Provided Medchem and Process Chemistry Summary of FDA approved drugs in 2022

1. Rubik’s
Chemistry
2022 FDA Approved Small
Molecule Drugs
Medchem And Process
Chemistry
Part I
Rubik’s Chemistry
Email: wypman86@gmail.com (Paypal)

2. 2
Checklist
1 Quviviq daridorexant insomnia
2 Cibinqo abrocitinib refractory, moderate-to-severe atopic dermatitis
3 Pyrukynd mitapivat hemolytic anemia

3. Daridorexant (Quviviq)
Structure Basic Facts PK/PD (human)
Target
orexin receptor
(OX1R, OX2R)
Dosage 25 or 50 mg
Cmax
Approved Date Jan 7, 2022 AUC0-24h
Approved Use insomnia Tmax 1.3 h (food)
Company Actelion, Idorsia, J&J Vd
References Physical Properties fbound 99.7%
1. WO2015083094
2. WO2015083070
3. WO2015083071
4. WO2013182972
MW 450.93 F (%) 62
pKa 6.5 T1/2 8 h
logP (calc) 3.04 CL
logD7.4 (calc) 3.04 Metabolism CYP3A4 (89%)
HBD 1 Excretion feces, urine
O
N N
N
O
N
N
H
N
Cl
Molecular Weight: 450.93

4. Drug Quviviq Ingredient daridorexant Use Treat insomnia Company Idorsia (J&J)
4
June 13, 2022 WO2013182972 A1
A
B
C
SAR Statistics
compound # 999
MW range 386-615
TPSA range 38.1-130
AlogP 0.22-8.7
pKa 9.3-14.0
h_logD 2.69-8.1
Similarity Map Analysis (UNITY fingerprint, % Tanimoto similarities)
Show 3 major structure clusters (A, B, C) The drug is in the cluster A.
O
N N
N
N
N
H
N
(R
5
)n O X
N
N
H
N
(R
5
)n O
N
N
H
N
S
N
A B C
Representative structure in each cluster
Three diffrent cores N
Me
R
N
R
Me
N
R
O
Ar1
O
Ar1
O
Ar1
O
N N
N
O
N
N
H
N
Cl
Daridorexant

5. Drug Quviviq Ingredient daridorexant Use Treat insomnia Company Idorsia (J&J)
5
June 13, 2022 WO2013182972 A1
O
N N
N
O
N
N
H
N
Cl
O
N N
N
O
N
N
N
Cl
Me
O
N N
N
O
N
N
N
Cl
Me O
N N
N
O
N
N
H
N
Cl
O
O
N N
N
O
N
N
H
N
Cl
F
O
N N
N
OCF3
N
N
H
N
Cl
O
N N
N
O
N
N
H
N
O
O
O
N N
N
O
N
N
H
N
F3CO
O
N N
N
O
N
N
H
N
Me
Me
O
N N
N
O
N
N
H
N
Me
O
N N
N
O
N
N
H
N
Cl
Substituents
screening
Substituents
screening
Substituents
and stereo
pyrrolidine
screening
S
N
O
Substituents
screening
5,6-aromatic
rings
screening
∗
∗
6V9S
N
O
N
N
N
N
N
O
Cl
OX1R selective molecule
PNAS 2020, 117, 18059-18067

6. Drug Quviviq Ingredient daridorexant Use Treat insomnia Company Idorsia (J&J)
6
WO2015083094; WO2015083070; WO2015083071
O
N N
N
O
N
N
H
N
Cl
O
N
N
N
O
OH
HATU
DIPEA
Column
O
I
O
HO
N NH
N
Cs2CO3
CuI
Citric acid
Extraction
O
N
N
N
O
OH
N
H
OH
O
N
OH
O
Boc N
N
H
O
Boc
H2N Cl
N
Boc
N
H
N Cl
N
H N
H
N Cl
MeCN/H2O
TEA
Acidification
Boc2O HATU
DIPEA
DCM
Crude
AcOH
100 °C
Crude
HCl
dioxane
Et2O
filtration
xHCl
N
H
OH
O
O
N
N
N
O
N
N
H
O
O O
O
O
N
N
N
O
N
OH
O
O
N
N
N
O
N
N
H
O
NH2
Cl
O
N N
N
O
N
N
H
N
Cl
Conc. H2SO4
1M NaOH
Extraction
amide
coupling
ester
hydrolysis
amide
coupling
ring -
closing
MeOH
Route 1
Route 2
Preparation of seed, Used for
5 g batch of crystal formation
O
N N
N
O
N
N
H
N
Cl
Amorphous
0.1 M HCl (0.2 mL)
EtOH (0.8 mL)
Evaporation
iPrOH (0.05 mL)
or MIBK (0.05 mL)
room temp.
4 days
O
N N
N
O
N
N
H
N
Cl
HCl
Crystal
Making HCl Crystal

7. Abrocitinib (Cibinqo)
Structure Basic Facts PK/PD (rats)
Target JAK1 inhibitor Dosage 1mg/kg (IV). 3 mg/kg (po)
Cmax, u
Approved Date Jan 14, 2022 AUC0-24h
Use
refractory, moderate-to-
severe atopic dermatitis
Tmax
Company Pfizer Vd 1.04 L/kg
References Physical Properties fbound
1. WO2020261041; 2. WO2020008391;3. OPRD
2021, 25, 3, 608–615; 4. J. Med. Chem. 2018, 61,
3, 1130–1152; 5. CA2899888; 6. WO2014128591
7. IN201921025659; 8. WO2020088659
MW 323.42 F (%) 95.6
pKa T1/2 1.1 h
logP (calc) CL
<9 (HLM)
26.6 mL/min/Kg (H)
logD7.4 (calc) Metabolism
CYP2C19
CYP2C9
HBD Excretion in urine as M1 & M2
N
N
H
N
N
N
H
S
O
O
Molecular Weight: 323.42
July 9, 2022

8. Drug Cibinqo Ingredient abrocitinib Use atopic dermatitis Company Pfizer
8
CA2899888
SAR Statistics
compound # 274
MW range 322.4-458.9
TPSA range 75-137
slogP 0.21-5.2
pKa 10.1-14.0
h_logD -1.4-7.1
Similarity Map Analysis (UNITY fingerprint, % Tanimoto similarities)
3 major scattered clusters, with two outlier.
A B
C
N
Me
S
O
O
N
N
H
N
R
A (Aromatic) B (Alkyl) C (Sulfonamide)
N
Me
S
O
O
N
N
H
N
Alkyl
N
Me
Y
S
O
O
N
N
H
N
X
R
X = N, Y = C
X = C, Y = N
N
N
H
N
N
N
H
S
O
O
abrocitinib
July 9, 2022

9. Drug Cibinqo Ingredient abrocitinib Use atopic dermatitis Company Pfizer
9
July 9, 2022 CA2899888; J. Med. Chem. 2018, 61, 3, 1130–1152
N
N
H
N
N
N
H
S
O
O
abrocitinib
N
N
H
N
N
N
H
S
O
O
N
N
H
N
N
C
H2
S
O
O
N
N
H
N
N
N
H
S
O
O
N
N
H
N
N
N
H
S
O
O
N
N
H
N
N
N
H
S
O
O
O
N
N
H
N
N
N
H
S
2
H
C
O
O
The pyrrolo
pyrimidine
consistent
cis,trans
stereo impact
varying
between
CH2 and NH
varying
between
CH2 and NH
Screening
Alkyl, aryl and
amine groups
N
N N
H
N
H
N
S
O
O
N
N N
H
N
N
O
N
tofacitinib (JAK1/3, JAK2)
(rheumatoid arthritis)
JAK1 IC50: 0.015 uM
JAK2/JAK1 = 5
Clint < 8 uL/min/mg
JAK1 IC50: 0.006 uM
JAK2/JAK1 = 69
Clint < 58 uL/min/mg
increae potency
and selectivity
piperdine ring
replacement
Improve
Clint
Lower LogD
replace phenyl
with alkyl group
N
N N
H
N
X
S
Y
O
O
R
X = N, Y = N: Sulfamide
(lower potency, selectivity)
X = CH2, Y = CH2: Sulfone
(high potency, lower selectivity)
X = C, Y = N: reverse sulfonamide
(high potency, varied selectivity)
N
N N
H
N
H
N
S
O
O
Me
balanced between
potency, selectivity
and clearance
N
N N
H
N
N
N
NC S
O
O
N
N N
H
N
N
CN
baricitinb (JAK1/2)
(rheumatoid arthritis)
Eli Lilly/Incyte
ruxolitinib (JAK1/2)
(primary myelofibrosis)
Incyte
N
N N
H
N
N
O
N
tofacitinib (JAK1/3, JAK2)
(rheumatoid arthritis)
Pfizer
N
N N
H
N
N
NH
O
CF3
upadacitinib (JAK1)
(rheumatoid/psoriatic arthritis)
AbbVie
PDB: 6BBU

10. Drug Cibinqo Ingredient abrocitinib Use atopic dermatitis Company Pfizer
10
OPRD 2021, 25, 3, 608–615
N
N N
H
N
H
N
S
O
O
N
N N
H
Cl N
H
H
N
Me
R
N
H
Me
O
R
Route A
Route B
R = SO2Pr
R = OR, NH2
+
O
OH
O
O
N3
O
O
N
O
H
N
DPPA
Et3N;
BnOH
50 °C
50-62%
C
O
N2
BnOH
OBn
O
Higher convergence
Required fully functionalized
diaminocyclobutane
Low yield, batch size limitation
Better physical properties
(Solubility, crystallinity)
Required a post fragment union
amination
Acyl azide buildup prior to heating
Add DPPA to a preheated solution of acid
> 50 °C
O
H2N OBn
O
+
degenerative
O
H
N NHCbz
O
O
H
N OBn
O
< 60 kg scale > 600 kg supplied
N
H
H
N OBn
O
MeNH2, LiBH4
AcOH, EtOH;
HCl
44-51%
HCl
H2N
NHCbz
HCl
N
N N
Cl
N
N N
N
Me
NHCbz
DIPEA
+
N
N N
N
Me
NH2
2HBr
IPA
92-95%
HBr
EtOAc
76-81%
N
N N
H
N
Me
H
N
S
O
O
S
O
O
Cl
MeTHF, NEt3
then NaOH
75-76%
Ts
Ts Ts
> 100 kg
7/9/2022

11. Drug Cibinqo Ingredient abrocitinib Use atopic dermatitis Company Pfizer
11
July 9, 2022 OPRD 2021, 25, 3, 608–615
N
N N
N
Me
Ts
NH2
O
1) PhI(OAc)2
2) AcOH/HBr
(58%)
N
N N
N
Me
NH2
2HBr
Ts
PG is critical
Hofmann Rearrangment
N
N N
H
N
Me
N
H
O
CDI, MeTHF
then H3PO4(aq)
(81%)
N
N N
H
N
Me
NH2
H3PO4
Lossen Rearrangment
OH
Required PG
Reaction conditions need
to be tuned judiciously
preinstalled oxidation state
O
O
O
Me
Me
O
O
N
H
Me
Me
Me
SpRedAm
MeNH3Cl
Succinic acid
(74%, > 99:1 dr)
biocatalytic reductive amination
HOOC
COOH
N
N N
H
N
Me
O
O
Me
Me
N
N N
H
Cl
IPA
DIPEA
(81%)
N
N N
H
N
Me
N
H
O
OH
HONH3Cl
NaOMe/MeOH
(94%)
CDI, MeTHF
Then H3PO4
(81%) N N
N
N
Me
2HN
P OH
O
O
OH
H
H
N
N N
H
N
Me
H
N
S
O
O
N
S
O O
Me
N
N
THF,
H
2O,
NaOH
(84%)
Ts protected pyrrolopyrimidine
is not compatible with next step
Ideal for large scale reaction
Poor solubility in organic solvent
but good in acidic/base aq solution
Core is reactive
Reaction heterogeneity
Crystallized after
adding water
N
S
O O
Me
N
N
N
S
O O
Me
N
N
S
O O
Me
N
N
S
O O
Me
N
Me
OTf
N
S
O O
Me
N
Cl
S
O
Me
O
F
S
O O
Me
Sulfonyl transfer reagents
O P O
O
N3
DPPA
Azide reagents
S N3
O
O
TsN3
Si N3
Me
Me
Me
TMSN3
F3C S N3
O
O
TfN3
N3 S N3
O
O
N S N3
O
O
HN
HSO4
S N3
O
O
F
F
F
F
F
F
F
F
F
NfN3

12. Mitapivat(Pyrukynd)
Structure Basic Facts PK/PD (human)
Target
pyruvate kinase M2
PKM2
Dosage 20 mg/ 2 daily
Use hemolytic anemia Cmax 389.9 ng/mL
Approved Date Feb 17, 2022 AUC0-24h 1623.8 ng*h/mL
Company Agios F (%) 73%
T1/2 3-5
References Physical Properties CL/F 12.7 L/h
1. CA2944788_US20100331307
2. WO2019104134 A1
3. WO2019104134 A1
4. FDA Mitapivat (Pyrukynd)
MW 450.56 Tmax 0.5-1 h
pKa 7.9 Vd 42.5 L
logP (calc) 3.2 fbound 97.7%
logD7.4 (calc) 2.8 Metabolism CYP3A4
HBD 1 Excretion
urine(49.6%)
feces (39.6%)
N
S O
HN
O
N
O
N
Molecular Weight: 450.56

13. Drug Pyrukynd Ingredient Mitapivat Use hemolytic anemia Company Agios
13
SAR Statistics
compound # Ca. 650 analogues
MW range 400-697
TPSA range 78-171
h_logP (MOE) 1.9-7.2
h_pKa (MOE) 4.3-14.0
h_logD (MOE) 1.4-7.5
Similarity Map Analysis (UNITY fingerprint, 95% Tanimoto similarities)
The compound library has very high similarity. At 95% Tanimoto similarities, it
can be divided in 3 clusters. The drug in the Cluster C topside.
July 9, 2022
A
B
C
N
S O
HN
O
N
O
N
R
B
MeO
N
S O
HN
O
N
O
N
R
C
(H)Me
1-2
R'
S O
HN
O
N
O
N
R
A

14. Drug Pyrukynd Ingredient Mitapivat Use hemolytic anemia Company Agios
14
July 9, 2022
N
S O
HN
O
N
O
N
mitapivat N
S O
HN
O
N
O
N
N
S O
HN
O
N
O
N
Me
N
S O
HN
O
N
O
N
F
N
S O
HN
O
N
O
N
O
N
S O
HN
O
N
O
N
O
O
N
S O
HN
O
N
O
N
N
S O
HN
O
N
O
N
N
S O
HN
O
N
O
N
N
S O
HN
O
N
O
N O
R1
S O
HN
O
R3
O
scaffold
R2
N
S O
HN
O
N
O
N
mitapivat
Major substitute
H
R2 = H, Me, F, Cl, OH, OMe, CF
3
N
N
∗
∗
diazapane
cyclic ring
substituted aromatic
carbamate
X
Y
∗
0-1
5X1V

15. Drug Pyrukynd Ingredient Mitapivat Use hemolytic anemia Company Agios
15
July 9, 2022
N
S O
HN
O
N
O
N
N
S O
O
Cl
N
S O
HN
O
OH
O
HN
N
•2HCl
CDI, DMA;
then
90%
HN
N
•2HCl
N
NH
Boc
O
1) NaBH(OAc)3
toluene/IPA
2) HCl/H2O
acetone
92%
+
N
S O
HN
O
OEt
O
NaOH
THF/H2O
then HCl
91%
H2N
OEt
O pyridine
CH3CN
99%
+
N
S O
HN
O
N
O
N
N
S O
HN
O
N
O
NH
O
Acetic acid, DCM
NaBH(OAc)
3
49%
N
S O
HN
O
N
O
N
Boc
HCl, MeOH
then
NaHCO3
95%
N
S O
HN
O
OH
O
HN N Boc
HOBt, EDC
DMF
82%
Process Route
Medchem Route