-P-D- galactopyranosyl)-3-bromo-U/-l,2,4-triazol-l-yl]-5-chloro-2-

(trifluoromethyl)pyridine (160 mg, 0.25 mmol) in THF (5.0 mL) and water (0.3 mL) triphenylphosphine (260 mg, 0.99 mmol) was added and the mixture was stirred 16 h at 50 °C. The mixture was concentrated and purified by column chromatography (DCM/MeOH= I/O- 10/1, Silica-CS 20 g, 30 mL/min, silica gel, UV 254) to afford the product (133 mg, 87 %). ESI-MS m/z calcd for ^slfeBrClFsNsOs] [M+H]⁺: 620.0; found: 620.2. 'H NMR (400 MHz, DMSO-d₆) 8 8.84 - 8.82 (m, 1H), 8.41 (d, J= 2.0 Hz, 1H), 7.44 - 7.32 (m, 5H), 5.49 (s, 1H), 4.73 (d, J= 6.4 Hz, 1H), 4.60 (d, J= 9.6 Hz, 1H), 4.56 (d, J = 6.4 Hz, 1H), 4.04 - 4.02 (m, 1H), 3.97 (d, J= 10.8 Hz, 1H), 3.81 (d, J= 12.0 Hz, 1H), 3.65 - 3.59 (m, 2H), 3.06 (s, 3H), 2.84 (dd, J= 9.2, 2.8 Hz, 1H), 2.02 - 1.84 (m, 2H).

3-[5-(4,6-O-Benzylidene-3-[(2-terf-butoxycarbonyl)hydrazinyl]-3-deoxy-2-O- methoxymethyl-p-D-galactopyranosyl)-3-bromo-lH-l,2,4-triazol-l-yl]-5-chloro- 2-(trifluoromethyl)pyridine

To a cooled (-78 °C) solution of 3-[5-(3-amino-4,6-O-benzylidene-3-deoxy-2-O- methoxymethyl-P-D-galactopyranosyl)-3-bromo-17/-l,2,4-triazol-l-yl]-5-chloro-2-

(trifluoromethyl)pyridine (120 mg, 0.19 mmol) in DCM (5.0 mL) a solution of tert- butyl 3-(trichloromethyl)oxaziridine-2-carboxylate (60.9 mg, 0.23 mmol) in DCM (1 mL) was added dropwise and the mixture was stirred 2 h at -78 °C. The mixture was concentrated and purified by reversed-phase chromatography (MeCN/H2O = 1/20-5/1, C-18 column, 30 mL/min, UV 214) to afford the product (66 mg, 46 %). ESLMS m/z calcd for ^HsiBrClFsNeO?] [M+H]⁺: 735.1; found: 735.1. 'H NMR (400 MHz, DMSO-de) 6 8.88 (s, 1H), 8.45 (s, 1H), 8.41 (d, J= 2.0 Hz, 1H), 7.40 - 7.37 (m, 5H), 5.47 (s, 1H), 4.71 (d, J= 6.0 Hz, 1H), 4.67 (d, J= 9.6 Hz, 1H), 4.59 (d, J= 6.4 Hz, 2H), 4.23 (d, .7= 2.8 Hz, 1H), 4.02 (d, J= 11.6 Hz, 1H), 3.85 - 3.76 (m, 2H), 3.59 (s, 1H), 3.08 (s, 3H), 3.03 - 3.00 (m, 1H), 1.39 (s, 9H).

Intermediate 94

3-[5-(3-Azido-4,6-O-benzylidene-3-deoxy-2-O-methoxymethyl-p-D- galactopyranosyl)-3-chloro- LH- 1 ,2,4-triazol- 1-yl] -5-chloro-2- (trifluoromethyl)pyridine

To a cooled (0 °C) solution of3-[3-amino-5-(3-azido-4,6-O-benzylidene-3-deoxy-2-O- methoxymethyl-P-D-galactopyranosyl)-l//-l,2,4-triazol-l-yl]-5-chloro-2- (trifluoromethyl)pyridine (240 mg, 0.41 mmol) in MeCN (10.0 mL) CuCl (90 mg, 0.91 mmol) and CuCh (122 mg, 0.91 mmol) were added followed by pentyl nitrite (77 mg, 0.66 mmol). The mixture was stirred 1 h at rt, and then stirred 4 h at 80 °C. Water (20 mL) was added and the mixture was extracted with EtOAc (3 x 30 mL). The combined organic phases were dried over ISfeSCU, concentrated, and purified by column chromatography (EtOAc/PE = 0/1— 1/1 , Silica-CS 20 g, 30 mL/min, silica gel, UV254) to afford the prodct (189 mg, 76 %). ESLMS m/z calcd for [C23H20CI2F3N7O5] [M+H]⁺: 602.1; found: 601.8. *H NMR (400 MHz, DMSO-d₆) 8 8.89 (s, 1H), 8.51 (d, J = 2.0 Hz, 1H), 7.45 - 7.39 (m, 3H), 7.34 - 7.32 (m, 2H), 5.61 (s, 1H), 4.76 (d, J = 92 Hz, 1H), 4.59 (s, 2H), 4.46 (d, J= 2.8 Hz, 1H), 4.11 - 4.00 (m, 2H), 3.84 (d, J= 11.6 Hz, 1H), 3.66 - 3.63 (m, 2H), 3.19 (s, 3H). 3-[5-(3-Amino-4,6-O-benzylidene-3-deoxy-2-O-methoxymethyl-p-D- galactopyranosyl)-3-chloro- TH- 1 ,2,4-triazol- 1-yl] -5-chloro-2-

(trifluoromethyl)pyridine

To a solution of 3-[5-(3-azido-4,6-O-benzylidene-3-deoxy-2-O-methoxymethyl-P-D- galactopyranosyl)-3-chloro-lrt-l,2,4-triazol-l-yl]-5-chloro-2-

(trifluoromethyl)pyridine (185 mg, 0.31 mmol) in THF (10 mL) and water (2.5 mL) triphenylphosphine (322 mg, 1.23 mmol) was added and the mixture was stirred 16 h at 50 °C. The mixture was concentrated and purified by column chromatography (DCM/MeOH= I/O- 10/1, Silica-CS 20 g, 30 mL/min, silica gel, UV 254) to afford the product (165 mg, 83 %). ESI-MS m/z calcd for [C23H22CI2F3N5O5] [M+H]⁺: 576.1; found: 576.3. 'HNMR (400 MHz, DMSO-d₆) 8 8.84 (s, 1H), 8.43 (d, J= 2.0 Hz, 1H), 7.44 - 7.39 (m, 3H), 7.34 - 7.32 (m, 2H), 5.49 (s, 1H), 4.74 (d, J= 6.8 Hz, 1H), 4.60 (d, .7= 9.6 Hz, 1H), 4.57 (d, J = 6.4 Hz, 1H), 4.06 - 3.96 (m, 2H), 3.81 (d, J= 11.6 Hz, 1H), 3.65 - 3.60 (m, 2H), 3.07 (s, 3H), 2.84 (dd, J= 9.6, 3.2 Hz, 1H), 1.78 (br s, 2H).

3-[5-(4,6-O-Benzylidene-3-[(2-tert-butoxycarbonyl)hydrazinyl]-3-deoxy-2-O- methoxymethyl-p-D-galactopyranosyl)-3-chloro- 1H- 1 ,2,4-triazol- 1-yl] -5-chloro-

2-(trifluoromethyl)pyridine

To a cooled (-45 °C) solution of 3-[5-(3-amino-4,6-O-benzylidene-3-deoxy-2-O- methoxymethyl-P-D-galactopyranosyl)-3-chloro-U/-l,2,4-triazol-l-yl]-5-chloro-2- (trifluoromethyl)pyridine (165 mg, 0.29 mmol) in DCM (5.0 mL) a solution of tertbutyl 3-(trichloromethyl)oxaziridine-2-carboxylate (97.7 mg, 0.37 mmol) in DCM (1 mL) was added and the mixture was stirred 30 min at -45 °C. MeOH (5 mL) was added and the mixture was concentrated to a volume of 3 mL that was purified by reversed- phase chromatography (MeCN/JLO = 1/20-5/1, C-18 column, 30 mL/min, UV 214) to afford the product (68 mg, 34 %). ESLMS m/z calcd for [C28H31CI2F3N6O7] [M+H]⁺: 691.2; found: 691.2. 'HNMR (400 MHz, DMSO-d₆) 8 8.89 (s, 1H), 8.46 (s, 1H), 8.43 (d, J= 1.6 Hz, 1H), 7.44 - 7.36 (m, 5H), 5.47 (s, 1H), 4.72 (d, J= 5.6 Hz, 1H), 4.67 (d, J = 10.0 Hz, 1H), 4.60 (d, J = 6.8 Hz, 2H), 4.23 (d, J= 2.4 Hz, 1H), 4.02 (d, J = 12.0 Hz, 1H), 3.84 - 3.77 (m, 2H), 3.59 (s, 1H), 3.09 (s, 3H), 3.03- 3.00 (m 1H), 1.39 (s, 9H).

Intermediate 95

3-[5-(3-Azido-4,6-O-benzylidene-3-deoxy-2-O-methoxymethyl-p-D- galactopyranosyl)-3-iodo- 1H- 1 ,2,4-triazol- 1-yl] -5-chloro-2- (trifluoromethyl)pyridine

To a cooled (0 °C) solution of3-[3-amino-5-(3-azido-4,6-O-benzylidene-3-deoxy-2-O- methoxymethyl-P-D-galactopyranosyl)-lZ/-l,2,4-triazol-l-yl]-5-chloro-2- (trifluoromethyl)pyridine (410 mg, 0.70 mmol) and diiodomethane (5.65 g, 21.1 mmol) in MeCN (10.0 mL) tert-butyl nitrite (77 mg, 0.66 mmol) was added. The mixture was stirred 1 h at rt, and then stirred 3 h at 80 °C. Water (50 mL) was added and the mixture was extracted with EtOAc (3 x 30 mL). The combined organic phases were dried over Na2SC>4, concentrated, and purified by column chromatography (EtOAc/PE = 0/1— 1/1, Silica-CS 20 g, 30 mL/min, silica gel, UV254) to afford the prodct (365 mg, 75 %). ESLMS m/z calcd for [C23H20CIF3IN7O5] [M+H]⁺: 694.0; found: 693.8. ‘H NMR (400 MHz, Chloroform-d) 6 7.95 - 7.91 (m, 2H), 7.39 - 7.34 (m, 3H), 7.29 - 7.26 (m, 2H), 5.36 (s, 1H), 4.71 (d, J = 7.2 Hz, 1H), 4.55 (d, J= 9.6 Hz, 1H), 4.51 (d, J = 7.2 Hz, 1H), 4.18 (d, J= 2.8 Hz, 1H), 4.03 (dd, J= 12.8, 1.2 Hz, 1H), 3.97 (t, J= 10.0 Hz, 1H), 3.84 (dd, J= 12.4, 1.2 Hz, 1H), 3.36 (d, J= 1.2 Hz, 1H), 3.30 (dd, J = 10.0, 3.2 Hz, 1H), 3.11 (s, 3H). 3-[5-(3-Azido-4,6-(?-benzylidene-3-deoxy-2-(?-methoxymethyl-p-D- galactopyranosyl)-3-vinyl- 1H- 1 ,2,4-triazol- l-yl]-5-chloro-2-

(trifluoromethyl)pyridine

A solution of 3-[5-(3-azido-4,6-(9-benzylidene-3-deoxy-2-(9-methoxymethyl-P-D- galactopyranosyl)-3-iodo- l //- 1 , 2, 4-triazol- l -yl]-5-chloro-2-(tri fluoromethyl Jpyridine (120 mg, 0.17 mmol), 2,4,6-ethenylboroxin-pyridine complex (83.3 mg, 0.35 mmol), K2CO3 (71.7 mg, 0.52 mmol) and Pd(dppf)C12 (24.3 mg, 0.035 mmol) in 1,4- dioxane/JtO (12 mL, 5: 1) was purged three times with nitrogen and stirred 16 h at 40 °C. The mixture was concentrated and purified by column chromatography (PE/EtOAc = 1/0— 1/1, Silica-CS 20 g, 30 mL/min, silica gel, UV 254) to give the product (95 mg, 87 %). ESI-MS m/z calcd for [C25H23CIF3N7O5] [M+H]⁺: 594.1; found: 594.2. 'HNMR (400 MHz, Chloroform-d) 5 8.07 (s, 1H), 8.02 (s, 1H), 7.45 - 7.35 (m, 5H), 6.69 (dd, J = 17.6, 11.2 Hz, 1H), 6.36 (dd, J= 17.6, 1.6 Hz, 1H), 5.60 (dd, J= 11.2, 1.6 Hz, 1H), 5.44 (s, 1H), 4.77 (d, J = 7.2 Hz, 1H), 4.64 - 4.60 (m, 2H), 4.26 (d, J = 2.8 Hz, 1H), 4.14 - 4.09 (m, 2H), 3.92 (dd, J = 12.8, 1.2 Hz, 1H), 3.43 (s, 1H), 3.37 (dd, J = 10.0, 3.2 Hz, 1H), 3.16 (s, 3H).

3-[5-(3-Amino-4,6-(?-benzylidene-3-deoxy-2-(?-methoxymethyl-p-D- galactopyranosyl)-3-ethyl- 1H- 1 ,2,4-triazol- l-yl]-5-chloro-2- (trifluoromethyl)pyridine

To a solution of 3-[5-(3-azido-4,6-O-benzylidene-3-deoxy-2-O-methoxymethyl-P-D- galactopyranosyl)-3-vinyl-U/-l,2,4-triazol-l-yl]-5-chloro-2-(trifluoromethyl)pyridine (95 mg, 0.16 mmol) in EtOAc (30 mL) PtCL (7.3 mg, 0.032 mmol) was added and the mixture was stirred 4 h at rt. The mixture was filtered, concentrated, and the obtained material was dissolved in THF (10 mL) and water (1 mL). Triphenylphosphine (126 mg, 0.48 mmol) was added, and the mixture was stirred 6 h at 50 °C. The mixture was concentrated and purified by column chromatography (DCM/MeOH=l/0~20/l, Silica- CS 20 g, 30 mL/min, silica gel, UV 254) to afford the product (59 mg, 65 %). ESLMS m/z calcd for [C25H27CIF3N5O5] [M+H]⁺: 570.2; found: 570.2. 'H NMR (400 MHz, Chloroform^/) 5 8.49 (d, J= 1.6 Hz, 1H), 7.97 (d, J= 1.2 Hz, 1H), 7.41 - 7.36 (m, 5H), 5.47 (s, 1H), 4.62 (s, 2H), 4.36 (d, J = 9.2 Hz, 1H), 4.26 (s, 1H), 4.06 (d, J = 12.8 Hz, 1H), 3.97 - 3.90 (m, 2H), 3.41 (s, 1H), 3.30 (s, 3H), 2.94 - 2.92 (m, 1H), 2.79 (q, J = 7.6 Hz, 2H), 2.40 - 2.35 (m, 2H), 1.33 (t, J= 7.6 Hz, 3H).

3-[5-(4,6-O-Benzylidene-3-[(2-tert-butoxycarbonyl)hydrazinyl]-3-deoxy-2-O- methoxymethyl-p-D-galactopyranosyl)-3-ethyl-lH-l,2,4-triazol-l-yl]-5-chloro-2- (trifluoromethyl)pyridine

To a cooled (-78 °C) solution of 3-[5-(3-amino-4,6-O-benzylidene-3-deoxy-2-O- methoxymethyl-P-D-galactopyranosyl)-3-ethyl-lrt-l,2,4-triazol-l-yl]-5-chloro-2- (trifluoromethyl)pyridine (59 mg, 0.10 mmol) in DCM (5.0 mL) a solution of tert-butyl 3-(trichloromethyl)oxaziridine-2-carboxylate (40.8 mg, 0.16 mmol) in DCM (1 mL) was added dropwise and the mixture was stirred 2 h at -78 °C. The mixture was concentrated and purified by reversed-phase chromatography (MeCN/FLO = 1/20-5/1, C-18 column, 30 mL/min, UV 214) to afford the product (37 mg, 52 %). ESI-MS m/z calcd for [C30H36CIF3N6O7] [M+H]⁺: 685.2; found: 685.4. 'H NMR (400 MHz, Chloroform-d) 5 8.27 (d, J= 1.2 Hz, 1H), 7.94 (s, 1H), 7.35 - 7.30 (m, 5H), 6.21 (br s, 1H), 5.38 (s, 1H), 4.65 (d, J= 6.4 Hz, 1H), 4.60 (s, 1H), 4.55 (d, J= 6.8 Hz, 1H), 4.36 (d, J= 10.0 Hz, 1H), 4.26 (s, 1H), 4.02 - 3.94 (m, 2H), 3.87 (d, J= 11.6 Hz, 1H), 3.31 (s, 1H), 3.16 (s, 3H), 3.01 (d, J= 10.0 Hz, 1H), 2.73 (q, J= 7.6 Hz, 2H), 1.37 (s, 9H),

1.26 (t, J= 7.6 Hz, 3H).

Other processes

Synthesis of (3R,4R)-4-fluoropyrrolidin-3-ol HC1

Abbreviations:

Bz: benzoyl

DBN: 1,5-Diazabicyclo [4.3.0]non-5-ene

DCM: dichloromethane

DMSO: dimethylsulfoxide

EDTA: ethylenediaminetetraacetic acid

HFIP: hexafluoroisopropanol

HPLC: high pressure liquid chromatography

NBS: A-bromosuccinimide

S al en : N,N' -Di sali cyli dene -ethyl enedi amine

TBME: /-butyl methyl ether

THF : tetrahydrofuran

TLC: thin layer chromatography

Synthesis of (2,5-dihydro-lH-pyrrol-l-yl)(phenyl)methanone (CFOH-2)

N - Boc-2 , 5-d i h yd ro CFOH-1 CFOH-2 -1H-pyrrole N-Boc-2,5-dihydro-lH-pyrrole (500g, 2.95 moles) in THF (250ml, 0.5 vol) was added to a stirred mixture of THF (2250ml, 4.5 vol), water (250ml, 0.5 vol) and concentrated hydrochloric acid (369ml, 1.5 equiv) at 10-20°C. The reaction was heated to 35-45°C and maintained at this temperature for 6-8 hours when analysis (TLC) showed no starting material remaining. THF was removed from the reaction mixture under vacuum at < 45°C, and water (2500ml, 5 vol) charged. The reaction mixture was cooled to 15-20°C and sodium carbonate (563g, 1.8 equiv) charged slowly. The reaction mixture was stirred for 15-30 minutes at 15-20°C, cooled to 0-10°C and benzoyl chloride (424g, 1.02 equiv) added over 30-45 mins maintaining the temperature at 0- 10°C. The temperature was allowed to increase to 15-20°C, and the reaction stirred at this temperature for 2-3 hours when analysis (TLC) showed complete reaction. The reaction mixture was filtered and the solid washed sequentially with ethyl acetate (2500ml, 5.0 vol) and water (1500ml, 3 vol). The biphasic mixture was stirred for 10- 15 mins and the layers separated. The aqueous layer was washed with ethyl acetate (2 x 1500ml, 2 x 3 vol), the organic layers combined, washed sequentially with water (1000ml, 2 vol), 2% aqueous sodium hydroxide solution (2 x 1000ml, 2 x 2 vol) and water (1000ml, 2 vol) and concentrated under vacuum at < 45°C to afford Compound CFOH-2 (420g, 80% th yield).

Synthesis of (6-oxa-3-azabicyclo[3.1.0]hexan-3-yl)(phenyl)methanone (CFOH-4)

To a mixture of CFOH-2 (493g, 2.84 moles) DMSO (1479 ml, 3 vol) and water (197ml, 0.4 vol) at 5-15°C was slowly added N-bromosuccinimide (659g, 1.3 equiv) portionwise maintaining the reaction temperature at 5-15°C. After 1-2 hours the reaction was deemed complete, and the reaction mixture charged to water (2958ml, 6 vol) at 5-15°C, maintaining this temperature during the addition. The reaction mixture was stirred for 2-3 hours at 5-15°C, filtered and the solid washed with water (986ml, 2 vol). To the water wet solid was charged TBME (986 ml, 2 vol), the slurry stirred for 1-2 hours, filtered and the solid washed with TBME (246ml, 0.5 vol). This procedure was repeated, and the solid dried at <40°C.

To the above solid in THF (2465ml, 5 vol) at 5-15°C was added 10% aqueous sodium hydroxide solution (171g sodium hydroxide in 1710 ml water) maintaining the temperature at 5-15°C. The reaction was stirred at this temperature for 1-2 hours when analysis (TLC) showed complete consumption of starting material. The layers were separated, and the aqueous layer extracted with ethyl acetate (2 x 986ml, 2 x 2 vol). The combined organic layers were washed with saturated sodium chloride solution (2465ml, 5 vol), dried over sodium sulphate, filtered and the solution concentrated at < 45°C to a final volume of 1-2 vol. Ethyl acetate (493 ml, 1 vol) was charged, and the solution concentrated at <45°C to a final volume of 1-2 vol, and this procedure was repeated once more. The crude residue was charged to TBME (986ml, 2 vol) at 10- 20°C, maintaining this temperature during the addition, and the mixture stirred at 10- 20°C for 2-3 hours. The solid was filtered, washed with TBME (246ml, 0.5 vol) and dried at < 40°C to afford CFOH-4 (315g, 59% th yield).

Synthesis of ((3R,4R)-3-fluoro-4-hydroxypyrrolidin-l-yl)(phenyl)methanone (CFOH-6)

O F_< PH

/ \ (S,S)-(+)- Salen X /'

/ \ Cobalt catayst / \

N PhCOF, HFIP i

Bz ^Bz

CFOH-4 CFOH-6

To (S,S)-(+)-Salen Cobalt catalyst (22.3g, 0.1 equiv) in /-amyl alcohol (560ml, 8 vol) at 10°C (±2.5°C) was added sequentially DBN (2.3g, 0.05 equiv), hexafluoroisopropanol (155g, 2.5 equiv) and CFOH-4 (70g 1 equiv) while maintaining the temperature at 10°C (±2.5°C). The reaction mixture was stirred at 10°C (±2.5°C) for 15-30 mins, followed by the sequential addition of benzoyl fluoride (80g, 1.75 equiv) over 15-30 mins and /-amyl alcohol (140ml, 2 vol), while maintaining the temperature at 10°C (±2.5°C). The reaction was stirred at 10°C (±2.5°C) for 120-144 hours, ethyl acetate (1050 ml, 15 vol) added, and the temperature raised to 25-35°C. The reaction was stirred at this temperature for 5-15 mins before 8% aqueous sodium bicarbonate (700ml, 10 vol) was charged. The biphasic mixture was stirred for 15-30 mins, the layers separated, and the aqueous phase washed with ethyl acetate (350ml, 5 vol).

The organic layers were combined and 7% aqueous EDTA solution (700ml, 10 vol) added; this was stirred for 15-30 mins before the addition of 10% aqueous sodium chloride solution (70 ml, 1 vol). Stirring was continued for a further 5-10 mins before the aqueous layer was separated. This process was repeated a further 4 times. Activated carbon (SC-40, 70g, 1 wt) was added to the organic layer and stirred for 1-2 hours before filtration through Hyflow filter aid. The organic layer was concentrated under vacuum at < 45°C to afford the crude CFOH-6, with a typical purity of 80-90% HPLC area and a chiral purity of 93-95% HPLC area.

Synthesis of (3R,4R)-4-fluoropyrrolidin-3-ol HC1 (CFOH-7)

CFOH-6 CFOH-7

To crude CFOH-6 (77g, 1 equiv) in dioxane (231ml, 3 vols) was added concentrated hydrochloric acid (385ml 5 vol) and water (77ml, 1 vol) and the reaction heated to 90- 100°C for 16-18 hours. On reaction completion (TLC) the reaction was cooled to ambient temperature and DCM (770ml, 10 vol) charged. The biphasic mixture was stirred for 15-30 mins and the aqueous layer removed. The aqueous layer was extracted with DCM (3 x 385ml, 5 vol), and activated carbon (SC-40, 77g, 1 wt) charged to the aqueous layer. This was stirred for 1-2 hours before filtration through Hyflow filter aid. The carbon treatment was repeated twice more. The solution was concentrated under vacuum at < 55°C, n-butanol (385ml, 5 vol) added and the solution reconcentrated under vacuum at < 55°C. //-butanol (154ml, 2 vol) was charged and the solution concentrated under vacuum at < 55°C. This process was repeated one more time. To the concentrate was added //-butanol (193ml, 2.5 vol) and the mixture heated to 110-120°C for 30-45 mins. The mixture was subsequently cooled to 25-35°C, held at this temperature for 2-3 hours and the resulting solid isolated by filtration. The material can be recrystallized from //-butanol (2.5 vol) to upgrade the purity and chiral purity if required. Three to four recrystallisations are required to upgrade the chiral purity to > 99.5% (HPLC area) with a purity of > 99.9% HPLC area and a yield of 40- 45%th (for the ester hydrolysis and recrystallisations).

Purification process

5-B romopyri din-3 -yl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-lJ/- l,2,3-triazol-l-yl]-l-thio-a-D-galactopyranoside (38.36 kg, 58.17 mol) was suspended in methanol (1148 L) under an inert atmosphere at <25 °C. Sodium methoxide solution (25 wt% in methanol, 1.26 kg, 5.83 mol) was charged followed by a methanol line rinse (2.5 L) and the mixture was stirred at 18 to 25 °C for 3 h. The mixture was heated to gain full solution then filtered, followed by a methanol filter wash (115 L). The combined filtrates were distilled in vacuo at up to 60 °C to approximately 690 L then cooled to 30 to 40 °C. Water (276 L) was added and the mixture stirred at 30 to 40 °C for 1 hour. The mixture was cooled to 0 to 10 °C, stirred at this temperature for 2 hours then filtered. The filter cake was washed with a mixture of methanol (46 L) and water (31 L) at 0-10 °C. The crude material was dried in vacuo at 58 °C to deliver 28.86 kg of crude 5-Bromopyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-lJ/-l,2,3-triazol- 1 -yl]- 1 -thio-a-D-galactopyranoside.

The crude 5-Bromopyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-lJ/-l,2,3-triazol- l-yl]-l-thio-a-D-galactopyranoside was dissolved in methanol (867 L) at reflux. The solution was distilled in vacuo at up to 60 °C to approximately 510 L then cooled to 30 to 40 °C. Water (207 L) was added and the mixture stirred at 20 to 28 °C for 2.5 hours. The mixture was filtered then the filter cake was washed with a mixture of methanol (34 L) and water (23 L) at 23 °C. The crude material was dried in vacuo at 58 °C to deliver 26.94 kg (50.51 mol, 86.8% yield) of 5-Bromopyridin-3-yl 3-deoxy-3-[4-(3,4,5- trifluorophenyl)- IT/- l , 2, 3 -triazol- l-yl]-l -thio-a-D-galactopyranoside. References

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Claims

We Claim: 1. A D-galactopyranose compound of formula (1)

wherein the pyranose ring is β-D-galactopyranose, A1 is selected from a) a phenyl substituted in one ortho carbon atom of the phenyl ring in relation to the covalent bond to the pyrazol ring with one group selected from one of F, Cl, Br, I, CN, C1-3 alkyl optionally substituted with one to three F, or OC1-3 alkyl, optionally substituted with one to three F; and optionally substituted on one to four of the additional carbon atoms of the phenyl with a group independently selected from halogen; CN; OH; C2-4 alkenyl; an ethynyl; a spiro heterocycle; -COOH; -CONR2aR3a, wherein R2a and R3a are independently selected from hydrogen, C_1-3 alkyl, and cyclopropyl, or R2aand R3a together with the nitrogen may form a heterocycloalkyl; C1-3 alkyl, optionally substituted with a F; C1-3 alkyl, optionally substituted with an ethynyl; cyclopropyl, optionally substituted with a F; OC_1-3 alkyl, optionally substituted with a F; O-cyclopropyl, optionally substituted with a F; NR4aR5a, wherein R4a and R5a are independently selected from hydrogen, C1- alkyl and c 11a 11a 3 yclopropyl; C(=O)-R , wherein R is selected from hydrogen and C1-3 alkyl; and R6a-CONH- wherein R6a is selected from C_1-3 alkyl and cyclopropyl; b) a benzothiazolyl substituted with a group selected from a halogen; CN; OH; C_2-4 alkenyl; an ethynyl; a spiro heterocycle; -COOH; -CONR7aR8a, wherein R7a and R8a are independently selected from H, C 7a 8a 1-3 alkyl, and cyclopropyl, or R and R together with the nitrogen may form a heterocycloalkyl; C_1-3 alkyl, optionally substituted with a F; C1-3 alkyl, optionally substituted with an ethynyl; cyclopropyl, optionally substituted with a F; OC1-3 alkyl, optionally substituted with a F; O-cyclopropyl, optionally substituted with a F; NR9aR10a, wherein R9a and R10a are independently selected from H, C_1-3 alkyl, and cyclopropyl; C(=O)-R11b, wherein R11b is selected from H and C alkyl; and R12a-CONH 12a 1-3 - wherein R is selected from C1-3 alkyl and cyclopropyl; c) a pyridinyl substituted in one ortho carbon atom of the pyridinyl ring in relation to the covalent bond to the pyrazol ring with one group selected from one of F, Cl, Br, I, CN, C1-3 alkyl optionally substituted with one to three F, or OC1-3 alkyl, optionally substituted with one to three F; and optionally substituted on one to three of the additional carbon atoms of the pyridinyl ring with a group independently selected from halogen; OH; CN; C2-4 alkenyl; an ethynyl; a spiro heterocycle; - COOH; -CONR^13aR^14a, wherein R^13aandR^14a are independently selected from H, C1-3 alkyl, and cyclopropyl, or R^13aandR^14a together with the nitrogen may form a heterocycloalkyl; C1-3 alkyl, optionally substituted with a F; C1-3 alkyl, optionally substituted with an ethynyl; cyclopropyl, optionally substituted with a F; OC1-3 alkyl, optionally substituted with a F; O-cyclopropyl, optionally substituted with a F; NR^15aR^16a, wherein R^15a and R^16a are independently selected from H, C1-3 alkyl and cyclopropyl; C(=O)-R^17a, wherein R^17a is selected from H and C1-3 alkyl; and R^18a- CONH- wherein R^18a is selected from C1-3 alkyl and cyclopropyl;

B¹ is selected from the group consisting of a) phenyl, naphthalinyl, biphenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, quinoxainyl, indolyl, indazolyl, benzimidazolyl, benzisoxazolyl, benzisothiazolyl, benzoxazolyl, benzothiazolyl, benzodi oxolyl, dihydrobenzodioxinyl, dihydroquinolinonyl, dihydrobenzothiophene-2,2-dioxide, pyrrolyl, furanyl, thiazolo[4,5-b]pyridinyl, thienyl, pyrazolyl, isoxazolyl, isothiazolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, or thiadiazolyl; optionally substituted with one or more substituents selected from the group consisting of cyano, nitro, OH, C2-alkynyl, halogen, C1-6 alkyl, halo-Ci-6 alkyl, branched C3-6 alkyl, C3-6 cycloalkyl optionally substituted with a methyl, C3-6 cycloalkyl, C1-6 alkoxy, halo-Ci-6 alkoxy, C1-6 alkylthio, carboxy, C1-6 alkoxycarbonyl, C1-6 alkylsulfonyl, CONH2, COR^21aR^22a wherein R^21aand R^22a are independently selected from H and C1-3 alkyl, and (R^19a)(R^20a)N wherein R^19a is selected from hydrogen, C1-6 alkyl, C1-6 alkylcarbonyl, or C1-6 alkylsulfonyl and R^20a is selected from hydrogen or C1-6 alkyl, or (R^19a)(R^20a)N taken together is any one of azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, optionally substituted with one or more substituents selected from halogen, C1-6 alkyl, and C1-6 alkylcarbonyl; or b) (C1-6 alkyl-SO2)phenyl, (C1-6 alkyl SO2)(halo)phenyl, (aminoSO2)phenyl, (di-Ci-6 alkylaminoSO2)phenyl, ((C1-6 alkyl-NHSO2)-Ci-6 alkyl )phenyl, (pyrrolyl)phenyl, (imidazolyl)phenyl, (oxazolyl)phenyl, (tetrazolyl)phenyl, ((pyridinyl)methyl)phenyl, phenoxy phenyl, (benzyl oxy )phenyl, ((methyl)thiazolyl)- phenyl, (thiazolyl)-benzenesulfamido, ((methyl)thiadiazolyl)benzenesulfamido, (methyl)-benzothiazolonyl, or fluoropyrazolopyrimidinyl;

R¹ is selected from H, C1-3 alkyl, CN, halogen, C2-4 alkenyl, and C1-3 alkyl substituted with one to three halogen; or a pharmaceutically acceptable salt or solvate thereof.

2. The compound of claim 1 wherein A¹ is

R⁵ is selected from H, halogen and OC1-3 alkyl, optionally substituted with a F; and R⁶ is selected from H and OC1-3 alkyl, optionally substituted with one to three F.

3. The compound of claim 1 wherein A¹ is

R⁸ is selected from H or halogen;

R⁹ is selected from H or halogen; and

R¹⁰ is H. The compound of claim 1 wherein A¹ is

wherein the asterix * indicates the carbon atom of the pyridinyl ring that is covalently attached to the pyrazole; wherein R¹¹ is selected from F, Cl, Br, I, CN, C1-3 alkyl substituted with one to three

F, and OC1-3 alkyl, optionally substituted with one to three F;

R¹² is selected from H or halogen;

R¹³ is selected from H or halogen; and

R¹⁴ is H.

5. The compound of claim 1 wherein A¹ is

wherein the asterix * indicates the carbon atom of the benzothiazol ring that is covalently attached to the pyrazole; wherein R¹⁵ is selected from H or halogen, such as H or F; wherein R¹⁶ is selected from H or halogen, such as H, F or Cl; wherein R¹⁷ is selected from H and C1-3 alkyl, such as H or methyl; wherein R¹⁸ is H.

6. The compound of claim 1 wherein A¹ is

wherein the asterix * indicates the carbon atom of the benzothiazol ring that is covalently attached to the pyrazole; wherein R¹⁹ is selected from H or halogen, such as H or F; wherein R²⁰ is selected from H or halogen, such as H or F; wherein R²¹ is selected from H and C1-3 alkyl, such as H; wherein R²² is H.

7. The compound of claim 1 wherein A¹ is

wherein the asterix * indicates the carbon atom of the benzothiazol ring that is covalently attached to the pyrazole; wherein R²³ is selected from H or halogen, such as H or F; wherein R²⁴ is selected from H or halogen, such as H or F; wherein R²⁵ is selected from H or halogen, such as H or Cl; wherein R²⁶ is H or methyl, such as H.

8. The compound of claim 1 wherein A¹ is

wherein the asterix * indicates the carbon atom of the benzothiazol ring that is covalently attached to the pyrazole; wherein R²⁷ is selected from H or halogen, such as H or F; wherein R²⁸ is selected from H or halogen, such as H or F; wherein R²⁹ is selected from H or halogen, such as H or Cl; wherein R³⁰ is H or methyl, such as H.

9. The compound of any one of claims 1-8 wherein B¹ is selected from the group consisting of phenyl, pyridinyl, and benzothiazolyl; optionally substituted with one or more substituents selected from the group consisting of halogen, CN, Ci-6 alkylthio, Ci-6 alkylsulfonyl, Ci-6 alkoxy optionally substituted with a halogen, Ci-6 alkyl, branched C3-6 alkyl, C3-6 cycloalkyl optionally substituted with a methyl, C3-6 cycloalkyl, COR^21aR^22a wherein R^21aand R^22a are independently selected from H and C1-3 alkyl, and halo-Ci-6 alkyl.

10. The compound of claim 9 wherein B¹ is selected from the group consisting of phenyl substituted with one, two or three substituents selected from the group consisting of Cl, F, Br, cyclopropyl, C3-6 cycloalkyl optionally substituted with a methyl, C1-3 alkyl, SCH3, OCF3, CN, and CF3; pyridinyl substituted with one, two or three substituents selected from the group consisting of halogen, eg. F, Br and Cl, C3-6 cycloalkyl, OCF₃, SCH₃, C1-3 alkyl, CONH₂, CONHCH3, CON(CH₃)₂, and CF₃; and benzothiazolyl substituted with one or two substituents selected from the group consisting of methyl, F, Cl, Br, CN, SO2CH3, SCH3, OCH3, and CF3.

11. The compound of any one of claims 1-10 wherein R¹ is selected from H, CN, halogen, or C1-3 alkyl, such as methyl.

12. The compound of claim 1 selected from any one of the group consisting of: 6-{ 5-{3-Deoxy-3-[4-(2, 3-difluoro-4-methylphenyl)-lH-l, 2-pyrazol-l -yl]-P-D- galactopyranosyl}-3-methyl-lH-l,2,4-triazol-l-yl}-2 -methylbenzothiazole,

5-Chl oro-1 -{5-{3-deoxy-3 -[4-(2, 3 -difhroro-4-m ethylphenyl)- 1H-1, 2-pyrazol-l -yl]~P- D-galactopyranosyl } -3 -methyl- 1H- 1 ,2,4-triazol- 1 -yl } -2-(trifluoromethyl)benzene, 5-Chl oro-1 -{5-{3-deoxy-3-[4-(7-fluorobenzothiazol-5-yl)-lH-l, 2-pyrazol-l -yl]-P-D- galactopyranosyl}-3-methyl-lH-l,2,4-triazol-l-yl}-2-(trifluoromethyl)benzene, 5-Chl oro-1 -{5-{3-deoxy-3 -[4-(7-fluoro-2 -methylbenzothiazol-5-yl)-lH-l,2-pyrazol- 1 -yl]-P-D-galactopyranosyl } -3 -methyl - 1H- 1 ,2,4-triazol - 1 -yl } -2- (trifluoromethyl)benzene,

5-Chl oro-1 -{5-{3-deoxy-3-[4-(4-fluorobenzothiazol-6-yl)-lH-l, 2-pyrazol-l -yl]-P-D- galactopyranosyl}-3-methyl-lH-l,2,4-triazol-l-yl}-2-(trifluoromethyl)benzene, 5-Chl oro-1 -{5-{3-deoxy-3-[4-(5-fluorobenzothiazol-7-yl)-lH-l, 2-pyrazol-l -yl]-P-D- galactopyranosyl}-3-methyl-lH-l,2,4-triazol-l-yl}-2-(trifluoromethyl)benzene, 5-Chl oro-1 -{5-{3-deoxy-3-[4-(6,7-difluorobenzothiazol-5-yl)-lH-l, 2-pyrazol-l -yl]- P-D-galactopyranosyl } -3 -methyl- 1H- 1 ,2,4-triazol- 1 -yl } -2-(trifluoromethyl)benzene, 1 -{5-{3-[4-(4-Chl oro-2, 3 -difluorophenyl)- 1H-1, 2-pyrazol-l -yl]-3 -deoxy -P-D- galactopyranosyl } -3 -methyl- 1H- 1 ,2,4-triazol- 1 -yl } -5-chloro-2- (trifluoromethyl)benzene, 5-Chloro-l-{5-{3-deoxy-3-[4-(2,3,4-trifluorophenyl)-lH-l,2-pyrazol-l-yl]-P-D- galactopyranosyl}-3-methyl-lH-l,2,4-triazol-l-yl}-2-(trifluoromethyl)benzene, 1 -{5-{3-[4-(2-Chl oro-3 -fluorophenyl)- 1H-1, 2-pyrazol-l -yl]-3-deoxy-P-D- galactopyranosyl } -3 -methyl- 1H- 1 ,2,4-triazol- 1 -yl } -5-chloro-2- (trifluoromethyl)benzene,

1 -{5-{3 -[4-(4-Bromo-2,3-difluorophenyl)-lH-l, 2-pyrazol-l -yl]-3 -deoxy -P-D- galactopyranosyl } -3 -methyl- 1H- 1 ,2,4-triazol- 1 -yl } -5-chloro-2- (trifluoromethyl)benzene,

5 -Chi oro- 1 - { 5 - { 3 -deoxy -3 - [4-(2, 3 -difluoropheny 1)- 1 H- 1 , 2 -py razol - 1 -y 1 ] -P -D - galactopyranosyl}-3-methyl-lH-l,2,4-triazol-l-yl}-2-(trifluoromethyl)benzene, 5-Chl oro-1 -{5-{3-deoxy-3-[4-(2, 3-difluoro-4-methoxyphenyl)-lH-l, 2-pyrazol-l -yl]- P-D-galactopyranosyl } -3 -methyl- 1H- 1 ,2,4-triazol- 1 -yl } -2-(trifluoromethyl)benzene, 5-Chloro-l-{5-{3-deoxy-3-{4-[2,3-difluoro-4-(trifluoromethyl)phenyl]-lH-l,2- pyrazol-l-yl}-P-D-galactopyranosyl}-3-methyl-lH-l,2,4-triazol-l-yl}-2- (trifluoromethyl)benzene, 5-Chloro-l-{5-{3-deoxy-3-{4-[2,3-difluoro-4-(l-methylethenyl)phenyl]-lH-l,2- pyrazol-l-yl}-P-D-galactopyranosyl}-3-methyl-lH-l,2,4-triazol-l-yl}-2- (trifluoromethyl)benzene,

5-Chl oro-1 -{5-{3-deoxy-3-[4-(4,5-difluorobenzothiazol-6-yl)-lH-l, 2-pyrazol-l -yl]- P-D-galactopyranosyl } -3 -methyl- 1H- 1 ,2,4-triazol- 1 -yl } -2-(trifluoromethyl)benzene, 5-Chl oro-3 -{5-{3-deoxy-3-[4-(4,5-difluorobenzothiazol-6-yl)-lH-l, 2-pyrazol-l -yl]- P-D-galactopyranosyl } -3 -methyl- 1H- 1 ,2,4-triazol- 1 -yl } -2-(trifluoromethyl)pyridine, 5-Bromo-3 -{5-{3-deoxy-3-[4-(4,5-difluorobenzothiazol-6-yl)-lH-l, 2-pyrazol-l -yl]- P-D-galactopyranosyl } -3 -methyl- 1H- 1 ,2,4-triazol- 1 -yl } -2-(trifluoromethyl)pyridine, 5-Bromo-l -{5-{3-deoxy-3-[4-(4,5-difluorobenzothiazol-6-yl)-lH-l, 2-pyrazol-l -yl]- P-D-galactopyranosyl } -3 -methyl- 1H- 1 ,2,4-triazol- 1 -yl } -2-(trifluoromethyl)benzene, 5-Bromo-l -{5-{3-[4-(4-chl oro-2, 3 -difluorophenyl)- 1H-1, 2-pyrazol-l -yl]-3-deoxy-P- D-galactopyranosyl } -3 -methyl- 1H- 1 ,2,4-triazol- 1 -yl } -2-(trifluoromethyl)benzene, 3-{ 5-{3-[4-(4-Chl oro-2, 3 -difluorophenyl)- 1H-1, 2-pyrazol-l -yl]-3 -deoxy -P-D- galactopyranosyl } -3 -methyl- 1H- 1 ,2,4-triazol- 1 -yl } -5-chloro-2- (trifluoromethyl)pyridine,

1 -{5-{3-[4-(4-Chl oro-5 -fluoro-2 -methoxyphenyl)- 1H-1, 2-pyrazol-l -yl]-3 -deoxy -P-D- galactopyranosyl } -3 -methyl- 1H- 1 ,2,4-triazol- 1 -yl } -5-chloro-2- (trifluoromethyl)benzene,

1 -{5-{3-{4-[4-Chl oro-5-fluoro-2-(trifluoromethyl)phenyl]-lH-l, 2-pyrazol-l -yl} -3- deoxy-P-D-galactopyranosyl } -3 -methyl- 1H- 1 ,2,4-triazol- 1 -yl } -5-chloro-2- (trifluoromethyl)benzene,

1 -{5-{3-{4-[4-Chl oro-5-fluoro-2-(trifluoromethoxy)phenyl]-lH-l, 2-pyrazol-l -yl} -3- deoxy-P-D-galactopyranosyl } -3 -methyl- 1H- 1 ,2,4-triazol- 1 -yl } -5-chloro-2- (trifluoromethyl)benzene, l-{5-{3-[4-(4-Chloro-2,3-difluorophenyl)-lH-l,2-pyrazol-l-yl]-3-deoxy-P-D- galactopyranosyl}-3-methyl-lH-l,2,4-triazol-l-yl}-5-chloro-4-fluoro-2- (trifluoromethyl)benzene,

5-Chl oro-1 -{5-{3-deoxy-3-[4-(4,5-difluorobenzothiazol-6-yl)-lH-l, 2-pyrazol-l -yl]- P-D-galactopyranosyl } -3 -methyl- 1H- 1 ,2,4-triazol- 1 -yl } -4-fluoro-2- (trifluoromethyl)benzene, l-{5-{3-[4-(4-Chloro-2,3-difluorophenyl)-lH-l,2-pyrazol-l-yl]-3-deoxy-P-D- galactopyranosyl}-3-methyl-lH-l,2,4-triazol-l-yl}-4,5-dichloro-2- (trifluoromethyl)benzene,

4, 5-Dichl oro-1 -{5-{3-deoxy-3 -[4-(4,5-difluorobenzothiazol-6-yl)-lH-l, 2-pyrazol-l - yl]-P-D-galactopyranosyl } -3 -methyl- 1H- 1 ,2,4-triazol- 1 -yl } -2- (trifluoromethyl)benzene, 6-{5-{3-Deoxy-3-[4-(4,5-difluorobenzothiazol-6-yl)-lH-l,2-pyrazol-l-yl]-P-D- galactopyranosyl}-3-methyl-lH-l,2,4-triazol-l-yl}-2 -methylbenzothiazole, 6-{5-{3-Deoxy-3-[4-(2,3,4-trifluorophenyl)-lH-l,2-pyrazol-l-yl]-P-D- galactopyranosyl}-3-methyl-lH-l,2,4-triazol-l-yl}-2 -methylbenzothiazole, 6-{5-{3-[4-(4-Chloro-2,3-difluorophenyl)-lH-l,2-pyrazol-l-yl]-3-deoxy-P-D- galactopyranosyl}-3-methyl-lH-l,2,4-triazol-l-yl}-5-fluoro-2 -methylbenzothiazole,

5-Bromo-6-{ 5-{3-[4-(4-chl oro-2, 3 -difluorophenyl)- 1H-1, 2-pyrazol-l -yl]-3-deoxy-P- D-galactopyranosyl } -3 -methyl- 1H- 1 ,2,4-triazol- 1 -yl } -2 -methylbenzothiazole,

6-{5-{3-[4-(4-Chloro-2,3-difluorophenyl)-lH-l,2-pyrazol-l-yl]-3-deoxy-P-D- galactopyranosyl}-3-methyl-lH-l,2,4-triazol-l-yl}-5-cyano-2 -methylbenzothiazole, 6-{5-{3-[4-(4-Chloro-2,3-difluorophenyl)-lH-l,2-pyrazol-l-yl]-3-deoxy-P-D- galactopyranosyl}-3-methyl-lH-l,2,4-triazol-l-yl}-5-(trifluoromethyl)-2- methy lb enzothi azol e,

6-{ 5-{3-Deoxy-3-[4-(4,5-difluorobenzothiazol-6-yl)-lH-l, 2-pyrazol-l -yl]-P-D- galactopyranosyl}-3-methyl-lH-l,2,4-triazol-l-yl}-5-fluoro-2 -methylbenzothiazole, 1 -{5-{3-[4-(4-Chl oro-2, 3 -difluorophenyl)- 1H-1, 2-pyrazol-l -yl]-3 -deoxy -P-D- galactopyranosyl } -3 -methyl- 1H- 1 ,2,4-triazol- 1 -yl } -5-cy ano-2- (trifluoromethyl)benzene, l-{5-{3-[4-(4-Chloro-2,3-difluorophenyl)-lH-l,2-pyrazol-l-yl]-3-deoxy-P-D- galactopyranosyl}-3-methyl-lH-l,2,4-triazol-l-yl}-5-cyclopropyl-2- (trifluoromethyl)benzene, l-{5-{3-[4-(4-Chloro-2,3-difluorophenyl)-lH-l,2-pyrazol-l-yl]-3-deoxy-P-D- galactopyranosyl}-3-methyl-lH-l,2,4-triazol-l-yl}-2-(trifluoromethyl)-5- methylbenzene, l-{5-{3-[4-(4-Chloro-2,3-difluorophenyl)-lH-l,2-pyrazol-l-yl]-3-deoxy-P-D- galactopyranosyl}-3-methyl-lH-l,2,4-triazol-l-yl}-2-(trifluoromethyl)-5-(l- methylcyclopropyl)benzene, l-{5-{3-[4-(4-Chloro-2,3-difluorophenyl)-lH-l,2-pyrazol-l-yl]-3-deoxy-P-D- galactopyranosyl}-3-methyl-lH-l,2,4-triazol-l-yl}-2-(trifluoromethyl)-5- (methy Ithi o)b enzene,

5-Bromo-l -{5-{3-[4-(4-chl oro-2, 3 -difluorophenyl)- 1H-1, 2-pyrazol-l -yl]-3-deoxy-P- D-galactopyranosyl } -3 -methyl- 1H- 1 ,2,4-triazol- 1 -yl } -4-fluoro-2- (trifluoromethyl)benzene, 3-{5-{3-[4-(4-Chloro-2,3-difluorophenyl)-lH-l,2-pyrazol-l-yl]-3-deoxy-P-D- galactopyranosyl}-3-methyl-lH-l,2,4-triazol-l-yl}-2-(trifluoromethyl)-5- methylpyridine,

5-Chloro-l -{5-{3-deoxy-3-[4-(2, 3-difluoro-4-isopropylphenyl)-lH-l, 2-pyrazol-l -yl]- P-D-galactopyranosyl } -3 -methyl- 1H- 1 ,2,4-triazol- 1 -yl } -2-(trifluoromethyl)benzene, 5-Chl oro-1 -{5-{3 -deoxy-3 -[4-(2,3-difluoro-4-ethenylphenyl)-lH-l, 2-pyrazol-l -yl]-P- D-galactopyranosyl } -3 -methyl- 1H- 1 ,2,4-triazol- 1 -yl } -2-(trifluoromethyl)benzene,

5-Chl oro-1 -{5-{3-deoxy-3-[4-(2, 3-difluoro-4-ethylphenyl)-lH-l, 2-pyrazol-l -yl]-P-D- galactopyranosyl}-3-methyl-lH-l,2,4-triazol-l-yl}-2-(trifluoromethyl)benzene,

5 -Bromo-3 - { 5 - { 3 -deoxy-3 - [4 -(2 , 3 -difluoro-4-methoxyphenyl)- 1 H- 1 ,2-pyrazol - 1 -yl] - P-D-galactopyranosyl } -3 -methyl- 1H- 1 ,2,4-triazol- 1 -yl } -2-(trifluoromethyl)pyridine,

1 -{5-{3-[4-(4-Chl oro-2, 3-difluoro-5-methoxyphenyl)-lH-l, 2-pyrazol-l -yl]-3- deoxy-P-D-galactopyranosyl } -3 -methyl- 1H- 1 ,2,4-triazol- 1 -yl } -5-chloro-2- (trifluoromethyl)benzene,

5-Chloro-l-{5-{3-deoxy-3-[4-(6,7-difluoro-2-methylbenzothiazol-5-yl)-lH-

5-Chl oro-1 -{5-{3 -deoxy-3 -[4-(5,6-difluorobenzothi azol -4-yl)-lH-l, 2-pyrazol- 1 -yl] -P-D-galactopyranosyl } -3 -methyl - 1H- 1 ,2,4-triazol - 1 -yl } -2- (trifluoromethyl)benzene,

6-{5-{3-[4-(4-Chloro-2,3-difluorophenyl)-lH-l,2-pyrazol-l-yl]-3-deoxy-P-D- galactopyranosyl}-3-methyl-lH-l,2,4-triazol-l-yl}-2,5-dimethylbenzothi azole,

6-{ 5-{3-[4-(4-Chl oro-2, 3 -difluorophenyl)- 1H-1, 2-pyrazol-l -yl] -3 -deoxy -P-D- galactopyranosyl } -3 -methyl- 1H- 1 ,2,4-triazol- 1 -yl } -5-m ethoxy -2- methy lb enzothi azol e, 6-{ 5-{3-[4-(4-Chl oro-2, 3 -difluorophenyl)- 1H-1, 2-pyrazol-l -yl]-3 -deoxy -P-D- galactopyranosyl } -3 -methyl- 1H- 1 ,2,4-triazol- 1 -yl } -2-methyl-5- (methy Ithi o)b enzothi azol e,

6-{ 5-{3-[4-(4-Chl oro-2, 3 -difluorophenyl)- 1H-1, 2-pyrazol-l -yl]-3 -deoxy -P-D- galactopyranosyl } -3 -methyl- 1H- 1 ,2,4-triazol- 1 -yl } -2-methyl-5- (methylsulfonyl)benzothi azole,

4-Bromo-6-{ 5-{3-[4-(4-chl oro-2, 3 -difluorophenyl)- 1H-1, 2-pyrazol-l -yl]-3- deoxy-P-D-galactopyranosyl } -3 -methyl- 1H- 1 ,2,4-triazol- 1 -yl } -2- methy lb enzothi azol e,

6-{5-{3-[4-(4-Chloro-2,3-difluorophenyl)-lH-l,2-pyrazol-l-yl]-3-deoxy-P-D- galactopyranosyl}-3-methyl-lH-l,2,4-triazol-l-yl}-4-(trifluoromethyl)-2- methy lb enzothi azol e,

1 -{5-{3-[4-(4-Chl oro-5, 6-difluorobenzothiazol-7-yl)-lH-l, 2-pyrazol-l -yl]-3- deoxy-P-D-galactopyranosyl } -3 -methyl- 1H- 1 ,2,4-triazol- 1 -yl } -5-chloro-2- (trifluoromethyl)benzene,

1 -{5-{3-[4-(7-Chl oro-5, 6-difluorobenzothi azol -4-yl)-lH-l, 2-pyrazol-l -yl]-3- deoxy-P-D-galactopyranosyl } -3 -methyl- 1H- 1 ,2,4-triazol- 1 -yl } -5-chloro-2- (trifluoromethyl)benzene,

1 -{5-{3-[4-(4-Chl oro-5, 6-difluorobenzothi azol-7-yl)-lH-l, 2-pyrazol-l -yl]-3- deoxy-P-D-galactopyranosyl } -3 -methyl- 1H- 1 ,2,4-triazol- 1 -yl } -5-chloro-4-fluoro2- (trifluoromethyl)benzene,

3-{ 5-{3-[4-(3, 4-Dichl oro-2 -fluorophenyl)- 1H-1, 2-pyrazol-l -yl]-3 -deoxy -P-D- galactopyranosyl } -3 -methyl- 1H- 1 ,2,4-triazol- 1 -yl } -5-chloro-2- (trifluoromethyl)pyridine,

3-{5-{3-[4-(4-Chloro-2,3-difluorophenyl)-lH-l,2-pyrazol-l-yl]-3-deoxy-P-D- galactopyranosyl}-3-methyl-lH-l,2,4-triazol-l-yl}-2-(trifluoromethyl)-5- ethylpyridine, 5-Bromo-3 -{ 5-{3 -[4-(4-chl oro-2, 3 -difluorophenyl)- 1H-1, 2-pyrazol-l -yl]-3- deoxy-P-D-galactopyranosyl } -3 -methyl- 1H- 1 ,2,4-triazol- 1 -yl } -2-(trifluoromethyl)-6- methylpyridine, l-{5-{3-[4-(4-Chloro-2,3-difluorophenyl)-lH-l,2-pyrazol-l-yl]-3-deoxy-P-D- galactopyranosyl}-3-methyl-lH-l,2,4-triazol-l-yl}-5-chloro-3-fluoro-2- (trifluoromethyl)benzene,

1 -{5-{3-[4-(4-Chl oro-2, 3 -difluorophenyl)- 1H-1, 2-pyrazol-l -yl]-3 -deoxy -P-D- gal actopy ranosy 1 } -3 -methyl - 1 H- 1 , 2, 4 -tri azol - 1 -yl } -3 , 5 -di chi oro-2 - (trifluoromethyl)benzene, l-{5-{3-[4-(4-Chloro-2,3-difluorophenyl)-lH-l,2-pyrazol-l-yl]-3-deoxy-P-D- galactopyranosyl}-3-methyl-lH-l,2,4-triazol-l-yl}-5-chloro-2-(trifluoromethyl)-3- methylbenzene,

3-{ 5-{3-[4-(4-Chl oro-2, 3 -difluorophenyl)- 1H-1, 2-pyrazol-l -yl]-3 -deoxy -P-D- galactopyranosyl } -3 -methyl- 1H- 1 ,2,4-triazol- 1 -yl } -5-chloro-2-(N- methylcarbamoyl)pyridine,

6-{5-{3-[4-(4-Chloro-2,3-difluorophenyl)-lH-l,2-pyrazol-l-yl]-3-deoxy-P-D- galactopyranosyl}-3-methyl-lH-l,2,4-triazol-l-yl}-4-chloro-7-(trifluoromethyl) benzothiazole, l-{5-{3-[4-(4-Chloro-2,3-difluorophenyl)-lH-l,2-pyrazol-l-yl]-3-deoxy-P-D- galactopyranosyl }-3-methyl-lH-l, 2, 4-triazol-l-yl}-5-chl oro-2 -methylbenzene, 1 -{5-{3-[4-(4-Chl oro-2, 3-difluoro-6-methoxyphenyl)-lH-l, 2-pyrazol-l-yl]-3 - deoxy-P-D-galactopyranosyl } -3 -methyl- 1H- 1 ,2,4-triazol- 1 -yl } -5-chloro-2- (trifluoromethyl)benzene,

1 -{5-{3-Deoxy-3-[4-(2, 3-difluoro-5-methoxyphenyl)-lH-l, 2-pyrazol-l -yl]-P- D-galactopyranosyl } -3 -methyl- 1H- 1 ,2,4-triazol- 1 -yl } -5-chloro-2- (trifluoromethyl)benzene,

3-{ 5-{3-[4-(4-Chl oro-2, 3-difluoro-6-methoxyphenyl)-lH-l, 2-pyrazol-l-yl]-3 - deoxy-P-D-galactopyranosyl } -3 -methyl- 1H- 1 ,2,4-triazol- 1 -yl } -5-chloro-2- (trifluoromethyl)pyridine,

3-{5-{3-[4-(4-Chloro-5-cyano-2,3-difluorophenyl)-lH-l,2-pyrazol-l-yl]-3- deoxy-P-D-galactopyranosyl } -3 -methyl- 1H- 1 ,2,4-triazol- 1 -yl } -5-chloro-2- (trifluoromethyl)pyridine,

3-{ 5-{3-[4-(4-Chl oro-2, 3 -difluoro-5 -methylphenyl)- 1H-1, 2-pyrazol-l -yl]-3- deoxy-P-D-galactopyranosyl } -3 -methyl- 1H- 1 ,2,4-triazol- 1 -yl } -5-chloro-2- (trifluoromethyl)pyridine,

3-{ 5-{3-[4-(4-Chl oro-2, 3-difluorophenyl)-lH-l, 2-pyrazol-l -yl]-3 -deoxy-P-D- galactopyranosyl J-1H-1, 2, 4-triazol-l-yl}-5-chloro-2-(trifluoromethyl)pyridine,

3-{ 5-{3-[4-(4-Chl oro-2, 3 -difluorophenyl)- 1H-1, 2-pyrazol-l -yl]-3 -deoxy-P-D- galactopyranosyl } -3 -cyano- 1H- 1 ,2,4-triazol- 1 -yl } -5-chloro-2- (trifluoromethyl)pyridine,

3-{ 5-{3-[4-(4-Chl oro-2, 3 -difluorophenyl)- 1H-1, 2-pyrazol-l -yl]-3 -deoxy -P-D- gal actopy ranosy 1 } -3 -ethyl - 1 H- 1 , 2, 4 -tri azol - 1 -yl } - 5 -chi oro-2 - (trifluoromethyl)pyridine, 5 -Chi oro-3 - { 5 - { 3 -deoxy-3 - [4 -(2 , 3 -difluoro-4-m ethylphenyl)- 1H-1 ,2-pyrazol - l-yl]- -D-galactopyranosyl}-3-methyl-l -l,2,4-triazol-l-yl}-2- (trifluoromethyl)pyridin,

13. The compound of any one of claims 1-12 for use as a medicine.

14. A pharmaceutical composition comprising the compound of any one of the previous claims and optionally a pharmaceutically acceptable additive.

15. The compound of any one of the claims 1-12 for use in a method for treating a disorder relating to the binding of a galectin-3 and galectin-9 to a ligand in a mammal, wherein said disorder is selected from the group consisting of inflammation, such as acute post myocardial infarctions (MI), acute coronary syndrome, acute stent occlusion, acute myocardial reperfusion injury, acute pneumonitidies, acute lung injury (ALI), acute kidney injury (AKI), acute hepatitis, acute on chronic liver failure, acute alcohol hepatitis, acute pancreatitis, acute uveitis, acute pancreatitis related liponecrosis, acute retinitis, acute nephritis, acute myocarditis, autoimmune or autoreactive myocarditis, giant cell myocarditis, chronic autoimmune diseases in all organs, (e.g. lung, liver, kidney, heart, skin, muscle, gut), chronic bacterial infections, chronic viral related inflammation; fibrosis, such as pulmonary fibrosis, liver fibrosis, kidney fibrosis, ophthalmological fibrosis and fibrosis of the skin and heart, acute post-surgical ocular fibrosis, acute transplantation rejection of the kidney, heart, lung, liver, and pancreas, acute post explosion /improvised explosive devices, acute post toxic dust (such as dust from terror attack known as 9/11), acute chemical exposure, chronic lung fibrosis, interstitial lung fibrosis (IPF), Interstitial Lung Disease (ILD), Childhood ILD (ChILD), such as nonspecific interstitial pneumonia (NSIP), Crytogenic organising pneumonia (COP), Desquamative interstital pneumonia (DIP), Sarcoidosis; dermatomyositis; chronic liver fibrosis; chronic alcohol fibrosis, chronic viral fibrosis, chronic diabetic fibrosis diabetic nephropathy, chronic glomerulonephritis, renal artery stenosis, endometriosis; scarring; keloid formation; aberrant scar formation; surgical adhesions; scleroderma; systemic sclerosis; septic shock; cancers, such as carcinomas, sarcomas, leukemias and lymphomas, such as T- cell lymphomas; metastasising cancers; autoimmune diseases, such as psoriasis, rheumatoid arthritis, Crohn’s disease, ulcerative colitis, intestinal fibrosis, ankylosing spondylitis, systemic lupus erythematosus; metabolic disorders; coagulopathies, such as thrombosis proneness idiopathic (thrombophilia), autoimmune based thrombophilia, microthrombosis at multiorgan failure, COVID-19 related coagulopathy, thrombophilia in cancer disease; cardiovascular disorders, such as cardiac fibrosis, cardiac failure, left and right atrial fibrillation, atheromatosis, arterial inflammation, arterial calcification, aortic stenosis; heart disease; heart failure; aortic stenosis, atherosclerosis, pathological angiogenesis, such as ocular angiogenesis or a disease or condition associated with ocular angiogenesis, e.g. neovascularization related to cancer; and eye diseases, such as age-related macular degeneration and corneal neovascularization; atherosclerosis; endocrine disorders, such as Addison, autoimmune hypophysitis; metabolic diseases such as diabetes; type 2 diabetes; insulin resistance; obesity; Diastolic HF; atrophic diseases in the brain, such as Alzheimer’s and Parkinson’s, atrophic diseases in the cerebellum, such as cerebellar atrophy, atrophic spinal diseases such as ALS; disorders related to transplantation in organs, such as anti -rejection prophylaxis, anti-acute rejection, anti-chronic rejection; acute burn; acute inflammatory reaction; chronic acute skin graft rejection; chronic scarring; asthma and other interstitial lung diseases, including Hermansky-Pudlak syndrome, pulmonary arterial hypertension, Rheumatoid disease associated interstitial lung disease RA-ILD, Systemic Sclerosis SSc-ILD, lung disease with fibrosis such as COPD (Chronic Obstructive Pulmonary Disease) and asthma; Otosclerosis, mesothelioma; post-surgery disorders, such as anti-keloid, anti-stricture, antiadhesion, anti-thrombosis, fibrosis/scar reduction following cosmetic procedures; toxin exposure disorders, such as toxic hepatitis, cholera toxin related, mushroom toxin based acute renal failure, pertussis toxin, aeromonas hydrophila enterotoxin, cadmium induced cardiac toxicity, helicobacter O-antigen related toxicity, LPS based toxicity, Streptozotocin toxicity, asbestos exposure, Nephrogenic Systemic Fibrosis (Post Contrast Agents); Tissue injury, such as Spinal cord injury, Peripheral nerve repair; congenital hepatic fibrosis; hereditary fibrosing poikiloderma with tendon contractures, myopathy, and pulmonary fibrosis; liver disorders, such as non-alcoholic steatohepatitis (NASH) or non-alcoholic fatty liver disease, liver cirrhosis of various origins, such as alcoholic and non-alcoholic, autoimmune cirrhosis such as primary biliary cirrhosis and sclerosing cholangitis, virally induced cirrhosis, cirrhosis induced by genetic disease, moderate hepatic impairment; fibrotic disorders such as advanced liver fibrosis and cirrhosis due to different aetiology (such as non-alcoholic steatohepatitis, alcoholic steatohepatitis, viral hepatitis and autoimmune liver diseases); Liver cancer, cholangiocarcinoma, biliary tract cancer; neurodegenerative disorders such as Parkinsons disease, Alzheimers disease, cognitive impairment, cerebrovascular diseases such as stroke, traumatic brain injury, Huntington's disease, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), peripheral nephropathy.