A Reliable and Innovative Partner
to Speed up Your Success
Outline
Overview ∙ Experience ∙ Services ∙ Granlen
Corporate Locations
美国加州圣地亚哥
–太平洋彼岸的“人间天堂”，
中国郑州 - 重要交通枢纽，商
贸中心，国家园林城市
最适于居住的城市
Zhengzhou, China
- The key transportation and
business central garden city
San Diego, CA
- The Paradise on Earth；the
most livable city
About Granlen
• Provides reliable chemistry related services
for the biotech, pharmaceutical, diagnostic,
cosmaceutical, and related industries with:
– A broad spectrum of chemistry
– A wide range of drug discovery services
– An integrated drug development process to IND
The Granlen Difference
Satisfy your needs
Speed your success
Committed to Total Quality Excellence
Granlen’s Strengths
Synthetic Organic Chemistry
Medicinal Chemistry
Combinatorial Technologies
Drug discovery and development to IND
Immunogens and bioreagents
6
Synthetic Organic Chemistry
Heterocyclic and macrocyclic derivatives
Natural products and derivatives
Peptides, carbohydrates, glycopeptides, etc.
Silanes, Polyamines and guanidines
Process development and large scale
synthesis – mg to multi-kg scale
Medicinal Chemistry
 Hit-to-lead
 Lead Optimization
–
–
–
–
Natural products
SAR studies
Liability removal
Automation for expansion
Integrated preclinical discovery services
Medicinal Chemistry
Target Expertise
Kinases
Microtubules
Polymerases
Proteasome
Reverse Transcriptase
RNA
GPCRs
Other key enzymes
Therapeutic Experience
Oncology
Infectious
Antiviral
Antibacterial
Anti-TB
Metabolic disorders
Obesity
Dyslipidemia
Diabetes
Our History of Success
Medicinal Chemistry and Drug Development
Oncology
Microtubule polymerization inhibitor (Phase II)
Kinase inhibitor (Phase II)
Proteasome Inhibitor (Preclinical)
Antiviral
An HBV drug (Phase III)
An HIV drug (Phase II)
An HCV drug (Phase II)
An HIV drug (Phase I)
An HCV candidate (IND)
CombiChem and Automation
for Medicinal Chemistry
Solution-phase chemistry - parallel or indexed
Solid-phase methodologies
•
•
•
•
•
Method development
Focused libraries and parallel synthesis
Supporting material modification
Solid-phase extraction technology
Library enumeration and tracking
Expertise in nucleoside libraries and
focused heterocyclic libraries
Example Heterocycles (1)
N N
HetX
HetX
R1
NH2
N
S
N
HN Ar
R3
tetrahydrothieno[2,3b]quinoline-2-carbonitrile
NH
N
R4
R
Triazole
R1
O
Thiadiazolopyrimidineones
N
Ar
R3
Azapurine
S
R
N
H
N
N
NH2
dihydrotriazines
N
H
N
S
Ar
O
R
N
H
S
X
HN
N
H
O
R
N
S
S
O
N
H
S
Thiazolyl imidazothiazole
S
N
H
Indolomorphinans
N
R
Br
O
imidazothiazole
N
N
R
N
N
N
O
N N
N
Bi-functional linker
O
N
Ar
S N
Isothiazole
R
N
R
NH
OR
1,2,4-triazine
HO
O
Desipromine haptan
O
N
N
N
R
S
N
N
OH
N
CH3
N
OH
Benzothiazole Derivatives
N
O
R
N
Y
N
X
R
O
O
Benzothiazole
NH2
N
possible library
Ar
N
H
Ar
N
O
N
N
N
R2
N
NH
tetrahydropyrimidine
Ar
HN
H3C
N
N
N N
N
Ar
Ar
R5
N
Ar
O
S
N
tetrahydroquinoline-3carbonitrile
S
X
N
SH
N
O
R
O
Imidazolpyrimidine
Ar
N
S
N
H
Thiazolyl imidazopyrimidine
12
Example Heterocycles (2)
Ar
N
N
HN
Ar
O
Z
N
Ar
R
N
N
N
R
N
X
N
N
O
R
O
O
O
O
O
O
O
O
O
(
N
N
O
m
n
COOR
Quinazoline
R
O
O
n
O
R
N
X
R1
N
N
X
Pyrimidine
N
R
R2
N
R2
N
Z
O
O
N
H
S
R3
N
O
N
H
S
Triazine
X
HO
N
N
()
N
N
N
R
Pyrimidotriazinedi
one
O
O O
O
N R
X
N
R
N
Thieno[2,3-b]pyridine
N
X
purine
HN
N
N
S
N
m
N
N
N
N
N
R
R
O
N
R
R3
()
N
N
H
X
NH2
NR
N
R
Pyridine
Aryl quinoxaline
Pteridine
N
Ar
N
H
X
O
N
R1
O
N
Z
NH2
R2
N
Y
N
R
Ar
(
N
O
R
)
Y
X
)
X
Thiazolone
R1
N
R
N
N
R
Pyridine amine
R
O
O
O
O
N
O
X
13
Carbohydrate Derivatives
O
p-TolO
O
OAc
Me O
O
BzO
OAc
O
BzO
OAc
Me O
O
OAc
BzO
O
OBz
H3C
O
OBn
O
BzO
OAc
BzO
H3 C
BzO
O
O
OMe
BzO
BzO
HO
OH
O
O
O
O
O
O
O
O
O
HO
O
O
BzO
O
O
O
O
O
HO
OH OH
OBz
O
OAc
p-TolO
HO
O
OAc
OAc
OAc
O
O
O
F
OBz
BzO
O
O
O
OAc
S
O
O
OAc
p-TolO
HO
BnO
OAc
HO
S
OAc
O
BzO
OAc
Me O
OAc
HO
BzO
O
BzO
OAc
S
BnO
OAc
OAc
OAc
N3
BzO
OAc
BzO
O
BzO
OAc
F
BzO
Me
OAc
O
p-TolO
OAc
F
BzO
OAc
O
O
O
O
BnO
O
O
MeO
O
Nucleosides and Libraries
O
X
N
N
O
HO
R'
R
N
N
OH
N
N
N
O
HO
N
N
3'-deoxy-2-amino A
R1
N
N
HO
N
R3
NH
HO
exo-triazine ribose
1
O
N
NH2
HO
HO
OH
8-C-substitited 2-amino A
O
N
N
N
R2
OH
2,8-disubstituted G
O
R
N
R
N
N
NH2
O
HO
O
NH
N
N
O
HO
F
O
OR
3'-fluoro U
OH
R1
R2
N
NH
R
N X
N
N
N
R
N
O N
O
HO
7-deazaadenosines
N
8-alkylthio A
R1
OH
OR
R
R2
HN
R1
O
HO
O
3'-fluoro C
OCH3
S
HO
HO
HO
F
N
R2
HO
O
N
NH
N
N
N
O
3'-substituted C
3'-deoxy-2-amino A
N
N
HO
O
R1
N
R
N
OH
clitocines
N
N
O
OH
N
R
N
HO
R2
N
X
NO2
R2
OH
R4
R5
NHR
N
8-substituted A
NH
O
R'
OH
R3
N
N
N
O
HO
N
3-deaza-G
Ar
HO
HO
NH2
R
HO
R1
HO
2-aminoadenosines
O
HO
N
NH
N
triciribine
N
N
N
R2
OH
HO
N
O
OH
R2
H
N
R3
R4
HO
N
HN
R1
O
N N R1
O
HO
R2
N
HO
OH
N
R2
H
N
N
7-deaza-A
N
NH2
N
R3
R2
OH
HO
R1
N
O
3-deaza-G
N
N
O
NH2
OH
NR1R2
R1
N
HO
R
3'-modification
NH
N
O
HO
HN
R
N
HO
HO
OH
pyrazolo[4,3-d]rimidine
O
N
O
F
Y
R
arobino sub-C
Representative Nucleosides (Overall)
OH,NH2
N
O
O
HO
N
N
N
O
O
O
N
N
H, NH2 HO
Cl, OH
H, F, I, Br
CH3, Et
HO
N
O
S
N
N
OH, NH2
O
HO
N3, HO
O
N
H, CH2OH
CH2-Pyrrol
N
O
COOR,OMe
HO
H, CH3
OH
F, HO
S
N
NH2, Cl, H HO
OH, OMe
N
H,Cl, NH2
N
F
HO
N
N
O
HO
H,F,CH3
OH
OH, NH2
O
H,NH2
NH2,N=CHMe2
N
H, I
N
HO
O
HO
H, F
N3
OH
F, HO
N
N
N
H
O
H, F, CH3
OH
HO
O
MeO, HO
H,NO2
O
N
N
N
O
HO
HO
N
N
N
H,CH3
OH
N
O
OH H, OH,
OMe, F
HO
N
R
N
O
H,CH3
OH
N
NH
O
O
N
OR
O
H, Me
N
N3,HO
F, MeO
OH
O
O
H, NH2,I, Cl
OH, OMe
H,CH3
F,N3,HO
O
HO
O
HO
H,F,OH,CH3
H, OH, F, OMe
N
N
O
NH2
H, Cl, NH2, Me, OH
OMe, NMe2,Het
H, F, Br, I, OH, CH3
Et, CF3, CHF2,OMe
CHO, CH2OH, Het
CO2H, CO2R, CONHR
H,OH
OH, Cl, F
I, N3,OMe
MeO, F
N3, HO
N
CF3, Me, I, H
OH, NH2
N
F
O
HO
O
HO
N
H,OH
OH, NH2
H, Me,
CH2OH
H, Cl
NH2
OH
MeO
OH
HO
O
N
N
N
N
O
HO
N
N
N
N
H, Br
I, CH3
HO
N
Cl, NH2
NH2, Cl, H
OH, OMe
OH,NH2
F
OH, Cl, NH2
OH, NH2
OH
MeO
N
O
O N
N
OH
F
N
HO
H, F, Br, I,
CF3, CH3, Et
OMe, CH2OH
HO
OH
F
HO
H, Cl, NH2
NHR, Me, OH
OMe, Ar, Het
HO
O
N
N
N
NH
O
N
R
Diversified Nucleosides
R
NH2
NH
N
N
O
HO
O
O
X
F
Me O
O
NH2
NH
N
Me O
OH
NH2
NH
N
N
F
O
O
HO
O
HO
N
N
N
Y
O
HO
X
OH
N
N
O
Ar
O
O
F
N
OAc
N
N
O
O
HO
HO
N
O
N
R
R
O
N
BzO
Me O
N
O N
O
N
HO
N
R
O
HO
N
OH
N
N
N
R
HO
O
Ar
O
N
N
N
HO
N
R
HN
O N
O
OH R
N
HN
HO
OAc
HN
HN Bz
N
O
O
O
NH2
R
HO
R
OH R
Cl
N
N
O
O
HN Bz
N
N
N
O
HO
Cl
N
R
NH
N
HO
S
HN
N
OH
F
OH
O
R
N
O
HO
O
HO
X
NH
N
S
HO
O
O
O
N
N
O
HO
HO
NH
OH
HO
OH
O
X
O
N
S
O
HO
O
N
N
HO
NH
O
N
F
NH2
NH
HO
X
N
HO
O
X
N
O
O
N
O
HO
O
HO
O
O
O
HO
OH
F
N
O
HO
N
O
HO
X
O
O
N
N
NH
O
N
R
O
Series I – 3’-Fluoro-3’-deoxynucleosides
Series II – 2’-Fluoro-2’-deoxyarabinonucleosides
Series III – Azido- and Amino-Nucleosides
Series IV – Isocytidines and Isoguanosines
Series V - 4-Deoxy-/3-Deaza-Uridines and Pyridinone Nucleosides
Series VI – 6-Deamino- and Alkyl Purine Nucleosides
Series VII – Thio-Nucleosides
Series VIII – 2’-C-Methyl Nucleosides
Series IX – Halo-Purine Nucleosides
Series X – 3’-O-Methyl Nucleosides and Riboses
Series XII – 5-Modifided Pyrimidine Nucleosides
Series XIV – 5-Fluorinated Methyluridines
Example Nucleosides & Nucleotides
Nucleosides, nucleotides, dinucleotides, phosphonates, tri-phosphates, etc.
O
DMTO
NH
N
O
O
N
O
O
O
-O
P
N
N
O
RO P
X
HO
O
O
-
N
N
O
P
O
O
O-
O
-
O
O
-O
N
NH2
R
OR
S
N
X
N
O
R
O
P
O
X
R
Z
R
O
O
NH
O
P
R
O
P
O
O
O
O-
N
N
O
O
R'
R
NVOC
O
O
B
R4
R1
R3 R2
O
P
O
O
N
O
O
O
O
P
P
O
O
O
R
Triphosphates and triphosphonates
OH
R = H, OMe
dinucleotide
O
O
P
O
NH
H
OMe NH2
O
N
O
P
NH
N
O
O
O
R
N
O O
N
P
N
O
N
X
phosphonates
P
O
OH
HO P O
N
O
O
N
O
-
phosphonamidite
NH2
NH2
OR
O
N
O
NH2
O
O
O
P
NC
H-phosphonate
N
O
O
R
O P O
+
H HNEt3
O-
O
R
N
O
O
R
N
O
MMTO
NH
-
R
HO P
N
N CH3
N
O
N
new phosphoramidite
OR
Me
R
P
NC
Me
MMTO
O
N
N
N
O
R
P
NC
Ar
DMTO
O
O
NHBz
Ar
N
OR
NH
N
R
Nucleoside Phosphoramidites
O
R
NH
N
DMTrO
NHBz
R
O
DMTrO
O
NC
O P O
N
N
N
O
O
OTBDMS
NC
O P O
N
OTBDMS
Nucleoside Triphosphates (NTPs)
O
NH
HO
N
O
OH OH
LC (TIC)
LC (UV)
O
O
1) P(O)(OMe)3
proton sponge
2) POCl3
1) ion exchange column
2) reverse phase column
3) Pyrophosphate
3) Lyopholization
O
O
O
-O P O P O P O
OOOn Et3NH+
NH
N
O
OH OH
O
Other Products with Different Applications
O
R
H2N
ROOC
ROOC
N
N
N
COOR
X
HN
COOR
HO
COOR
N
OH
HO
O
MRI Contrasting Agents
HO
Dipropofol
N
N
N
H, NH2
OH
Cl-
N
S
N
O
N
N+
HO
O
NH2
N
O
O
Mega 8
Flavor Additive
NH+
NC
O-
OH OH CH3
N
O
Phenothiazine
R
O Ru
O
N+
O
OH
N+
O
R
Complex /bio-reagent
OH OH
Catalyst
SO3H
O
X
Adenosine Receptor Agonist
SO3H
R
O
N
N N
O
N
H
OH OH
HSP30 inhibitor
Cl
HO
O
Cl
N
O
Cl-
DDAIP-HCl
O
O
NH
O
O
N
N3,H2N
Antiviral Agent
O
Anticancer Agents
R
O
LXR Agonist
33
Nucleoside Bases and Building Blocks
O
Me
O
N
O
O
I, CHO
CHF2
HN
N
H
S, O
Cl
CH3
N
N
N
H
N
N
N
H
HN
S, O
S, O
N
H
N
H
N
N
H
NH2,Me
Br, I aklynyl
Cl,OMe,OBn
OBn
N
N
H,I
COOMe
Cl
H, I, NC
N
N
N
N
H
NH2,NHAc OH, OBn
HN
OMe
NHBoc
NH2
I, H
N
N
O
O
OH
N
H
Cl
N N
THP
N
HN
N
H
O
0-2
N
H,Me
N
N
N
NHPiv
Cl,OMe
Br, I H,Me
Br
NH2
O NH2
EtO
O
P
EtO
NHBoc
N
EtO P O
OEt
EtO P O
O
R O
O
N
N
N
NH
N
N
NH2
N
NHBoc
HCl O
COOH
O
O
N
Ph
OH
B
OH
NHBoc
Ph
N
OH
B
OH
N
Ph
OH
H2 N
N
N
B
N
OH
OH
O
N
B
N
MeO,
HO
OH
OH,
OMe
N
O
N
O
Cl
OH
N
O
COOH
O
Cl
HO
Cl
OH
O
N
H
N
COOH
COOH
OEt
PivHN
N
O
O
NHBoc
N
NH
N
AcO
AcO
AcO
O
O
OAc
NH2
Natural Products and Derivatives
H2N
NH2
O
N
O
H2N
CH3 HN
O
H
HO
HO
H
N
H
N
O
H
H
CH3 H
N
CH3
O
H
N
H
HO
N
H
O
N
R2
NH
S
R3
CH3
H
HO
OH
m
l
OH
O
OH
N
S
O
H
O
HO
O
O
N
HO
Bleomycin Antitumor Antibiotics
NH2
H H
N
H
OH
R1
n
OH
OH
5'-Alkylresorcinols isolated from Hakea
trifurcatea DNA cleaving agents
R1 = OCONH2, OH; R2 = SMe, +SMe2
7 Bleomycins including: Bleomycin A2, Bleomycin
demethyl A2, and Decarbamoyl Bleomycin Demethyl A2
>48 steps each for the total synthesis
X
H
OR
O
O
OR
H
OR
Oridonin
Our Specialties
 Carbohydrates, nucleosides/tides, & libraries
 Phosphoramidites, phosphates, triphosphates,
C-phosphonates
 Natural product total synthesis
 Heterocycles, macrocycles, super-chelating and
MRI contrast agents
 Silane, peptide, polyamine derivatives
 Immunogens/antigens and bio-reagents
 Prodrug and conjugation technologies
Chemistry Services
Chemistry &
Drug Discovery
Preclinical
Development
Clinical
Development
Hit to lead & lead optimization
Screening & focused libraries
Custom Synthesis
Hit and Lead Optimization
 Hit re-synthesis for activity confirmation
 Lead selection and optimization for SAR studies
 Design & synthesis of analogs for lead
improvement
Optimize potency, selectivity, specificity, and safety
Improve PK, PD, and druggability
 Enhancement of IP coverage
Screening and Focused Libraries
 Screening library enhancement
Drug-like or Lead-like (Ro5)
Toxicophore filtration
 Focused libraries around specified targets
Structure/Ligand-based design
Optimization by virtual screening
 10-50 mg per sample with >90% purity
Custom Synthesis
 Products, intermediates, scaffolds, building
blocks, monomers, raw materials
 Reference and competitor compounds
 Drug standards, metabolites and impurities
 Immunogens/antigens, bio-reagents
 Radiolabeling method development
IND-Enabling Preclinical Services
Chemistry &
Drug Discovery
Preclinical
Development
Clinical
Development
 Process development research & LSS
 Analytical method development and stability studies
 Regulatory and documentation
Process Development & LSS
 Route scouting to Route finalization
 Reaction condition / process optimization
 Efficient processes for multi-kilo scales
 Scalable and transferable
processes
 Kilo to ton scale manufacture
Analytical Services
 Develop and validate analytical methods
 Establish drug criteria for drug substances and
pharmaceutical products
 Drug stability studies:
– Freeze-thaw
– Forced degradation
– Accelerated and long-term stability
Intellectual Property Protection
Intellectual Property Protection
Highest Priority
Isolated facility to ensure IP protection
Strict documentation procedures
Professional management team focused on
IP protection
Intellectual property belongs to the client
Our Clients
 Global clients in US, Canada, Singapore, Japan, India,
Europe, India, and China
 Custom synthesis, drug discovery, analytical method,
process development, LS synthesis, pre-clinic CMC etc
 Services include
 Focused libraries, hit design and synthesis, lead optimization for SAR
 Synthesis of nucleosides, phosphoramidites, triphosphates, heterocyclic
and macrocyclic derivatives, drug standards, metabolites, impurities, etc
 Conjugation, asymmetric compounds, formulation products, organic
materials, dyes, bio-reagents, etc
 Pre-clinical development, methods and pharmaceutical
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Example 1 - Asymmetric Synthesis Project
Challenges:
 Intermediate was not stable for purification
 Hard to control minor racemization
Solutions and Results:
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Optimized and developed the whole synthetic route and process
Overcame possible racemization and decomposition problems
Scaled up to >30 g with general column purification (no HPLC)
High quality (>98%) w/ high chiral purity (ee: >90%) products satisfied
client’s need
Working strategy:
 Planed together with client to maximize the efficiency
 Bi-weekly tele-conference to update
 Client’s project leader controlled and guided the project to fit
client’s overall objectives
Example 2 - Drug Discovery Project
 Participated in the project plan from very early stage
 Designed potential hit/lead structures to be selected
 Designed routes and worked out synthesis
 Bi-weekly report and adjust direction as needed
 Submitted high quality samples for biological tests
and write-up document
 Secure confidentiality and client owns the IP
 Luckily, a great lead was discovered
Example 3 – IND Enabling Drug Development
 Require: pre-clinical CMC and pharmaceutical for IND
 Explored possible routes and finalized the best one
 Fine-tuned reaction conditions and processes (batches)
 Allow cost reduction of 80% for production
 3 kg high quality product met drug requirements and
used for clinical studies
 Developed anal method, established drug criteria, QC
 Provided all documents to support IND application
Example 4 –New Amidites and NTPs
 Required: new modification on nucleosides
 Designed and planned together with client
 Worked out the new chemistry for modifications,
fine-tune the protocols for amidites and NTPs
 Bi-weekly report and adjust focus as needed
 Submitted high quality final new amidites and NTPs,
and write-up document
 Secure confidentiality and client owns the IP
Here is what one of our clients said:
Haoyun,
Very impressive! No one can beat you on this area.
Please send me the invoice for this PO.
Best Regards,
John
Operation & Facilities
 Headquartered in San Diego, CA (Sign CDA in US)
 Operation in Zhengzhou, China
The transportation and business central garden city
Hydrogenator, high-pressure reactors, shakers, large
evaporator, and 100 L reactors for large scale synthesis
 Anal/semi-preparative HPLCs, lyophilizer, LC-MS, NMR,
HRMS, FT-IR, UV-Vis, DSC/TG, X-ray, polarimeter,
stability test chambers, etc
Corners of Granlen
The quality of our equipment is nothing
when compared to the quality of our people!
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One View in Zhengzhou
Summary
Highly experienced management
Unique specialties and highly skilled teams
Quality > Reliability > Costs
No challenge to great or small (Serve/Help)
Timely communication for high efficiency
Continuously improving infrastructure
We deliver regardless what it takes
We Work Harder!
The Reliable Leading Nucleoside Pioneer!
[email protected]
Skype: haoyun.an
QQ: 1015260133
1-760-846-6460 (US)
011-86-158-38132863 (China)
011-86-371-86026726 (China)